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MEGAVITAMIN THERAPY THE AMERICAN PSYCHIATRIC ASSOCIATION TASK FORCE REPORT ON MEGAVITAMIN AND ORTHOMOLECULAR THERAPY IN PSYCHIATRY Canadian Schizophrenia Foundation August 1976
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MEGAVITAMIN THERAPY

THE AMERICAN PSYCHIATRIC ASSOCIATIONTASK FORCE REPORT ON MEGAVITAMIN ANDORTHOMOLECULAR THERAPY IN PSYCHIATRY

Canadian Schizophrenia Foundation August 1976

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MEGAVITAMIN THERAPY

This is the second report published by the Canadian Schizophrenia Foundation to givewider dissemination to its members and to members of similar organizations in theU S A of corrections to the findings of the American Psychiatric Association Task ForceReport #7, Megavitamin and Orthomolecular Therapy in Psychiatry

The findings, opinions, and conclusions of these reports do not necessarily representthe views of the officers, members of the board, or all members of the Foundation Eachreport does represent the thoughtful judgment and consensus of Dr A Hoffer and DrH Osmond who prepared it, and it is considered a useful and substantive contributionto the ongoing analysis and evaluation of problems, programs, issues, and practices in agiven area of concern: orthomolecular psychiatry

A. Hoffer, M13., Ph.D,, F.A,O.P., F,R.S.C.(C)President Canadian Schizophrenia Foundation

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MEGAVITAMIN THERAPY

In Reply to the American Psychiatric Association Task Force Report onMegavitamins and Orthomolecular Psychiatry

A Hoffer, PhD ,MD, F AO P ,R C P(C)

H Osmond,MB,MRCP,FRCPsych

Canadian Schizophrenia Foundation2135 Albert StreetRegina, SaskatchewanS4P 2V1

ACKNOWLEDGEMENT

The authors gratefully acknowledge the assistance of the Academy of OrthomolecularPsychiatry which made publication of this book possible with a grant of $2,000

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An Examination o

Summary

Addendum

Section I - Brief Abstract of Orthomolecular Treatment bySaskatchewan Group

- Brief Abstract of Corroborative Reports

- Pauling Paper

Letters to the Editor

- Comments on B. J. Wyatt's Comment (1974) onL. Pauling's Report

- Comments on the Double-Blind (Placebo) Methodology

Efficacy and Toxicity

Letters

References

Reading List in Orthomolecular Psychiatry

- REAL Attempts to Corroborate with Failure to Confirm toOriginal Studies

Copyright 1976 by Dr. A. Hoffer and Dr. H. Osmond. Published by the Canadian Schizophrenia Foundation.2135 Albert Street. Regina, Saskatchewan S4P 2V1. No part of this book may be reproduced by any mechanical,photographic. or electronic process or in the form of a phonographic recording, nor may it be stored in aretrieval system transmitted. or otherwise copied for public or private use without written permission of theauthors

Section II

Section III

Section IV

Section V

Section VI

Section VII

Section VIII

Section IX

Section X

Section XI

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We decided to answer the AmericanPsychiatric Association Task ForceReport on Megavitamins and Ortho-molecular Psychiatry with some reluc-tance since this kind of controversy istedious and not really productive—thereare many other things to do connectedwith the well-being of schizophrenicpatients which should have higherpriority than answering the criticisms of acommittee none of whose membersappear to have had direct clinical chargeof a single schizophrenic patient treatedby orthomolecular psychiatric therapy

However, colleagues have pointed outto us that we had a special responsibilityfor replying to these critics, and if wefailed to do so it would be assumed thatour default indicated that we acceptedsome or perhaps most of their criticismsOur reluctance as we shall note later onhas been much more on account of themultitude of errors than upon the highquality of the criticisms There is much tobe gained from the observations andeven strictures of an intelligent, faircritic. We are not so conceited or soprovincial as to deny that, especiallywith the benefit of hindsight, experi-ments might have been done differentlyand papers discussing and describing our

studies might have been differentlywritten However, having completed ourcritical study of our critics we feel that ithas been worth the effort and hope thatour readers will agree

As far as the Task Force members areconcerned we would remind them ofBernard Shaw's aphorisms: "If you wouldinjure your neighbor—better not do it byhalves "

Since the report was clearly intendedto injure us it was doubly botchedbecause, according to the AmericanPsychiatric Association, it was supposed-ly a fair inquiry and as such it was afailure from the start The moment thatwe doubted the impartiality of thechairman and committee members(presumably selected by him) it ceased tobe an unbiased inquiry The APA's dutywas to ask us whom we would considerto be unbiased among their 25,000members or so, or how undue bias, oneway or another, could be assured againstTheir arbitrary assumption that theyknew best is far more serious than theerrors of Lipton, Mosher, Ban, et al

That four-fifths of the committee camefrom two institutions and that the othermember was a rival experimenter in-dicated ineptitude and insensitivity.

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an examination ofthe american psychiatric association

task force report"megavitamins and orthomolecular

therapy in psychiatry"american psychiatric association, 1973

The Task ForceThis report begins by stating that "we

shall examine carefully and critically theclaims, the supporting evidence, thetheoretical basis and the contraryevidence in detail." It is wholly properfor a professional association to study anew treatment in this way The reportends with these words, "this review andcritique has carefully examined theliterature produced by megavitamin pro-ponents and by those who have attempt-ed to replicate their basic and clinicalwork " It concludes that in this regard"the credibility of the megavitaminproponents is low " The value that oneattaches to the Task Force conclusionsdepends largely upon the intelligence,zeal, honesty, and detachment withwhich its members approached theobjective which they had set for them-selves In this paper, we shall examinethe composition of the Task Force, thenature of its report, and the manner inwhich it set out to examine megavitaminand orthomolecular therapy in psy-chiatry,

To attain their stated objectives, a lackof bias and prejudice was essential Itmay surprise those who believe that theAmerican Psychiatric Association wouldnever allow its name to be attached to adocument which did not meet thesecriteria to learn that three years beforethis report was published the chairman ofthat Task Force was conducting himselfin a manner which did not suggestimpartiality Indeed, his behavior in-dicated to many who heard him speakthat he had already made up his mindand was not inclined to change it

At a public meeting in Californiaarranged by Mr Joe Desilva of Local 770in Los Angeles, Dr. Morris Lipton read apaper on the theoretical aspects ofmegavitamin therapy and touched brieflyon treatment At this time none of theBan-Lehmann studies had been reportedand Wittenborn's work was still inprogress Nevertheless, Dr Lipton's con-clusions, which he expressed then,closely resembled what was publishedlater by the committee of which he waschairman

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We are not the first to have questionedthe propriety of using this report as asource of information Linus Pauling,1974, wrote: "The APA Task ForceRepoft, 'Megavitamin and Ortho-molecular Therapy in Psychiatry,' dis-cusses vitamins in a very limited way(niacin only) and deals with only one oftwo aspects of the theory Its argumentsare in part faulty and its conclusions areunjustified " j Hoffer, 1974, following along and detailed examination, com-mented: "It is a mistake to use it as areference source in evaluating mega-vitamin therapy because it is a mine ofmisinformation " These remarks maydisappoint those who had supposed thatthe APA would provide a useful andreliable document, but they are lessunexpected when one studies both thecomposition of the committee and itsmodus operandi

When a committee is formed to reporton a controversial issue, one assumesthat the matter is important enough towarrant a careful, scholarly, anddetached examination. The APACouncil on Research and Developmentwas correct in appointing a Task Force toexamine megavitamin therapy for thiswas a matter of interest, concern, anddiscussion among both psychiatrists andthe public However, the Council erredgravely in failing to instruct the sub-committee, chaired by Dr M Lipton,that not only must the committee be fairand objective, but they must also appearto be so *

A committee can appear to be faireven when they are not truly so by usingtwo procedures either alone or together.

First: It may include among itsmembers those who have had directpersonal experience with the new treat-ment These knowledgeable members ofthe committee can examine the data,question witnesses in an intelligent

Lord Devlin. a former British Law Lord (roughly theequivalent of a Supreme Court Justice in the U.S.A.),was quoted in the London Times, June 26, 1975, assaying in his Charley Lecture that "a judge's mosti mportant qualities were impartiality and second. theappearance of impartiality

manner, and, finally, explain, reason,and argue with other members of thecommittee. It is with this in mind that indemocracies government committeesalways include members of the majorpolitical parties One-party committees,however admirable their members maybe, are always suspect If a minority ofmembers believe that a report is in-correct or unfair they can then register anofficial dissenting view which is pub-lished with the majority opinion Thepresence of members experienced withthe treatment under review means thatthose appearing before the committeeknow that they will be questioned by anyone - of its members This deters peoplefrom presenting mere hearsay evidenceor opinions which cannot be backed withpersonal experience

Second: Proponents of opposing viewsmay be allowed to cross-examine eachother. This is a procedure which waseventually done in the prolonged andcontroversial F D A vitamin hearingsheld in Washington recently Dr MilesRobinson, M D , asked to be allowed tocross-examine some of the witnessesappearing before the hearing examinerThis right was at first denied him, but DrRobinson took the matter to court Theexaminer was then rebuked and orderedto re-open the hearings to allow thecross-examination. The United StatesCourt believed that a public inquiryshould make every effort to determinethe truth and decided that cross-examination, which had been deniedearlier, would further this process Eitherof these approaches alone increases thechances of objectivity, but to have evenan appearance of fairness and so warrantpublic and professional confidence, bothshould have been employed.

In fact, neither was used Consequent-ly the committee appears to have beenbiased, and as we shall show, thisappearance is not misleading No pro-vision was made to ask any physicianexperienced in the use of megavitamintherapy to appear before it, even thoughthere were plenty available and willing todo so Yet it has been reported thatsessions were held in which members Of

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the committee consulted other psy-chiatrists and sought their views, eventhough they had never published anydata on megavitamin treatment

An official or legal body whichconducted its affairs in such a mannerwould be promptly discredited TheAPA's posture is the more questionablesince it has always been very strong forconstitutional and personal freedom andfrequently advocates the humane andsensitive conduct of governmental andsocial affairs Perhaps the APA hasforgotten that charity begins at home

Dr. Morris Upton, The ChairmanIn all committees the choice of

chairman is important and indeedcrucial As we have noticed Dr Liptonmade an unfavorable impression on theorthomolecular psychiatrists and otherswhom he addressed in California. He toldthe California audience that he had neverused megavitamin therapy and did nottreat schizophrenics Nevertheless, onthe strength of having received his Ph D.at the same university where Elvehjemand Woolley discovered that nicotinicacid was the antipellagra vitamin, helaunched into a poorly informed attackon the megavitamin treatment and itstheoretical underpinning. Since heseemed to be so antagonistic, dogmati-cally self-assured and, in addition,ignorant about the matter in which hewas going to inquire, one of us (AH)requested the APA to remove him fromthe Task Force on vitamin therapy inpsychiatry This request was rejected onthe grounds that the APA Council onResearch and Development would insurethe objectivity of its subcommittee andmonitor its reports

Recently Leff (1975) confirmed ourconclusion that Dr Lipton was the mainauthor of the report when he stated," 'I'dwarn people of megadoses for mega-periods' says Dr. Lipton, who wrote theAPA Task Force Report." Lipton has,since 1970, been the chief crusaderagainst orthomolecular psychiatry.

Since this was the APA's officialposition, it must bear full responsibilityfor the errors and misrepresentations of

its Task Force There can be no questionthat the Association's highest officersknew that there were cogent objectionsto the subcommittee chairman whomthey had appointed They made noattempt to remedy this in the meantime,long before the Task Force had made itsfinal report, Dr Lipton was circulating apreview of it, a copy of which came intoour possession

It is a poor augury when the chairmanof an important Task Force appears to beprejudiced, but it is worse still if severalother committee members should also besuspect

Dr. Thomas BanIt is our contention that for a number

of reasons Dr Ban was prejudicedagainst the megavitamins from the startand that both the content and tone of hispublication and his public statementsreflect this prejudice. In 1966 Dr. Banwas offered a comparatively small grantof money by the Canadian Mental HealthAssociation to settle the matter of"Hoffer's megavitamin claims once andfor all " There is no reason to supposethat the Canadian Mental Health Assoc-iation directorship was particularly keenfor any positive affirmation of this workIt happened that one of us (AH) was amember of the CMHA AdvisoryCommittee and was present when Dr.Ban produced his final research protocol.At this meeting he outlined a simpleexperiment comparing nicotinic acid andtranquilizers against tranquilizers only. Itwas pointed out to him that he had notincluded provisions for ECT in Phase IIpatients He gave assurances that thiswould be done later on as his studiesdeveloped Another committee membermade the same point, but was remindedof Dr Ban's pledge Dr: Ban also statedthat no reports would be released untilthe entire study was completed Neitherof these pledges was kept

Since Dr Ban is a member of thecommittee responsible for the TaskForce's report stating "the credibility ofthe megavitamin proponents is low," hisown credibility is open to similarquestioning. He is well known for his

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tranquilizer studies and has publishedmany of them Some years ago heinformed one of us (AH) that much of hisincome derived from grants fromcompanies and other sources interestedin selling tranquilizers He was thusinherently likely to be caught in aconflict of interest He may well, in allsincerity, feel himself to be whollyunbiased, but one has only to ask whatwould have happened to many of hisgrants had he found niacin to be moreeffective than tranquilizers He wouldhave faced a painful dilemma It wasunfair to expect him to view thepersistence of megavitamin claims withanything but concern and suspicion DrBan's eagerness to disseminate his find-ings long before his final report appearedwas shown by his lecturing professionalgroups and attacking orthomolecularpsychiatry He cannot be considered adisinterested party to the dispute andquite apart from the effect this may havehad on his researches, the propriety ofhis being a member of the Task Force isquestionable In any official inquiry hewould have been obliged to declare hisposition

Psychiatrists who are supposedlyexperts on subconscious motivationapparently do not interest themselves inthe conscious motivation of those theywould have evaluate a new treatmentAccording to Lionel Penrose, who hasstudied these matters, two members of acommittee of five are quite sufficient tobias it in their direction should theychoose to collude With Doctors Liptonand Ban on the committee, the oddsagainst a fair and detached report weresmall; however, there was a thirdmember, Dr. Loren E Mosher.

Dr. Loren E. MotherDr Mosher was the head of the Center

for Studies of Schizophrenia of NIMHThis choice was a curious one since hehas frequently stated that it is hispersonal belief that schizophrenia is nota clinical entity and it is not a disease or aseries of diseases: He is a disciple of theScotsman, Dr R D Laing, and prefers toview schizophrenia as a way of life

(Siegler and Osmond, 1974) At ameeting in Washington arranged byNIMH (1973) in response to pressurefrom the American Schizophrenia Assoc-iation, Dr Mosher stated forcibly that ifevery psychiatrist in the U S A believedthat megavitamin therapy helpedschizophrenic patients, he would notbelieve it. He was being consistent For ifhe considers that schizophrenia is not anillness, it follows then that no chemo-therapy, particularly nutrient therapy,can possibly work While Dr Mosher'sforthrightness may be admirable, he canhardly be considered unbiased for he hasmade his biases perfectly clear Onemight, of course, wonder how the NIMHbureaucracy could possibly justify hisappointment to the schizophreniasection. It would be just as appropriatefor a well-known Christian Scientist tohead up a cancer program

Since the APA Task Force was pub-lished Dr Mosher presented a report onSoteria House, a special home forschizophrenic patients for the provisionof Laingian-type milieu therapy In thisreport he shows an interesting differencein attitude toward research data arisingfrom his own research and toward all thedata originating from orthomolecularpsychiatry Toward his own data hedisplays a friendly cheerful optimismconcluding that Soteria milieu showsgreat promise, even though at the end ofthe study period there is not even oneindex of improvement in which his groupwas better than the control group TheSoteria group required 167 days inresidence compared to 21 days' residencein a psychiatric ward by the controlgroup, a difference of 800 percent. ThisMosher truthfully describes as beingsignificantly larger There was no dif-ference in global psychopathology afterone year between the two groups But inspite of the fact that in every index ofchange there was no difference Mosherconcludes there is a trend favoring theirapproach The difference, so slight itdoes not appear in any of the tests, ismaximized in his sanguine report.

In striking contrast Mosher as amember of the Task Force adopts an

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entirely different stance. Here he findsno amount of data, no matter how greatthe difference, is persuasive. Here heminimizes the difference Had Mosherremained a pure critic as he was as a TaskForce member his position would haveremained less assailable, but havingexposed himself to public scrutiny bypublishing a report he has shown hisundoubted bias against orthomoleculartherapy and toward milieu therapy Thisis consistent with his remark several yearsago that he would not accept mega-vitamin therapy as valid even if everypsychiatrist in the U S A did

In April 1971 AH wrote to Chairman M.A Lipton requesting that he disqualifyhimself as chairman because of his un-doubted bias. He did not reply. June 81971 AH wrote to President R S. Garber,American Psychiatric Association,repeating this request These letters arereproduced in the appendix Since thenthe public activity of at least threecommittee members, Ban, Lipton, andMosher, have confirmed our suspicionsthat no prudent person or organizationwould have chosen them as unbiasedinvestigators in an important publicissue.

Dr R Wittenborn, Ph D., was aconsultant of the committee and pro-bably one of its least biased sources. It isnot certain, however, that NIMH was ofthis opinion when he was given fivehundred thousand dollars to conduct hisstudy Several years earlier, we were toldby a well-known U.S. psychiatrist fromthe midwest that he' had been ap-proached by the NIMH to direct thissame study He agreed on condition thatone of us (AH) was retained as a workingconsultant for the duration of the studyHe was promptly dropped from furtherconsideration Apparently Dr Witten-born did not make this demand; as apsychologist he may have been lessaware of the high feelings generatedamong psychiatrists by megavitamintreatment. However, he was not amember of the committee and so cannotbe held responsible for its conclusions.Of the five committee members, then,three by their own words and deeds seem

to us to have been grossly biased againstthe treatment they were supposedlyinvestigating with complete impartiality.In Lionel Penrose's view, which we havealready noted, this would make it almostcertain for the final outcome to reflectthe views of the majority.

The committee represented two in-stitutions: (a) the National Institute ofMental Health which since 1967 has beenas antagonistic toward the megavitaminapproach as it was against tranquilizersin 1955—it had two representatives, DrJ. Levine and Dr L R Mosher; (b) theNorth Carolina Department of Psychia-try, College of Medicine, with Dr M A.Lipton, Chairman of the Department andof this committee, and Dr F J. Kane,one of his professors Dr Kane was co-author with Dr Lipton of the privatelycirculated attack on orthomolecularpsychiatry in 1970 before the committeecompleted its studies or published itsreport in 1973 It is unlikely Dr Kanecould have differed significantly from hischief even had he wanted to do so.

The appearance of bias is so powerfulthat even if there had been none thecommittee was incapable of submittingn objective and fair reportRecently Emanuel (1975) wrote;

"Teachers and students alike deludethemselves as to the worth of what istransmitted but because the teachersoften play a role in the subsequent careerof students and become prestigiouscenters attracting the most able, thesedelusions become self-fulfilling pro-phecies In no branch of medicine isthere less to transmit than in my specialty—psychiatry—by supervision, correct-ness of approach and doctrinal conform-ity to an extent sometimes more appro-priate to a theological seminary Pro-bably the best training for any psy-chiatrist and perhaps internist too wouldbe a year or more in general practicewhere exposure to a wide range of humansuffering and human responses to itwould teach a sense of proportion."

Emanuel 's strictures against professorsmay just as aptly be applied against thiscommittee It is not our opinion alonethat committees can inhibit progress inmedicine Lasagna (1967) recently wrote,

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"Indeed, it is not impossible that a seriesof inaccurate opinions from a number ofdistinguished experts would snowballinto an overwhelming endorsement orcondemnation of a drug "Jain (1975) in aserious discussion of ethics refers to theenormous power wielded by establish-ment committees He discusses therelationship of physicians to physicians,but his views are just as applicable whenone considers the relation of new to oldideas He lists four reasons why com-mittees representing old ideas resist newideas These are: (1) human nature (i e ,interpersonal hostility); (2) territorialimperative (i e , the threat of the newideas against old, widely establishedideas); (3) financial factors; (4) thegeneration gap

The resistance of well-establishedideas no matter how mistaken againstnew ones is probably the major reasonfor the committee bias Their tran-quilizer-only idea of treatment is coupledfirmly to establishment professors,directors of research and administratorsThere may be a feeling that giving up theold ideas will mean losing their place inthe hierarchy of the establishment So farnot a single professor of psychiatry hasgiven public support to orthomolecularpsychiatry even though a substantialnumber have given it private support

Jain then lists the difficulties facingnew physicians The same fate meetsnew ideas We will repeat the difficultieshe lists, except that we are referring toideas "Doctors controlling the ethicscommittees are usually from theestablishment and it is no use complain-ing to them " "Most of the maneuvers bythe doctors in the establishment are doneunder the name of the university orhospital or a committee to which thedoctor belongs The result is that on thesurface, decisions appear to be based onsound medical reasoning not on personalbias which can only be uncovered afterexhaustive legal investigations " He thenquotes Sir Clifford Allbutt, "Unfortunate-ly, the same kind of medicine is playedwith the cards under the table in theintimacies of medical counsels Who isthere to note the significant glance, the

shrug, the hardly expressed innuendo ofone or other of our brethren? Thus, wework not in the light of public opinion,but in the secrecy of the chamber '

Did the Procedures Used Provide for aFair and Objective Examination of theData?

The bureaucratically inclined some-ti mes hope that by proper procedures theeffects of personal peculiarities andshortcomings can be avoided Thesehopes are frequently disappointed. Inthis case, however, inadequate pro-cedures combined with a committeethree out of five of whose members wereclearly prejudiced against megavitaminsmade an unbiased report most unlikelyBecause there was no orthomolecularpsychiatrist on the committee and nonewas asked to attend its deliberations,nobody checked to see whether theliterature had been examined properly,summarized fairly, and presented intel-li gently The committee's actions suggestthat they relied upon the inertia of theircolleagues to avoid criticism of theirreport They appear to have assumed thattheir task was to prevent the public andthe profession from worrying itselfunduly about orthomolecular psychiatry.In other words, the end was to encouragethe reader to adopt Dr Mosher's avowedposition, which as we have already notedwas that even if every psychiatrist in theUnited States believed in megavitamins,he would still not do so The means bywhich they set out to achieve this will beexamined in detail Unluckily, there aremany errors in the Task Force Reportand we keep finding new ones, yet unlessthese errors are exposed the casual readerunacquainted with the literature caneasily be misled into supposing that aReport published with the approval ofthe American Psychiatric Associationmust be accurate and truthful

It may seem unlikely that a responsibleprofessional organization such as theAPA would give one of its sub-committees such license and pay so littleattention to the composition of thatcommittee, but at the time when these

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matters came under the APA's scrutiny,Washington was heavily infected by theWatergate atmosphere. Minority viewswere not respected; "dirty tricks" were anaccepted necessity of political life;authority, whether presidential or pro-fessional, was looked upon as limitless Itwas assumed that the big battalions hadnot only the right but also the duty totrample upon those who disagreed withthem, using any means available. Ortho-molecular psychiatry was a nuisance toboth the APA and the NIMH, and somemembers of both these establishmentsapparently believed that anything thatwould damage it would be doing a publicservice It should not strain credulity thatif the CIA or FBI can sometimes beoverzealous in the defence of what manyconceive to be the public good, lessprestigious agencies should do likewise.The Title

The Task Force was appointed to studyvitamin therapy in psychiatry as the titleof the report suggests Instead, itattempted to deal with the megadoses ofvitamin B3 only, and entitled the reporterroneously "Megavitamin and Ortho-molecular Therapy in Psychiatry "Ortho-molecular therapy was not examinedbecause the committee stated that theyknew of no way by which it could betested

The ReportWe have read the report carefully and

then compared it with the originalsources When this was done, our earlyimpression that it was biased and hostilein tone was confirmed There are manyerrors and omissions, while its scholar-ship is of such low level that it cannot betrusted In the following pages we willshow this by using a point by pointexamination of the examples of bias anderror and sometimes sheer muddlement,

Introduction(1) On Page 5 the report claims that

we "shifted" our position (The readershould have a copy of the Task ForceReport #7 before him, read the wholebooklet, then reread each page as wecontinue with our discussion ) In science

the word "shift" is usually used as apejorative term implying that theory orpractice is constantly changing so thatduplication of experiments and re-futation of theories is impossible This isnot so In our original report (Hoffer etal., 1957) we listed a number of possiblemechanisms by which vitamin B3 couldwork These were: (1) Elimination of thevitamin deficiency We did not thinkthen nor do we think now that schizo-phrenia is due to a vitamin deficiencyThe concept of a vitamin dependencyhad not been developed, but when itcame along it created the possibility thatsome schizophrenics might be vitaminB3 dependent (2) Cerebrovasculareffects (3) Mass action on cellularmetabolism (4) Placebo effect (5)

Depletion of methyl groups (6) Restora-tion of acetylcholine esterase activity. (7)

Inhibition of DPNase (now calledNADase) activity (8) Acceleration ofdestruction of a schizophrenic toxin (9)

Direct antagonism to a schizophrenictoxin We, therefore, have put forward anumber of theoretical possibilities forfurther inquiry

As we gained more experience with ourtreatment, we improved it It wouldsurely be unreasonable and unenter-prising to continue recommending anoriginal pioneering effort and to useexactly the same dosage and exactly thesame substances decade after decade. Ifthe same rule were applied to tranquiliz-ers, psychiatrists would still be using thedoses of chlorpromazine and reserpinerecommended in 1955 Treatments, ifthey are any good, grow and evolve Forsome reason the committee seemed toexpect us to stand with the original dosesof the original vitamins as they were usedin 1952, thus ignoring the entire his-torical development of the ortho-molecular treatment It must be a matterof opinion as to whether the committee'sexpectations were naive, perverse, orboth

(2) Hormones are generally not usedby orthomolecular therapists unless thereis a definite indication such as hypothy-roidism, diabetes, etc

(3) Vitamin B3 was never considered a

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competitor against tranquilizers This isone of the notions developed by thecommittee Our original double-blindexperiments began before tranquilizersbecame available. They were, therefore,not included in the design of theseexperiments and were not used for thesestudies They were used in conjunctionwith the program for other patients andare still so employed using the standardindications We have been continuallysurprised by the number of psychiatristswho advise their patients that we neveruse tranquilizers When pressure fromtheir patients is great, they have fre-quently placed them on inadequate lowcloses of vitamins and promptly dis-continued the tranquilizers This has, onoccasion, caused relapse for which thevitamins were blamed We have alwaysmade it clear that even with correctcloses the response can be slow

(4) On Page 6 they correctly refer tothe orthomolecular view that the schizo-phrenias are a group of illnesses withdifferent biochemical aberrations, but,thereafter, they ignore this basic viewand do not distinguish between acuteand chronic patients In 1957, Hoffer etal concluded, "although many chronicambulatory schizophrenic persons haveresponded to nicotinic acid therapy,similar results have not been obtainedwith chronic schizophrenic persons inmental hospitals This suggests thateither the chronic process is differentfrom the acute process, or that it is moremalignant "

"Lack of response of nicotinic acidindicates that doses have been in-adequate or that the biochemistry andphysiology of schizophrenic personsdiffer in some hitherto unsuspectedmanner. The differences may be due toirreparable enzymatic damage as a resultof a long inhibitory process, irreparablefunctional destruction of vital cerebralcenters, the presence of biochemicalmechanisms not reversible by nicotinicacid, or an inability of the patient inchronic stages of the disease to as-si milate nicotinic acid adequately or toutilize nicotinic acid in the same way asthe patient in the acute stages Perhaps

the answers to these problems will comewith future research "

Cinader (1975), an immunologist, iswell aware of the importance of in-cliviclual variation in disease and therapy.In discussing controlled comparisonclinical trials he writes, "A treatmentselected by clinical trial may be in-appropriate for some patients whocannot be identified in advance Suchtreatment failure is due to the heter-ogeneity of the disease or of the responseof individuals to the disease or thetreatment or is due to both factors Abetter definition, that is, identification ofhomogeneous disease entities, is an age-old objective of clinical research "

We were aware of these factors manyyears ago and always described ascarefully as possible (within space limit-ations of medical journals) the kind ofpatients we had treated The committeeignores this surely not out of ignorance

(5) Page 6—The committee continual-ly quibbles about terms. There iscertainly nothing orthomolecular aboutI:CT or about foreign molecules such astranquilizers, but there is no reason whya name designed to direct attention tocorrection of metabolic disorders bynutrient therapy should be droppedbecause these other non-orthomolecularmethods are helpful adjuncts

(6) Page 7—The committee accuses usof making categorical statements withoutsystematic documentation This is notso Orthomolecular therapists haveprovided large quantities of data basedupon double-blind, clinically controlled,follow-up, and other studies The onlyli mitation has been the modern style ofmedical journals to reject papers theydeem too long Hawkins' statement was asummary of a vast experience Not one ofthe committee had ever personallytreated schizophrenics using the fulltreatment They are in no position to becritical. Even if Dr David Hawkins hadgiven them 2,000 case histories, wouldthey have been any more receptive?

By quoting our statement on pre-vention out of context, they deny readersan opportunity to see how this hy-pothesis was derived Before flour in the

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U S. A was enriched with smallquantities of nicotinamide, it wasthought that pellagra could not beinfluenced in so simple a manner. butenrichment of flour nearly eradicatedpellagra, a vitamin B3 deficiency Theuse of larger doses might preventdevelopment of vitamin B3 dependency.Since we have already seen this inchildren of some schizophrenic parentsour suggestion is hardly fanciful. Thecommittee may not agree, but since theyhave never used vitamin B3 in this waytheir criticism is founded on theirpersonal opinion and nothing else

(7) Page 7—While attacking our sug-gestions for prevention they make suchunnecessary errors as referring to theHuxley Institute for Biosocial Research asthe Huxley Society and to the Academyof Orthomolecular Psychiatry as theAssociation of Orthomolecular Psy-chiatrists There are many other similarexamples of simple carelessness through-out this document which should makereaders wary Authors who cannot getnames, titles, and dates correct may beeven less reliable in more complexmatters

(8) Page 8—We have received a favor-able press perhaps because we have beenopen and honest with reporters, but ourdiscussion with writers did not occuruntil they sought us out and many yearsafter publications in medical journalsWe have never had the same access tothe media as the APA with its greatresources and paid staff membersdoing public relations So far the TaskForce Report has not been very warmlyreceived This may be because manyscience writers have done their owninquiries and have concluded, as wehave, that this report is not worthy of animportant subject which bears on thelives and well-being of thousands ofsuffering people.

(9) Page 8—(lines 16-19) When thecommittee writes, "consequently when aserious scientific attempt is made toreplicate the clinical experiments underthe specific conditions for which theoriginal claims were made, one finds thatthe conditions have changed," this is

false So far, no one has repeated theoriginal double-blind experiments Theseused acute and subacute cases with acombination of vitamin B3 and ECT incomparison to placebo and ECT None ofthe reports listed in the Task Force Reportfollowed these procedures

However, their statements on Page 8,"The latter claim is probably correctbecause it is virtually impossible toreplicate studies in which each patientreceives a highly individualized thera-peutic program with from one to sevenvitamins in huge doses, plus hormones,special diets, other drugs and ECT, whichare added or subtracted not on the basisof proven biochemical abnormalities butrather on the basis of the clinicians'individual judgment as to the patient'sneeds It is also impossible to replicatestudies in which as many as five years oftreatment may be needed before resultsbegin to appear, " are not correct either.If this was their opinion one wonders whythey continued to write a report It ispossible to replicate far more comp-licated treatments than those which wehave described, and very few medical orsurgical treatments are completelystereotyped and without individual var-iation The studies must be publishedand those who wish to replicate themmust first examine what was in theoriginal work Where there is doubt, or ifnecessary details are lacking, the ethicalinvestigator aiming at replicationapproaches the original authors andseeks their advice and clarification Thiswas not done, whether due to careless-ness, incompetence, or lack of good willis a matter for the reader to decide

(10) Page 8—We have never claimedthat vitamin B3 is the crucial variable Itis one of several crucial variables Asmany of our studies show, ECT and otherchemotherapy can be crucial We cannotbe sure why the committee chose toimply that we claimed that B3 was thecrucial variable; perhaps they felt thatunwary readers, being persuaded of this,would fail to notice that importanttreatment components had beenomitted. Whatever the committee'smotives its members overlooked the fact

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that if they condemned a useful treat-ment unfairly the losers would not betheir professional opponents (us and ourcolleagues), but tens, perhaps hundredsof thousands of patients. What in othercircumstances might be consideredclever debating tricks becomes lessclever and more irresponsible here

(11) Page 8—Whenever the com-mittee refers to the negative double-blind experiments its Report employssuch flattering terms as "the rigorousdouble-blind studies with vitamin B3"and "the careful attempts at replication

deal with the explicit procedures." Ifan experiment which uses chronicpatients rather than acute or subacuteones, which ignores ECT as we originallyused it, and which uses entirely differentevaluative procedures can be called acareful attempt at replication, then thereis little hope in psychiatric research Thecommittee adopts the rule that everyexperiment purporting to be double blindwhich yields negative results is bydefinition "careful, rigorous " They donot, however, apply the same rule to theoriginal experiments done under ourdirection in Saskatchewan becausepresumably they consider that we wereso biased that even the sacred doubleblind was not to be trusted

We doubt whether this committee wasso ill-informed as not to know that for allthe faith placed in them, double-blindstudies can be badly designed andexecuted so that false conclusions result.For example, the University GroupDiabetes Program (UGDP) concludedthat biguanides (Phenformin) increasedcardiovascular mortality in diabetics.This was an expensive controlled experi-ment, but recently Biron (1975) wrote,"There were so many flaws and biases inthe design and execution of this trial,that experts in experimental design whometiculously appraised the methodologyand the results believe that there are fewreasons to ascribe the higher death rateto the oral drugs, but many reasons toattribute them to differences in thenumerous pertinent risk factors that werenot measured at time of entry into thestudy " In a satirical letter Biron (1975a)

referred to a Sugargate coverup, pointingout that the data could equally well beinterpreted as showing that insulin andglycemia control are more dangerousthan placebo But the UGDP scientistsnowhere discuss this finding In otherwords, double blinds do not guaranteethat the results of an experiment will beobjective or accurate

Restak (1975) attacks most doubleblinds from another approach supportingHoffer and Osmond's (1961, 1963) earlierviews Restak wrote, "one thing funda-mentally wrong is the design of thetypical experiment using human sub-jects All too often such experiments areset up in a manner that almost guaran-tees emotional distance and alienationbetween the experimenter and his sub-jects. It is not unusual for manycontemporary researchers to have nopersonal knowledge of the identity of theparticipants in their own experimentswhich are carried out via intermediariesAll- too often scientific objectivity isdistorted to include callousness and lackof concern for the human aspects ofresearch "

Several of the psychiatrists who wereclinically involved with the patients inWittenborn's and Ban's experiments laterbecame orthomolecular psychiatristsThey saw improvement not visible to thedirectors of the study because the sdirectors saw only paper and numbers,not patients. Their clinical observationswere more meaningful than the APAconjectures

(12) Page 1—It would seem to usthat one doctor experienced with a newtreatment would be much more trust-worthy than 1,000 who had never used itIf the committee wishes to play the 4numbers game, they might explain why ;over 1,000 psychiatrists had the temerity "to diagnose Senator Goldwater withoutever having examined him.

On Pages 1 and 2 the committee 4 6

extracted phrases or sentences from the ioriginal reports in such a way as to bring;out the worst possible interpretation ofwhat was said The only way to prove 'hostile bias is to examine the papers;which have been published, to abstract

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them briefly, and to highlight theconclusions therein We have, therefore,referred to a large number of originalreports as well as to the corroborativepapers which have been publishedThese are discussed in an appendix so asnot to burden the reader unduly Butthese reports should, be examined indetail and compared with the com-mittee's interpretations and conclusionsAs will be seen, the committee reviewhas been marred by errors of omission, ofdistortion, by incorrect references to theliterature, by bias obtained by a carefulselection of the literature and of the datapresented in any one paper Thus, fromabout 26 original reports they wereseemingly unaware of eight, but they hadaccess in the literature to 19 Out ofabout 29 corroborative reports theyshould have known about 15, butreferred to three or less But they diddiscuss any study which was negative nomatter how badly it had been done Inone case they were instrumental inhaving one such study published eventhough there had been no attempt by theauthors to publish until now It appearedin a free journal edited by one of thecommittee and distributed by NIMH,Washington

Because the committee ignored somany reports favorable to orthomolecu-lar therapy while paying attention to anynegative report, however obscure, itbecomes possible to give their bias amathematical form by using a frequencydistribution and the null nypothesis Thisshows:

Reports ReportsFavorable Unfavorable

Chi so 10 00 n c 001

NAD reports are not included sinceNAD is neither nicotinic acid nor nicotin-amide Not every favorable report wascounted ** This shows that the bettingodds that the committee surveyed theliterature fairly is less than .001, or one ina thousand that such a bias occurred bychance alone.

(13) Page 3, 4th paragraph—The com-mittee seems to be, or wants to appear,naive when discussing the role ofpharmaceutical companies in the popu-larizing of drugs At the present timedrugs hardly ever become popular unlessthere are forces which keep bringingthem to the attention of the medical andlay public When a pharmaceuticalcompany has a use patent on a drug it isAle to invest heavily in its advertisingknowing that other companies are pre-vented from profiting from the originalcompany's efforts Advertising consistsof spreads in medical journals, frequentvisits from friendly, personable, well-trained salesmen who leave samples andliterature, and articles sponsored inmedical journals Drugs which are notpatented are known in the pharmaceuti-cal jargon as "orphan drugs. " They areowned by no one and therefore are notpromoted by any particular companiesThe vitamins are orphan drugs Thismeans that there are no detail men, nomassive skillful advertisements to keepthe vitamins before physicians as thera-peutic agents An example is the pro-motion of atromid, a British drug used fortowering cholesterol and triglyceridesNicotinic acid, the orphan, is an evenbetter broad-spectrum hypolipidemicsubstance Nearly every physician knowsabout atromid which is constantly beforephysicians in their medical journals inthree- to four-page spreads There is noadvertising whatever for nicotinic acid,and very few physicians are aware of itsli pid-lowering properties

The committee admits there is a grainof truth in our charge that orphan drugsare less impressive to psychiatrists thanthose that have been massively ad-vertised They doubt whether there ismuch to this: "If however they containedthe full truth, psychiatry would indeed bein a sorry state, gullible to the seductionof advertisement, pitiful in its naivete"and so on

We have not counted any of the papers in Ortho-molecular Psychiatry edited by D R Hawkins and L.Fouling (19731 since higher chi squares would bemeaningless

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It is for our readers to judge whetherthe committee may not have been over-optimistic about psychiatrists' capacityto resist advertising If they are correctthen many drug companies are wasting agreat deal of money buying up space inthe journal of American PsychiatricAssociation and the APA's many otherpublications It is possible that these vastcompanies are so slipshod as not to knowthe benefits they gain from advertising?

Other psychiatrists are not quite asnaive as this committee for example,Samuel Gershon and Baron Shopsin(1973) in their book on lithium write,"another important factor contributing tothe delay in using lithium for psychiatricpurposes is undoubtedly that its readyavailability rendered it commerciallynon-profitable; drug companies neitherinvestigated nor promoted its use RowellLaboratories, a small pharmaceuticalhouse in Baudette, Minn , had theforesight and the initiative to support thenecessary investigational work finallyleading to the commercial marketing oflithium in 1969 " So far no Baudette-company has come forth for vitaminsand they still remain orphans However,a large number of pharmaceuticalcompanies, not listed among the giants,do provide the vitamin tablets necessaryfor orthomolecular therapy

The same conclusion was reached by areport released by the National Instituteof Mental Health in 1970 (revised in1974) entitled "Lithium in the Treatmentof Mood Disorders " This report isintroduced by Bertram S Brown,Director He obviously does not disagreewith this as there is no disclaimer.

On Page 1: "In the United States,however, neither the first report in 1949nor the impressive Danish work pub-lished in 1954 aroused any researchinterest in lithium "

"This situation seems strange at firstglance, for the discovery of the psycho-active properties of lithium was of greatsignificance "

On Page 2: "Lithium itself, moreover,was of no interest to the drug companiesuntil quite recently, because it is anatural product and therefore unpatent-

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able Thus, the resulting lack of com-mercial sponsorship further cloudedrecognition of lithium's potential "

Parsons (1974), a pioneer in thedevelopment of nicotinic acid as a 1broad-spectrum hypolipidemic agent, in 4;reply to a hypothetical question, "why isniacin with its long and impressive record j:not used more widely by clinicians?"stated, "as a non-patentable drug it hasnot enjoyed the commercial promotion 4of other lipid-lowering drugs " Parsonshimself is employed by a pharmaceuticalhouse and is speaking' from personalknowledge on these matters

The committee winds up Section II bysuggesting that megavitamin therapy has ylittle scientific support and that legiti-mate empirical attempts at scientific preplication have failed There are twomain classes of scientists: (a) those like ofLinus Pauling, Nolan D C Lewis, HKluver, Gyorgyi, and others who makeoriginal contributions; (b) those who "follow along and re-plough fields alreadyopened Of the committee members 1

none are in the first rank They may be I:

excellent representatives of then==psychiatric establishment, but are not inoted for their scientific contributionsThis may be why this entire APA reportreads more like a polemic as one would I :

find in Time Magazine, rather than like a 1learned discussion as might appear in4'Science. j•

The committee finally writes, "legiti-mate empirical attempts at scientific; -

replication have failed " The term legit-='imate is an unusual word in a scientific r:

document. Presumably, the committee;)considered all the positive studies illegiti-mate

The statement that the empirical3attempts to replicate failed is untrue foraas we shall show none of the studies4i C

extolled and praised by the committeef i

have made the slightest attempt tooreplicate

(14) Page 5—The committee wrote ,E:an alternative hypothesis proposed by"!

Hoffer " They ignored Osmond and;(Smythies in this reference perhaps:because they were then not aware that;Smythies had found evidence supporting"'

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the use of vitamin B3, Perhaps the intentwas to dissociate Hoffer from Osmondand Smythies They then state that theoxidation of adrenalin to adrenochromewas demonstrated long before we refer-red to it, but neglect to point out that wediscovered the psychotomimetic pro-perties of adrenochrome Oddly enough,the original work was completed at theUniversity of Saskatchewan under thefirst professor of biochemistry, Dr RogerManning, University of Saskatchewan atSaskatoon, in 1935

(15) Page 6—The committee refers toonly one out of nine possible explana-tions we gave for the action of vitaminB3, i e , the methylation ideas. This, aswe have already shown, is one of manypossibilities. They then state "not only isthere no evidence for adrenochrome for-mation in vivo, but the psychotomimeticproperties of adrenochrome have alsonot been replicated " Both these state-ments are demonstrably false; there is asubstantial body of evidence that adren-ochrome is made in vivo and this hasbeen summarized in detail in our bookThe Hallucinogens (Hoffer and Osmond,1967) This evidence may not satisfy thecommittee, but since they did not referto our book, we must assume that theywere ignorant of it and so are in noposition to judge

The last part of their statement issimply untrue Double-blind experimentsin Prague confirmed the hallucinogenicproperties of adrenochrome It is listed inNIMH-sponsored literature as an hall-ucinogen and is so recognized by Ban(56, APA Task Force Report Reference)who wrote "after a considerable dispute,however, the psychotomimetic pro-perties of adrenochrome were con-firmed " Yet here is Doctor Ban, a co-signer to a report which states that itspsychotomimetic properties have notbeen confirmed Several years ago heand one of us (AH) debated before agroup of psychiatrists in Newfoundland.When AH quizzed him about thisstatement he admitted that adreno-chrome's psychotomimetic propertieshad been confirmed. What is the point ofthe APA publishing reports which even

those who sign them agree are untrue?Surely Lincoln's warning has not beenwholly forgotten in Washington wherethe difficulties involved in fooling all ofthe people all the time have been shownup vividly in the last few years

(16) Page 6, second paragraph—"Intheir first experiments, started in 1952,they compared, in a double-blind study,patients given nicotinic acid and nicotin-amide at doses of 3.0 g per day for 30days with other treatments available atthat time. The major tranquilizers werenot yet available. ECT and sedation weregiven to all patients as needed, butinsulin shock and autonomic drugs wereavoided Assessment of results during thehospitalization was by clinical evaluationof symptom intensity At the end of the33 days the patients were dischargedhome or, rarely, to a mental hospital.Follow-ups after discharge from thehospital were by contact every threemonths with patients and relatives toassess adjustment to the community, joband family. The follow-ups were made bysocial workers who did not know thetreatment given, and occasionally byletters and questionnaires Follow-upvaried from about a year to somewhatmore than three years Re-admission tohospital was used as a criterion of failureof treatment The results showed onlysmall degrees of improvement on thevitamin over placebo during the hospital-ization, but a decreased relapse rate inthe first four years in the nicotinic addgroup related to use of drug either inhospital or upon follow-up "

We were hoping to find one of ourpapers abstracted correctly But this wasnot to be In this paragraph thecommittee confused two quite differentreports, the original double-blind reportof 30 cases, and a second follow-up studyon a larger group most of whom had notbeen treated in the double-blind experi-ment.

(17) Page 6—The committee writes,"During a period of five years a total of82 patients were studied, 43 of whomreceived placebo and 39 of whomreceived nicotinic acid." They did notinclude the important fact that 21 of the

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placebo patients also received ECT and15 of the vitamin group received ECTThis seems to us an attempt to neglectECT as an important variable Then theycontinue, "In this study, the nicotinicacid group had significant improvementin the hospital " What they did not saywas that 31 out of the 39 improvedcompared to only 18 out of the 43placebo group We reported this was ahighly significant difference They alsodid not record that doctors not in theresearch group were allowed the optionof requesting the medication given totheir patients be decoded if they feltthere was insufficient progress This wasrequested 18 times from the placebogroup and once from the vitamin group(chi sq = 19 p < 001) Then the

committee continues, "but little dif-ference in the relapse rate "

This is an astonishing distortion ofwhat we reported, equivalent to callingblack, white. We pointed out that overthe 5½ years of follow-up (June 1953 toDecember 1958) all patients from thesecond double-blind controlled experi-ment were given either 1 g of nicotinicacid or 1 g of placebo per day afterdischarge The two follow-up groupswere randomized. We, therefore, hadfour groups: (a) placebo in hospital andafter discharge; (b) placebo in hospitaland 1 g of niacin after discharge; (c)niacin in hospital followed by placebo;and finally, (d) niacin in hospital andafter discharge We showed results asfollows:

Group Treatment Percent of group requiring No. ofIn After readmissions after dis- 5-year

Hospital Discharge N charge, year after discharge Total cures

placebo placebo 20placebo niacin 8niacin placebo 29niacin niacin 25

It is obvious that the best record wasachieved by the niacin-niacin group andthe worst by the placebo-placebo groupThe other two groups were in between

We also reported that out of 118patient-years in community on niacinthere were seven readmissions, whilefrom 182 patient-years on placebo therewere 60 readmissions (chi square=20,p<0001)

The 20 placebo-placebo group re-quired 16 readmissions totalling 9. 1 yearswhile the 62 patients on niacin at onetime or another required 39 readmissionsfor a total of 11.2 years Had theyrequired the same number of days inhospital relative to the size of the groupthey would have required 28 2 years.

Finally, we concluded, based upon sixindices of improvement, : (1) condition incommunity, (2) number readmitted, (3)number of readmissions, (4) numberwell, (5) number much improved, (6)five-year cures, that the order of de-

creasing merit of treatment was asfollows: niacin-niacin.> placebo-niacin>niacin-placebo > placebo-placebo Therewas, in fact, a very significant differencewith those patients on niacin in and out ;of hospital doing much better. Threefive-year cures out of 20 on placebo- =placebo (15 percent) is surely different E

from 19 out of 62 or 30 percent in theniacin groups What did the committeeread?

Then they added, "The only patients ?who had a significant improvement withnicotinic acid continued after discharge;from the hospital were seven acutely illfemales "

It seems more charitable to ascribe this)statement to a deliberate attempt to b'

confuse rather than to accuse the authorsof being unable to read This is what AHwrote on page 54 of his book (1962): "A -r

total of 33 patients received nicotinicacid after discharge Of the nineteen'rated improved, only nine retained this! `l''

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status, but out of fourteen rated un-i mproved on discharge, seven improvedThis latter group, although small, is the

only group which differs significantlyfrom all the other groups listed in Table24 " This table showed the following:

Treatment in Dischargecommunity N evaluation

19 la) improved14 Ibl not improved

other treatment 31 lal improved18 lb) not improved

Statusincommunity —

well and muchimproved

What this table showed then was thatout of 14 patients discharged as un-improved on 1 g of niacin per day, sevenbecame well or much improved after atleast one year treatment in the com-munity In contrast, out of 18 dischargedas not improved not given niacin butgiven other treatment, only one becamewell or much improved On the otherhand, out of 19 discharged as improvedand continued on 1 g of niacin, only nineremained well or much improved whileout of 31 evaluated improved or dis-charged but not given niacin only 13remained well or much improved.***This shows that 1 g per day is enough toproduce improvement in some and not inothers, which is not surprising It hasalways been clear there is an optimumtreatment and follow-up dose. We findthe committee's capacity to distort ourfindings incomprehensible and are at aloss to account for it It appears to be adeliberate attempt to mislead unwaryreaders in the hope that they would notcompare the report with the originalsource If this was the intention then itwas doubly deplorable for apart from thefalsification it underestimates thecuriosity and zeal of some members ofthe public It suggests an arrogant andsupercilious approach to both the profes-sion and the public

(18) Page 7—The committee stated,"Positive claims for the efficacy ofnicotinic acid have been made by otherworkers " They then list a number of

••• The difference between niacin and other treatmentin the community was statistically significant. Chi sq= 3.7 If' <0.051.

published studies, while ignoring anumber, and list four reports they hadnever read These were APA references#33, 36, 37, and 40 These were papersread at the Brunswick Hospital meeting,but never published None of thecommittee members were present This isan example of padding It is customarynot to refer to unread papers unless this isnoted in the text.

(19) Page 8—The committee made thefollowing criticisms of megavitaminwork:(1) Contamination of studies by frequentuse of ECT We have always showndearly that ECT was an essential com-ponent of treatment for Phase II patientsIt is odd to term an essential ingredient acontaminant The committee stillattempts to play down ECT, presumablyto further their contention that vitaminB3 is the crucial variable(2) A nonrandom or biased selection ofthe small numbers in our studies com-pared with the total population at risk.For the first two double-blind studiesevery patient admitted who was schizo-phrenic was taken into the study,provided that his therapist allowed this tohappen This is the way most studies aredone We do not know of any studieswhere a random selection of all ad-missions has been used All that isrequired by classical double-blindmethodology is that the allocation ofpatients into the treatment groups israndomized The committee has createdsome new rules to suit their fancy: Thesize of the groups treated was adequateto test the null hypothesis and was

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somewhat larger than sample sizes usedby Ban and Lehmann If our work isquestioned on this count the samecriticism should be levelled at Ban andLehmann Ban (1972) is uncertainwhether 15 to 30 patients in any groupcan yield any conclusion at any accept-able level of thoroughness.(3) The lack of clearly specified initialdiagnostic groups or systematic rating ofpatients This is false The reader mustread our original papers where wedescribed in detail diagnostic criteria andevaluative methods used(4) The failure to specify chronicity. Thisis false as any examination of ourpublished data shows(5) Nicotinic acid was never the onlytreatment given We have repeatedlyemphasized that vitamin B3 was one ofthe main treatments in any series.However, we have seen hundreds ofpatients recover on vitamin B3 alone Weare prepared to demonstrate these to anyphysician who wishes to see our patientsand their clinical records So far over 50physicians have done so and are nowpracticing orthomolecular therapy(6)"The number of patients in the follow-up sample were small." This is amisleading criticism How many 10-yearfollow-up studies have been reportedwith tranquilizers? We have recently seenone Perhaps the committee will bringothers to our attention "Treatment andcomparison groups were not matched asto pre-treatment prognosis " This isanother after-the-fact suggestion whichmakes it look as if the committee wassearching desperately for every possiblecriticism of our work They were muchless critical of the Wittenborn and theBan and Lehmann double blinds whichwere not double blind Had they foundsuch errors in our work there would havebeen no end to their comments To befair, in the original protocol Ban termedhis study "semi-blind," but he conven-iently ignores this in this report(7) The committee is critical because inour original double-blind studies we didnot compare vitamin B3 against tran-quilizers We would have done so, buttranquilizers did not come into general

16

use until 1957 By then our firstexperiment was completed and oursecond one nearly completed Since thenwe have published many reports compar-ing vitamin B3 as a treatment componentagainst tranquilizers alone.(8) The final attack is a repetition ofearlier mistakes The committee wrote"In the first one the patients received thedrugs only in hospital, did not improvesignificantly in hospital but had alessened tendency to relapse for fouryears after discharge." The committeemanages to be confused about evenelementary reports We concluded thatthe vitamin B3 patients were better offthan placebo patients on discharge, butthat at the end of one year they hadreached a one-year recovery rate twice ashigh as the placebo group. This thecommittee terms "a lessened tendency."As usual they play down the positive andemphasize the negative more like hostileattorneys than scientific inquirers Thenthey say, "In the second study the reverseis true: there was an improvement in thehospital, but the subsequent relapse ratewas the same." As we showed earlier the 2second half of this statement is false Thecommittee then remarks, "These dif-fering results are hard to explain."Perhaps so; if one cannot read almostanything must be perplexing Bothstudies showed that patients on vitaminB3 therapy improved in hospital and hada significant decrease in relapse rates.;;But the committee falsely concludedwhite is black.

We do not find any inconsistencies inthe statements in the last paragraph onPage 8 It is true a few patients recoververy quickly on vitamin B3 therapy, but rthat most patients recover more slowly 1This is also true of tranquilizers. We donot understand why this is considered aninconsistency It is a general phenom-zenon of all therapeutic drugs But withorthomolecular therapy a large pro-) ,portion of patients recover fully to`become doctors, lawyers, professors,farmers, white collar workers, and so onWe have yet to see one schizophrenic:physician become normal on tranquilizertherapy only . " `

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(20) Page 9—The committee findsanother inconsistency between a reportby Saarma and Vasar (Ref 46) and theirreference to O'Reilly (Ref 47) They saySaarma et al cited negative finds fornicotinic acid in acute schizophreniaThis is what Saarma said, but thecommittee knew the O'Reilly study wason chronic patients only since they listedthe title of his paper accurately as"Nicotinic Acid Therapy and the ChronicSchizophrenic." (See Ref 47 ) It was alsoso listed by Saarma and Vasar whoprobably missed the word in theirproofreading

(21) Page 9—In complaining aboutour original methodology the committeecited three examples The first one isfrom Hoffer et al (1957) where theyextracted sentences from a paragraph:"When the adjustment rating is notavailable for a particular patient but hisprogress after discharge is adequatelyknown, , an impressionistic score isgiven, but the committee carefullyomitted the rest of the statement: "(forexample, good adjustment or pooradjustment) These findings, however,are excluded from the mathematicalevaluation of progress," Surely this is amost important statement to leave in,but if the committee had done so theywould have removed one of theirexamples of questionable methodologyHowever, this evaluative method wasused for nine patients out of the 30 asfollows: (a) from the placebo group fourhad poor adjustments; (b) from thenicotinic acid group, two; (c) from thenicotinamide group, two—both beingthen in mental hospital This exclusion ofa crucial qualifying sentence suggeststhat either deliberate falsification ormassive subconscious bias was at work.The APA Research Committee shouldhave been more diligent in monitoring itsTask Force

The second example of the committeeis an attack on Chinaglia (1965) and thethird example is an attempt to smear usThe committee writes, "Hoffer in abroadside for public distribution pub-lished in 1965 says, 'It (nicotinic acid ornicotinamide) does not cause any harm

(during pregnancy) to babies There isevidence that it can protect babiesagainst the harmful effects of othersubstances ' "

The New World Dictionary, SecondCollege Edition defines broadside asfollows: "(1) The entire side of a shipabove the water line; (2) (a) all the gunsthat can be fired from one side of a ship;(b) the simultaneous firing of these guns;(3) a vigorous or abusive attack in wordsespecially in a newspaper; (4) the broadsurface of any large object; (5) (a)(originally) a large sheet of paper printedon one side as with a political message orin 17th century England a popular balladalso broadsheet; (b) a large sheet ofpaper printed on one or both sides aswith advertising and often folded "

We have never mass circulated anycommunication, but have as a policyprepared printed information letterswhich are sent only to lay and profes-sional people who have written to us forinformation. Nowhere in the precisedefinition of broadside is there anythingremotely resembling anything we havedone However, definition #3 fits closestof all the APA Task Force Report

In our personal communications,which these letters were, we did not referto literature references. For the com-mittee to treat these private letters as ifthey were documents published in amedical journal is grossly unfair

We have been using niacin on severalthousand cases since 1952. A largenumber of females have become preg-nant and had normal children while onniacin There has been not one infantborn to these patients with any con-genital defect

Safety, Side Effects, and Relative Lack ofToxicity of Nicotinic Acid and Nicotin-amide, A. Hoffer (19696)

In this paper, AH differentiatedbetween side effects which may he anuisance and toxic effects which arepotentially harmful. Side effects include:(1) Vasodilation of the anterior part ofthe body with a sensation of heat anditching

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(2) Nausea occasionally followed byvomiting.(3) Rarely activation of peptic ulcer(4) Rarely dry skin and very rarelyincreased pigmentation of flexor sur-faces(5) Headaches

They are not dangerous and are easilycontrolled by lowering the dose or usingother means. Possible toxic reactions ofnicotinic acid include liver toxicity whichis rare, occurring about one-tenth of thefrequency with which it appears withtranquilizers It may alter the sugar-tolerance curve and may cause insulinrequirements to go up or down It mayincrease uric acid blood levels, but hasnot precipitated or aggravated gout.

There have been no reports of toxiceffects on the embryo Female rabbits onnicotinic acid produced normal litters.A H referred to findings which showedthat vitamin B3 could protect embryosfrom toxic effects of other drugs. Sub-stances which prevent vitamin B3 frombeing incorporated into NAD are terato-gens such as 6 aminonicotinamideNicotinic acid protects animals againstthese compounds Mosher (1970) quotedthese studies and had he found anyevidence whatever for any teratogeniceffect he would have certainly producedit He concluded, "at this time there islittle evidence either positive or negativewith regard to the possible teratogeniceffects of nicotinic acid " As he wasunaware of the earlier report this isunderstandable. He subsequently apolo-gized for his neglect to properly reportthe literature.

In a recent review Parsons (1974)discussed the side effects of nicotinicacid. He wrote, "Many clinicians areunduly concerned about the cutaneousflushing which niacin produces,apparently not realizing that with largedoses it subsides early in treatment Suchnegative attitudes have probably beenenhanced by glib review articles listingsymptoms and biochemical changeswhich occur during therapy, but failingto clarify which could be formidable " "Itis also well to emphasize that the flush isat worst merely a nuisance which is not

medically serious "The committee writes, "Hoffer for

example, in his 1967 pamphlet (18) andin his 1971 paper (13) cites violent****vasodilatation Here is what AH wrote,"Nicotinic acid produces a remarkablevasodilatation " The committee managesto transform remarkable into violent,evidence of bias which can hardly be loston students of psychopathology Toround off this example they omit adescription of how this flush recedes ifone continues to take niacin

In 1971 AH wrote, "It is still notclear how many of the gastrointestinaleffects are due to the vitamin and howmany to the vitamin filler " This is howthe committee summarized it, "Thegastrointestinal symptoms are attributedto the inert filler used in preparation ofthe B3 tablets " In this section thecommittee continues to distort both formand substance of what we wrote,presumably secure in the belief that theirpsychiatrist readers will not refer to theoriginal publications So far events havesupported their belief However, since ':FlIthey were entrusted by the APA tomake an honest and unbiased reportothers may now become curious to see ahow they carried out a duty to whichthey were pledged both to psychiatry andto the public This entire section on side teffects reads like one of the glib reportswith which Parsons takes issue. Re-garding peptic ulcer Parsons wrote,"Although in 1960 I reported five patientsin whom ulcers became active duringniacin therapy subsequent experiencehas failed to show any close correlation ""I do not hesitate to prescribe niacin in ahyperlipidemic patient with previousulcer "

With respect to liver toxicity high-lighted by the committee, Parsons states,Some of the serum enzymes used to

assess hepatic function may be mildly tomoderately elevated during therapy AAThese changes are usually not pro-gressive, often returning to normal whiletreatment continues Light microscopy ;ghas frequently shown no abnormality in

•'•' emphasis ours. not in the APA report

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hepatic tissue even when enzyme levelshave been considerably abnormal ""Similar liver enzyme changes occur withclofibrate therapy and appears to beinherent in these drugs without signifyinghepatic damage " Jaundice has been veryrare.

About hyperglycemia Parsons wrote,the changes in carbohydrate tolerance

have no clinical significance—unless theclinician incorrectly interprets them asevidence of diabetes " Discussing in-creased uric acid levels Parsons con-cluded, "Hyperuricemia occurs some-what less frequently but has not beenaccompanied by gouty arthritis or renalcalculi "

Parsons found pigmentary changes inthe skin not significant This he des-cribed as a localized velvety thickeningand tanning of the skin especially in theaxillae This change, which resemblesacanthosis nigricans, is of cosmeticimportance only It does not require thatthe drug be discontinued Wittenborn etal (1973) did not report any cases ofacanthosis nigricans They wrote, "Asubstantial portion of the sampledeveloped a pigmented hyperkeratosiswhich in some cases bore a disturbingsuperficial resemblance to acanthosisnigricans " They referred to a report byParsons But it is obvious that Parsonswho has been studying nicotinic acidsince 1956 is not disturbed It is not thetanning of the skin which is disturbing,but the unfamiliarity of Wittenborn andhis colleagues with this phenomenonwhich excited and disturbed them Thereare no reports that nicotinic acid causesacanthosis nigricans The committee'sstatement was false when they wrote,"and acanthosis nigricans have beenreported " From 853 patients treated withnicotinic acid for five years the CoronaryDrug Project Research Group did notreport a single case They did not evenmention it as a side effect

The committee referred to a case ofincipient psychosis produced by nico-tinic acid. They apparently read a letterto the editor by Heninger and Bowers(1968) who concluded that 1% g ofnicotinic acid produced a psychosis in a

subject who had also been taking LSD,hashish, and a curious form of psycho-therapy The committee did not refer to aletter of rebuttal, from Hoffer (1969)

Here he wrote "This pharmacologicallynaive report deserves little commentexcept that it will certainly be quotedwidely as evidence for niacin toxicity "We did not then realize that a committeeof the APA would be the first and onlygroup to prove this prediction correct

The committee's concluding paragraphon Page 44 of their report might beascribed to a serious concern for thewelfare of patients But since everyknown tranquilizer is many times moretoxic, one has to weigh the risks of: (1)Remaining chronically tranquilized andmore or less ill for life This as manyauthorities have indicated is occurring toan increasing number of patients with allthe increasing risks of irreversible con-ditions such as tardive dyskinesia andakinetic mutism (2) Recovering onthe orthomolecular approach while usingvitamins the rest of one's life Webelieve that given such a choice and notmisled by prejudicial comments mostpeople would choose the latter The risksare small We have still to see a singlepatient harmed by megavitamin therapyalthough we have seen those notbenefited During the same time we haveseen numbers of permanently impairedpatients on tranquilizers The costs interms of their lives and to the communityhave not yet been computed, but theymust be immense

(22) Page 10, Attempts at Replication—The committee continues to insist thatvitamin B3 is the crucial variable for theentire orthomolecular program They usethis to justify their single-mindedemployment of vitamin B3 in theirexperiments This sometimes seems to bea deliberate attempt to confuse—one isunwilling to believe in such massiveincompetence. Had Ban and Lehmannseen fit (as they had originally agreed) torepeat our original experiments using acombination of vitamin B3 and ECT, andhad the results turned out negative, thereis no doubt the committee would havedropped all reference to vitamin B3 as

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the crucial variable No matter how thecommittee squirms about the issue, thefact still remains that no one hasrepeated the original two double-blindexperiments Those who have employedthe entire orthomolecular techniquehave become enthusiastic users

(23) Page 11—The list of negative ref-erences on this page is interestingNowhere is there any reference in thebody of their report to our first studywhere we showed that nicotinic acidalone did not help chronic patients(O'Reilly, 1955) O'Reilly was a colleaguelocated at Saskatchewan Hospital, NorthBattleford At our request he ran a studywhich was published in Diseases of theNervous System. This was the firstpublished account of lack of response ofchronics We have since then alwaysmade this clear as is evident from thereview of our papers given earlier in thisreport O'Reilly (1955) is reference #47 inthe committee report Then they refer toAshby et al., who confirmed our report,and to Greenbaum who gave one-thirdthe active dose to schizophrenic child-ren No information was given about thenumber who were cases of infantileautism

The McGrath et al report discussed265 patients of whom 115 or 43 percentwere ill five years or more, 91 (34percent) were ill one to five years, and ofwhom only 59 (23 percent) were ill oneyear or less Thus, only one-quarter wereacute This is then a study of the effect ofnicotinamide on chronic schizophrenicsThere is no breakdown anywhere in thepaper between acute and chronics andresponse to treatment There is noevidence in this report to support thecommittee's statement "no improvementwas noticeable either after 30 days oftreatment or after one year in either theacute or chronic patients " McGrath etal also confirmed O'Reilly (1955)

The Wittenborn studies are reported inan interesting way And since DrWittenborn is introduced "as an excep-tionally experienced researcher in thearea of drug effects on mental illness" itis especially important to examine care-fully his "unusually comprehensive"

studies not only for what Dr Wittenbornreported, but the way this committee;used his data It is not clear just whatresponsibility Wittenborn himself must)bear for the committee's report since hefwas the consultant As with Ban the= '

committee seems to be expert at mud-i'dling roles in a deplorable manner We i

-will not concern ourselves with Witten-)born the consultant

We will list the Wittenborn conclusions and then the committee's in-terpretation when they are different.

Wittenborn et al (1973) compared theIeffect of nicotinic acid, 3 g per day,plus tranquilizers against nicotinic acid)alone on an experimental group of 47 ill).on the average 4.8 years against a controlgroup of 28 ill 3.0 years. They found: (1)'24 percent from the vitamin group were„dropouts and uncooperative compared';to 37 percent of the control This did notreach statistical significance, but sug- ; ±)gests a trend for more cooperation):among the vitamin group (2) A slightly'larger proportion in the nicotinic acid='

,

group remained in hospital each month ?This difference was not statistically))significant. (3) There was no difference inthe rate of readmission to hospital or inwnumber of days spent in hospital. (4)There was no significant difference innumber of patients requiring tram')))quilizers, or in the amount of tranquilizerrequired (dose) At the end of the first;month, 87 percent of the vitamin group ';+and 96 percent of the control group were-receiving tranquilizers, while at the endsof 12 months these values were 77percent and 89 percent At the end oftwo years they were identical at 75 r;;percent (5) There was no significant;:difference between the two groups"clinically (6) Home and community,adjustment was more favorable in the;control group than in the vitamin group. 4?(7) There were no cases of disturbedfcarbohydrate metabolism and gastroenteritis (8) A number of patients`developed a superficial pigmentation intheir skin

These findings were reported by the Yjcommittee except for their first state-1rment (1) Subjects on niacin tended to

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stay in the hospital longer, but thestatistical significance of this is un-certain What Wittenborn et al wrotewas that, "This difference continuedthroughout the course of treatment, butdid not meet the criterion for statisticalsignificance " There seems to be nothinguncertain about this last statement.

In a subsequent report (Wittenborn,1973) first delivered in Washington andlater published Wittenborn (1974) re-ported that he had examined a smallergroup of 24 patients selected on the basisof certain predictor indices Halfreceived nicotinic acid Ten of the 12patients in the vitamin group hadoutpatient adjustment scores of 0 60 orhigher at 24 months indicating a goodoutpatient adjustment score In thecontrol group only five out of 12achieved similar adjustment

Wittenbo n found "a high positivepredictor score was associated with aclinically important advantage for thosepatients whose treatment comprisedniacin supplementations " "For depres-sive retardation the percent of patientswith substantial disorder at 24 months isapproximately twice as great in theselected control group as in the selectedniacin supplementation group. Forschizophrenic excitement, the percent ofpatients with substantial disorder is morethan twice as great in the control groupat 12 and 24 months as it is in theselected niacin supplementation group "

Wittenborn (1973) stated, "There is aconceivable relationship between thefact that in the present sample patientswith a high predictive score responded

tell to niacin and the fact that Hofferand Osmond had claimed that niacin wasmore effective in relatively acutepatients than in chronic patients It isprobable that patients who, in thepresent sample, had a high positivepredictor score would have been class-ified by Hoffer and Osmond as acuteschizophrenics. Perhaps in this way thedifferential effect observed by themcould be in part explained " Wittenbornfurther states, "those patients withconditions diagnosed as schizophrenicwho come to treatment with a history of

strong interpersonal commitments willrespond well to niacin-supplementaltherapy " This he proposed as a testablehypothesis

The committee did not relish thissecond report and attempted to neutra-lize and obscure these findings by writingin their conclusion, "the fact that hefinds no significant difference betweenthe total control group and the totalvitamin group implies that a fraction ofhis experimental population may havehad their progress impeded by thevitamin addition " There is no evidencewhatever for this simplistic mathematicalconclusion. Had there been any sub-group identifiable in any way as a groupmade worse by vitamin B3, there can beno doubt Wittenborn upon the urging ofthe committee would have found it andreported it

The committee referred to a possibleone-quarter of the group who did well onvitamin B3 but neglected to refer to the20 percent of the total group who weremade worse on tranquilizers alone Thus,Wittenborn (1974) wrote, "one possibleexplanation for the paradoxical per-sistence of symptoms in these controlgroup patients with a good positivepredictor score draws on observationsthat there are patients with a favorablepremorbid history who may possibly beburdened by phenothiazine medicationin their remission " He wondered ifniacin might be antitoxic to the pheno-thiazines

But this is how the committee sum-marizes it: "although Wittenbornconsiders his data to be consistent withthe possibility that as many as one-quarter of his schizophrenic population(those with good premorbid adjustment)might be benefitted " We assume thatthis figure is derived by multiplyingone-third (i e , the number of subjectswith good premorbid personality) by10/12, i.e , the proportion who respond-ed to nicotinic acid plus phenothiazines.Note that the committee in criticizingour work never talks about nicotinic acidand ECT in the same sentence, but herethey want to leave the suggestion it wasthe phenothiazine which should be

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r

emphasized. This may be how thecommittee arrives at the one-quarterestimate.

Wittenborn in his papers does notmake this sort of calculation In ouropinion Wittenborn had discovered un-usual and one might think unnecessarycriteria for selecting Phase I patients Theproportion of Phase I patients, i e., acuteor less serious cases, varies with thesample Thus, from a cohort of schizo-phrenics seen for the first time inoutpatient clinics or by psychiatrists inprivate practice a much larger proportionare early, less serious, or Phase I. From acohort admitted to a mental hospital amuch smaller proportion are Phase I Outof one practice in Saskatoon about 50percent are early and AH is the firstpsychiatrist they have seen. The otherhalf have been to one or more before andare more apt to be Phase II Since goingto a mental hospital very often meansthat there is no other facility willing orable to take the patient they are morechronic, have already failed to respondto treatment, and are generally moreintractable It is, therefore, not surprisingto find only one-third of the Wittenborngroup were Phase I But to be fair andobjective the committee might haveabstracted Wittenborn's paper morecarefully Even so, there is no evidencefrom the Wittenborn studies that the twomain groups were suitably identical sincethe placebo group were 1 8 years lesschronic (4 8 compared to 3 0) Asubstantial fraction of the poorer prog-nostic vitamin group could have res-ponded without any significant dif-ference appearing, and a substantialproportion of the better prognosticplacebo group might have responded hadthey been treated with nicotinic acid.Thus, the one-quarter estimate is socrude as to be trivial

In other words, Wittenborn's studyconfirms our claims that a substantialfraction of schizophrenics, i e , Phase I,will respond to nicotinic acid withoutECT. But we must emphasize that this isseldom our recommendation today Thecommittee quibbles on the proportion inPhase I Even if we accept their estimate

22

of one-quarter based upon a mentalhospital admission cohort, this is still 3.appreciable Having admitted that one-quarter might be benefited the com-mittee, by a form of convoluted reason-ing which is very mysterious, states, "thefact that he finds no significant dif-ference between the total control groupand the total vitamin group implies afraction of his experimental populationmay have had their progress impeded bythe vitamin addition " One could just aswell argue that had there been a simpleplacebo versus niacin study omittingtranquilizers the results might have beeneven more significant in favor of vitamin IsB3

Wittenborn tried to save his study from =becoming too much in favor of niacin by 3suggesting that the 35 percent of his totalgroup were not really schizophrenic If ':this suggestion is accepted seriously,then the whole study must be injeopardy For who would give a —moment's consideration to an investiga- ::tion in which the chief scientist reportsthat one-third of the patients did not

;have the illness being studied?The committee totally ignored DeLiz's!3

(1973) charge that the Wittenborn study<did not maintain its double-blind status 1_Although Wittenborn maintained it wasdouble blind, he presented no evidence.;that it had remained so There were no=';questionnaires for either patient or staff:to determine whether they thought they;;:'.were getting niacin or placebo DeLiz;stated that some patients were aware;they were on placebo and at least onepurchased his own niacin This is not tobe construed as an attack on Wittenbornwho is an able research worker, but ori`the methodology of the double-blindtechnique It requires

th

ane

al super ;human effort to insure the double blind i'not broken

In the Wittenborn studies it wouldhave been impossible to insure it-remained double blind because of thevasodilation He attempted to cover this:by starting the entire group on 50Q;milligram tablets to give them all theflush and then changing the

placebo

group over to placebo But anyone with

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any experience with long-term niacin useknows that now and then throughouttreatment there will be random flushes,usually after the first dose in themorning We suspect that after a fewmonths nearly every patient on niacinwill know he has flushed and most of thegroup will know why

Furthermore, a number of patientswho developed pigmentation had theirmedication decoded and after a whilewere restarted on the niacin Thus, thedouble blind was not maintained throughno fault of the investigators (De Liz,1975; Adams et al , 1975)

We now come to the Canadian MentalHealth Association's studies begun with agrant given to Dr T Ban The reason theCMHA did this was that they becamedisturbed by the claims that addingvitamin B3 to the treatment programdoubled the recovery rate They in-structed Dr Ban to disprove once and forall time our claims One of us (AH) thatyear was on the Scientific AdvisoryCouncil and was familiar with the back-ground When Ban's initial design wasseen it was obvious he was prepared touse only Phase I treatment, i e , no ECTWhen this was pointed out to him heresponded with the reassuring statementthat after their first researches werecompleted they would continue withPhases II and III He also added therewould be no release of any informationuntil the entire program (Phases I and II)could be completed It now appears thathe had no intention whatever of goingbeyond Phase I treatment for all patientsand, as events showed, he rushed intoprint very soon after the first study wascompleted He was supported by CMHAwho circulated his first report to everypsychiatrist in Canada They have sincerefused to correct the misinformationdistributed therein claiming they cannotbe involved in any treatment contro-versy Examination of Table 1 of thecommittee report shows no evidencewhatever of any study repeating any ofour original double-blind studies(vitamin B3 and ECT as required)

For each of their published studies wewill abstract what the authors wrote and

this will be followed by the committee'sabstract

Study No. 1 (58 in Task Force Biblio-graphy) Also published in Int. Zeit. Klin.Pharm. Ther. and Tox., 54, 406-410,1972

In this study they treated 30 newlyadmitted schizophrenics They do notdescribe them as acute or chronic, but asnewly admitted. This is an interestingterm and suggests that the patients wereacute Anyone familiar with the DouglasHospital in Montreal knows that newlyadmitted patients there include a largeproportion of chronic cases, many ofwhom had failed to respond to treatmentin a number of psychiatric wards ingeneral hospitals The words newlyadmitted have no meaning whatever andthe authors would have been morehonest to have simply called themadmitted schizophrenics and to havedescribed their sample more carefully.Hoffer (1974) investigated these studiescarefully and wrote, "The patients weredivided into three groups, one groupreceiving nicotinic acid, one groupnicotinamide, and the third group place-bos Neuroleptic tranquilizers wereadministered to all the groups on arestricted scale It was intended toinvestigate the patients for two years, butonly six patients completed the entireperiod Nevertheless, 25 patients spentthe first three months in hospital and atthe end of this period their clinical statuswas assessed by means of the BriefPsychiatric Rating Scale (BPRS)

"It was found that there were statist-ically significant improvements in thetotal BPRS scores for all three groupsHowever, Table 3 of the research papershows that out of 15 BPRS items, thepatients receiving nicotinic acid im-proved in 11 items and the patientsreceiving nicotinamide improved in 12items, while the patients receivingplacebos improved in only six itemsThus, both the B3-treated groups scoredimprovements in approximately twice asmany items of the BPRS as the placebo-treated group The published paper alsoincludes clinical assessments of the

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patients at the end of the two-year studyThere were improvements in 10 out of 15items in both the nicotinic acid and thenicotinamide-treated groups, butimprovement in only six items in theplacebo-treated group Because 80 per-cent of the patients dropped out of thestudy before its completion, these resultsare much less reliable than the onesobtained at the end of the three-monthperiod in hospital, when few patients haddropped out However, the same generalpicture is obtained as at the end of thethree-month period; that is, both thenicotinic acid and the nicotinamide-treated groups improved in many moreI3PRS items than did the placebo group "

The committee reports, however, "theoverall therapeutic efficacy of nicotinicacid as the sole medication in newlyadmitted schizophrenic patients is notsuperior to the overall therapeuticefficacy of an inactive placebo In fact,the majority of newly admitted schizo-phrenic patients—in a placebo control-led two-year study with 30 patients—could not be sufficiently controlled withhigh dosages—3,000 to 8,000 mg perday—of nicotinic acid administrationFurther analysis of data revealed thatduring the two-year investigationalperiod—regardless of whether thepatients were kept on the project ornot—the average number of days spentin hospital was lowest in the placebo (211clays) and highest in the nicotinamide-treated group (353 days) However, thenumber of days spent in hospital wasonly slightly higher—214 days—in thenicotinic acid than in the placebo-treated patients (58) "

J Hoffer then properly concluded,"The summary of this study given in theTask Force Report doesn't mention theseresults Instead, it points out that theaverage number of days in hospitalduring the two-year period was 211 daysin the placebo-treated group, 214 days inthe nicotinic acid-treated group, and 353clays in the nicotinamide-treated group,showing that the length of time spent inhospital was not significantly differentfor the B3-treated groups compared tothe control group The conclusion to be

reached about the study depends onwhether one takes the average number ofdays spent in hospital as the criticalvariable, or whether one takes thenumber of symptoms of mental illnessalleviated in the course of the treatmentas the critical variable The latter is by farthe more reliable

"The Task Force Report has interpreted jthis study as demonstrating that (page15): ' The overall therapeutic efficacyof nicotinic acid as the sole medicationin newly admitted schizophrenic patientsis not superior to the overall therapeutic ?efficacy of an inactive placebo'

"This conclusion is based on theinsignificant differences in average dura-tion of hospital stays The evidencederived from actual psychiatric evalua-tion of the patients, which showed a !definite superiority of both the groups_receiving B3 over the control group, is."not even mentioned "

CMHA Study No. 3 (No 53 in biblio-graphy) from J Hoffer:

"The Task Force Report summary ofthe CMHA Study No 3 by Ramsay et'al (53) also gives a false representationof the actual findings On Page 15 the.Task Force Report states:

" From Study No 3: the overall;therapeutic efficacy of nicotinic acid as::an adjuvant medication in newly'admitted schizophrenic patients is in-ferior to the overall therapeutic efficacy;;of an inactive placebo

" In fact, the addition of nicotinic;'acid, in the dosage of 3,000 mg per day,;`to the regular phenothiazine treatment—1in a placebo-controlled six-months study"with 30 patients—prolonged the duration;of hospital stay and increased the=amount of neuroleptic medication refquired in treatment'

The results of this study," J Hofferconcluded, "do not show that patientslreceiving nicotinic acid were made worse;'because of it The difference in thee; ,average duration of hospital stays was;;not significant The difference in the;.average amounts of neuroleptic tran4"quilizers administered to the different`groups is of doubtful significance. The

is

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drugs were prescribed for more than halfthe duration of the study on the basis ofshort, outpatient interviews by residentpsychiatrists (psychiatrists in training)Even among experienced psychiatrists,the dosages of these drugs given to acuteschizophrenics are highly variable Thedosage of a tranquilizer drug prescribedfor a psychotic patient is a very crudeand very indirect indication of hisclinical status, and it can be influencedby a multitude of extraneous factors

"The direct and obvious method ofassessing the condition of patients is byobserving them If B3 had worsened thepatients, it would be detectable by aworsening of their symptoms In fact, itwas found that the B3-treated groupsimproved significantly The researchpaper states:

Of the three, the nicotinamide-treated groups showed statistically sign-ificant therapeutic improvement on moreindividual items (9) of the BPRS thaneither the nicotinic acid or the placebogroups; the latter two groups showedsignificant improvement on six and eightitems respectively (53).'

One may conclude that the B3-treated groups in this study did not, inthe overall assessment, improve morethan the control groups This has littlerelevance to orthomolecular therapy, inwhich 133 would not be used alone and insuch small dosages There is no evidencethat 133 worsened the condition of thepatients who were treated with it "

Contrary to the findings of an in-creased need for tranquilizers, Witten-born found no significant difference intranquilizer requirements, nor did he findany difference in the number of days inhospital Thus, Wittenborn demolishestwo of Ban's main criteria of improve-ment Ramsay et al. did not report anymean HOD scores, but did report meanMMPI scores (only 11 out of 30 were ableto complete MMPI) Half the groupcompleted the HOD Had they givenHOD scores perhaps some differencesmight have appeared Since as a rule theydowngraded positive responses, one isleft with the assumption there may have

been something there The fact that onlyhalf were able to do the HOD suggeststhese newly admitted patients were avery chronic group In Saskatchewanonly chronic patients incarcerated formany years had this low a completionrecord on the HOD test Acute andsubacute cases never had more than a 5percent rate of not being able tocomplete the HOD

CMHA Study No. 4 from J Hoffer:"The final CMHA collaborative study

was conducted on 30 chronic schizo-phrenic patients In this study one groupof patients was treated with 3 g ofnicotinic acid, one group with 3 g ofnicotinamide, and the third group wasgiven placebos The Task Force Report'ssummary of the results of the study is asfollows:

'From Study No. 4: the overalltherapeutic efficacy of nicotinic acid—in the dosage of 3,000 mg per day—as anadjuvant medication in chronicallyhospitalized schizophrenic patients isinferior to the overall therapeutic-efficacy of an inactive placebo In fact,in a one-year placebo-controlled studywith 30 patients, the active treatmentgroups fared worse than the placebogroup by all measures of assessment Theleast improvement and the greatestamount of deterioration was seen in thenicotinic acid group Moreover, it wasshown that patients in the placebo grouprequired less increase in their concomi-tant phenothiazine medication thanpatients in the two active treatmentgroups

"The actual published data shows thatevery statement in this summary is false.In the study, three methods of clinicalevaluation were used: the Clinical GlobalI mpression Scale (CGI), the NursesObservation Scale for Inpatient Evalua-tion (NOSIE), and the Brief PsychiatricRating Scale (BPRS) The patients wererated on these scales before the studybegan and after its conclusion, and theresults are these: the changes in all threeevaluation scales before and after treat-ment were insignificantly small for the

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patients in the two B3-treated groups andin the placebo group. There was noi mprovement and no deterioration in anygroup

"It is clear that a treatment of 3 g of B3per day did not benefit these chronicpatients This is a result to be expectedon the basis of the studies by Dr Hofferand Dr Osmond and by Dr. O'Reilly,who had already reported that chronicpatients, like the ones in this study, donot respond to 3 g of B3 alone At thesame time, contrary to the claims in theTask Force Report, there is absolutely noevidence that the administration of B3worsened the condition of the patientswho received it It can easily be shownthat the numerical variations in theclinical scales which were observed aresmall, random fluctuations which aredue to the inexactness of the evaluationmethods For example, on the CGI scale,the nicotinic acid-treated group wentfrom a pretreatment score of 4 1 down to3 9 after treatment, an improvement of0 2 points The placebo group went from4.2 down to 3 7—an-improvement of 0.5points The nicotinamide group alsoimproved by 0.5 points (4 7 to 4 2) Onthe basis of this the Task Force Reportstates that the nicotinic acid group'had the least improvement and thegreatest amount of deterioration ' Yet theCGI scale in this experiment is inexact bya minimum of 0 6 points; any change lessthan that is equivalent to no change atall The nicotinic acid group's 'improve-ment' by 0 2 points is not less than theplacebo and ni.cotinamide groups''i mprovement' of 0 5 points—all thesechanges are too small to have anysignificance

"The Task Force Report states: ' theactive treatment groups fared worse thanthe placebo group by all measures ofassessment ' This is false for the nicotin-amide group 'improved ' on the BPRS by1 3 points (improving from a pretreat-merit 45 9 to 44 6 after treatment), whilethe placebo group 'deteriorated ' by 1 6points (rising from 37.8 to 39 4).

"As it happens, BPRS was imprecise byat least 10 points, so these changes, too,are not significant The differences in the

average dosages of the tranquilizersadministered to the patients before andafter treatment were also insignificantlysmall There was no evidence that thepatients in the placebo group requiredless increase in their tranquilizer medica-tion than the B3-treated patients; thestatement to this effect in the Task ForceReport is wrong "

In APA Bibliography #56 Ban andLehmann also reported on 10 newlyadmitted patients (acute and subacute isgiven as a descriptive term, but no data isgiven on their chronicity) Three were onnicotinic acid, three on nicotinamide,and four on placebo In this study thenicotinic acid group required 164 mgtranquilizers/day and the placebo group259 mg per day However, they down-grade this by promptly pointing out theplacebo group had fewer days inhospital Neither of the indices has anyvalue in judging response to treatmentThere are too many clinical variables Inour own studies we never used durationof first treatment admission as acriterion, but we did use duration ofreadmission as a measure. Ban and !')4Lehmann studiously avoided this latterstatistic They can conclude, it wouldbe erroneous to amplify results of ourclinical trials with other negative reports'and to conclude that nicotinic acid hasno place in treatment of schizophrenic;patients" This was one of their few:correct statements, especially its first =part, based upon 10 patients in one study jand 30 in another Then they continuewith the meaningless and trivial state-ment, all one can say on the basis ofthese findings is that there is sufficient°evidence to suggest strongly that,nicotinic acid or nicotinamide is not the;treatment of choice for every schizo-;.phrenic patient under all possible;conditions and without any further'rl€€consideration " Is there any drug used for ::

any condition for which this statement,!would be untrue?

This statement was repeated by Dr JD Griffin, General Director, CanadianMental Health Association (ProgressReport 1) Since then and following hisretirement Mental Health Canada hasi

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changed its position and no longerofficially wishes to be involved in thecontinuing controversy

Study No. 7, from j Hoffer, page 26:"Study No 7 of the CMHA studies

by Ananth, Ban, and Lehmann, 1973, isentitled 'Potentiation of TherapeuticEffects of Nicotinic Acid by Pyridoxine inChronic Schizophrenics ' It was intendedin this experiment to test the finding oforthomolecular psychiatrists that B3 and136 (pyridoxine), when combined, havean enhanced effect in the treatment ofschizophrenia A 48-week double-blindstudy was conducted in which one groupof patients received nicotinic acid, onegroup pyridoxine, and a third groupreceived a combination of nicotinic acidand pyridoxine. All the patients werechronic schizophrenics The Task ForceReport summarized the results of thisstudy as follows (page 15):

" From Study No 7: the overalltherapeutic efficacy of combinedadministration of nicotinic acid andpyridoxine as an adjuvant medication inchronically hospitalized schizophrenicpatients is inferior to the overall thera-peutic efficacy of the component drugs '

"This summary is a completely in-accurate description of the actual find-ings in the study The results which wereactually obtained and reported in thepublished research paper were thefollowing:

" 'In this 48-week placebo-controlledstudy, the therapeutic effect of acombination of nicotinic acid andpyridoxine was compared with that oftreatment with either nicotinic acid orpyridoxine alone Of the three indices oftherapeutic effects, global improvementin psychopathology (BPRS and NOSIE)scores was seen in all three groups; thenumber of days of hospitalization duringthe period of the clinical study was lowerin both the nicotinic acid and thecombined treatment group; and only inthe combined treatment group was thedaily average dosage of phenothiazinemedication decreased. Thus, improve-ment in all three indices was noted in thecombined treatment group'

"And:" 'On balance, these results suggest

that the addition of pyridoxine maypotentiate the actions of nicotinic acid.Thus, pyridoxine seems to be a usefuladjunct to nicotinic acid therapy.' "

Study No.12, from john Hoffer, pages 24and 25:

"First, Study No 12, by Ananth, Ban,Lehmann et al is entitled, 'NicotinicAcid in the Prevention and Treatment ofArtificially Induced Psychopathology inSchizophrenics' (54) It consisted of astudy on chronic schizophrenics (PhaseIll) in which half the patients were givennicotinic acid in a dose of 3 g per day andhalf were given placebos, for two weeks.The neuroleptic tranquilizer therapywhich all the patients had been on waswithdrawn As might be expected, thepatients receiving placebos deterioratedsignificantly when the tranquil lizers werewithdrawn However, the patientsreceiving 3 g of B3 showed a markedstatistically significant improvement

"All the patients were then given verylarge doses of methionine, 20 g per day,along with their continued medication of3 g of B3 or placebos The hypothesistested in this experiment was thatmethionine, which has been shown toworsen the symptoms of schizophrenia,might exert this effect because it is amethyl group donor B3 , on the otherhand, is a methyl group acceptor. It washypothesized that the effectiveness of B3in schizophrenia results from thischaracteristic of the molecules of B3;that is, B3 might remove methyl groupsfrom some methylated compounds in thebody which could be causing the mentalillness

"After the administration of 20 g ofmethionine per day, all the patientsshowed a pronounced worsening of theirsymptoms The Task Force Report hasinterpreted this as showing that nicotinicacid does not neutralize the methyl-donating effect of methionine inworsening schizophrenia This con-clusion, however, is not justified,because there was a serious flaw jn theexperiment The patients were given 20 g

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of methionine per day, but only 3 g ofnicotinic acid Over 16 g of nicotinic acidis required to accept the methyl groupsdonated by 20 g of methionine. Theexperiment was bound to fail

"This flaw was acknowledged in theoriginal published research report as wellas in an official summary of it. The flaw isnot acknowledged or even mentioned inthe Task Force Report The only validfinding emer g ing from this study is thatB3 not only forestalled the deteriorationanticipated when tranquilizer medica-tion was withdrawn, but it produced asignificant improvement in the patientstreated with it This finding is notmentioned in the Task Force Report."

Methionine binds pyridoxine which isessential for the conversion of try-ptophan into coenzyme one, nicotin-amide adenine dinucleotide (NAD). Theinjurious effect of methionine is there-fore easily explainable It would bealmost a miracle if any quantity ofvitamin B3 could compensate for amethionine-induced pyridoxine deficien-cy

J. Hoffer therefore concluded (Page28):

"In summary, three of the five CMHAstudies provide evidence to support thefindings of orthomolecular psychiatry.The Task Force Report's description ofevery study is biased and misleading It isremarkable that the authors of the reportmake incorrect claims that B3 is worsethan a placebo, putting the mostnegative possible interpretation to someequivocal research findings, while noteven mentioning the research findingsthat showed B3 was of clear definitebenefit "

Recently, one of us (AH) criticized Ban(1975) for repeating his claim thatnicotinic acid did not protect patientsagainst toxic doses of methionine. In hisreply he produced a new objectionclaiming that patients on a combinationof nicotinic acid plus methionine and theamine oxidase inhibitor deterioratedmore The following letter was submittedto the Journal of Psychosomatics, butthey did not want to publish it as they did

not wish to continue the controversy.Apparently the editorial board believedthey had already given too much spaceto orthomolecular psychiatry.

"Sir:"In a recent reply to my letter, Ban

(1975) has retracted his earlier con-clusion 'Nicotinic acid failed to preventby prior administration or to relieve by `.subsequent administration the methio-nine-tranylcypromine-induced exacerba-tion of psychopathology' (Ananth et al.,1970, Canadian Psychiatric Association,15, 15-20, 1970) He had in the body of ftthis paper recognized that 3 g ofnicotinic acid was totally inadequate tocounteract any methyl-depleting effectwhich could be ascribed to methionine.But having recognized this he shouldhave concluded that his experiment wasirrelevant and trivial and added nothingwhatever one way or the other to anymethylation hypothesis However, Banfinds it very hard to admit he has erredand attacks the problem from anotherdirection Although this recent idea ofhis does not appear anywhere in his w

original paper, he now concludes that :nicotinic acid had a negative therapeuticeffect on the two toxic drugs he hadgiven his patients in large dosages '

It is interesting to read again hisoriginal paper This I urge every reader todo To help them follow the reasoning of )his earlier work I have subjected hispaper to a critical scientific look

In this paper, 20 chronic patients were iidivided into two groups of 10 each The:10 destined to receive nicotinic acid :

consisted of seven men and three,

women The control (placebo) group;consisted of three women and sevenmen This immediately shows that his,randomizations had broken down andthat the experiment no longer met therules of double-blind methodology Thewhole experiment should have beenscrubbed, especially by a group so keen;on methodology as Ban and his col -tleagues In effect the nicotinic acid;group were male and the placebo groupfemale

In his introduction he ascribed to us-

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incorrectly that we tested a hypothesisthat nicotinamide would prevent excessmethylation In fact, the hypothesis wetested was that the addition of vitaminB3 to the current treatment program(then ECT and psychotherapy) wouldimprove the outcome, and it did Wethen described a large number ofhypotheses to explain how it could work,and the methylation idea was one ofthem It was also one of our ideas(among a number of others) which led toour first pilot trials in 1953 Thesepreceded our double-blind experimentsin 1953 to which Ban makes noreference He leads the unwary reader tobelieve we did not do double blinds Wewere the first psychiatrists ever to dothem as is clear from our 1957 paper towhich Ban refers

Then Ananth et al (1970) claim theirexperiment was double blind It was notIt is impossible to double blind any studywith nicotinic acid as any physician whohas used it knows The initial dramaticflush usually (but not always) recedesand is seldom troublesome, but nearlyevery patient on maintenance medica-tion even for many years will flush nowand then, especially in the morning withthe first dose The flush is unmistakableby the flusher and anyone who sees itTherefore, it cannot be double blind Inour first experiment we used threetreatments, placebo, nicotinamide, andnicotinic acid in conjunction with ECT ifneeded and with psychotherapy No onein the unit knew that nicotinamide wasincluded and as it does not produce aflush it was not detected This, then, wasa true double blind

l3an is well aware of the fact that youcannot blind nicotinic acid because inhis first unpublished protocol he called ita semi-blind experiment No matter whathe called it, it was not blind, nor was anyevidence published that it was It isstrange that in studying the effect oftoxic quantities of methionine he did notuse a placebo comparison

After a two-week drug wash-outperiod, the male group were placed onnicotinic acid and the female group onplacebo Out of the male group (on

nicotinic acid) eight improved and twodeteriorated (P < 0 02) Out of the femalegroup six deteriorated and two improved(There is however some confusion sincethese figures do not agree with Table 3nor is it clear which scale is being used toevaluate response) (P < 0 05)

It is clear that in a group of mostlymale chronic schizophrenics whoneeded neuroleptic drugs all the time"

(quotation from Ananth et al ) nicotinicacid not only prevented a relapse, butproduced an improvement They had notreported for these patients on neuro-leptics only The placebo group deter-iorated as one would expect

For the next two weeks the entiregroup were placed on the amine oxidaseinhibitor tranylcypromine, 30 mg perclay But there is nothing in the report toindicate what happened to the patientsFor the next four weeks all the patientswere placed on 20 g of methionine perclay

But according to Ananth it wasmaintained for one week in six patientsand for two weeks in another four Thatis, half the group were dropped outbefore completing the four weeks Thismeans (also not mentioned by Ananth)that the same 10 were no longer on theamine oxidase inhibitor Nowhere isthere any indication which group, thenicotinic acid or placebo group, had thegreatest number of dropouts. Therefore,any meaningful evaluation is probablyi mpossible

The last period of four weeks theoriginal male nicotinic acid group wereswitched over to placebo while theoriginal placebo female group werestarted on nicotinic acid

In the female group (on nicotinic acidfor the first time) the deteriorationstarted by placebo at the beginning ofthe study and intensified by toxic dosesof methionine was not reversed bynicotinic acid

Seven patients continued to deter-iorate and three improved From theoriginal male group (on nicotinic acid)the original improvement caused bynicotinic acid and reversed by toxicdoses of methionine was not reversed by

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placebo These results are shown in thefollowing table taken from Ananth's ownresults:

worse no change better

a Patients originally onvitamin B3 and finally 6 1 3an placebo

b Patients originally onplacebo and finally on 7 0 3vitamin 03

It seems to me that these groups are notsignificantly different in terms of theirresponse to placebo and nicotinic acid

However, Ban writes, "Furthermore, itwas noted that after discontinuation ofboth tranylcypromine and methionineadministration there was deteriorationwith nicotinic acid and some improve-ment with placebo within a two-weekperiod " "It is this negative therapeuticeffect of nicotinic acid and not the lackof prevention of methionine-inducedexacerbations in schizophrenic patientsthat we keep on stressing, somethingwhich Dr Hoffer systematically andconsistently chooses to ignore "

In other words, Ban bases his entirecase on the fact that with nicotinic acid(given to the original female placebogroup), seven were made worse while inthe other group only six were made worseand one showed no change

Is there any reason why this findingshould not be ignored? Had the onepatient changed from none to deteriora-tion the results would have been identi-cal

Finally, Ban ignores the fact thatmethionine binds with pyridoxine andproduces a pyridoxine deficiency Thiswould be worse the longer patientsremained on the amino acid. Why wouldanyone expect vitamin B3 to compensatefor a vitamin B6 deficiency induced bymethionine?

Beaton et at (Biol. Psychiatry 10,45-52, 1975) found that methioninedecreased REM sleep in rats and micewhich was not reversed by nicotinamideTheir experiment suggests that meth-ionine does not increase methyl groups,but that the effect is due to a metabolite

30

of methionine-homocysteine We have,therefore, two possible ways by whichmethionine is toxic Yet Ban continues touse his early study as an argumentagainst vitamin B3 as a therapeutic agentfor schizophrenia.

The only reasonable conclusion fromhis entire paper is that it was poorlyconceived, badly executed, poorlyreported, and faulty in its conclusions.As I have said earlier, it is irrelevant andtrivial to the orthomolecular controversyand serves only those who refuse to readthe original papers pro and con and whoprefer to be led by authority and not byscholarship

The table on page 31 details thetreatment, patients, and indices ofchange used by Ban and Lehmann andthose we used

Yet the committee can write, "Thenegative findings in these carefullycontrolled studies are clearly at variancewith results claimed by megavitaminproponents " It would be surprisingindeed if the Ban-Lehmann studies couldhave come to any other conclusion since )?they used chronic patients mostly (evenif newly admitted) without ECT for thosefor whom it was indicated and did no „follow-up studies Had we done ouroriginal studies the way Ban-Lehmanndid we would have undoubtedly come totheir conclusions

It should also be made clear that eventhough they claim their studies were i,idouble blind (Ananth et at , 1973), it isimpossible to keep a patient on nicotinicacid unaware of the fact he flushes nowand then and equally impossible toprevent nurses or other staff from seeing.;the flush when it does occur They (realize they are on weak ground and ,most often refer to placebo-controlled `̀

studies, thus lulling the unwary readerinto believing these studies were double;:blind In our first double blind we used;nicotinamide as a hidden control, i e,;no one knew it was being used. In our;,:second study we did not use it, but toldeveryone we were including it Thus ourM'placebo and nicotinamide groups were:true double blinds and the second was;also by inference No attempt was madet;

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newly admittedmostly chronic

Study C3—30Study 14—30Study f1—30

psychiatric ward ingeneral hospital

previous treatment reported

treatment vitamin B3 plusECT as indicated

double blind withhidden control

vitamin B3 andtranquilizers

no hidden control. thereforenot double blind; originalplan used term semi-blind

criteria for improvement nl number times re- ttl duration of first treatmenthospitalization hospitalization

121 duration of re- 121 improvement in scaleshospitalization

131 clinical improvement 131 amount of tranquil izerused Per day

It

in these studies to make them reallydouble blind Finally, they presented noevidence that the code had not beenbroken by patients or staff, somethingsurely that no modern double-blindmethodologist would fail to do

In a recent report Ban and Lehmann(1975) caution physicians against the useof these dangerous vitamins invoking theHippocratic oath, primum non nocereThis is rather surprising when one readstheir report #12 wherein they showedthat schizophrenic patients who wereimproved by nicotinic acid were thengiven a combination of a monoamineoxidase inhibitor plus a toxic dose ofmethionine, 20 g per day, and so madeworse One wonders about the ethics ofworkers who in the name of scienceallow patients to be made worse whiletrying to frighten physicians away from avitamin considered safer than any tran-quilizer presently available. When werecall the cases of tardive dyskinesia,jaundice, incapacity to function,

obesity, and other toxic changes pro-duced by tranquilizers we are delightedwe have only to deal with a few cases ofnausea, flushing, and so on produced byvitamin B3 .

Claude Bernard emphasized in clinicalexperiments activities likely to harm andunlikely to help are by definitionexcluded In the Canadian experimentsof Lehmann and Ban this simplecondition was omitted and the omissionwas so flagrant as to throw doubt on thegood sense, the fairness, and even thehumanity of the experimenters Thisoccurred most obviously in the experi-ment where chlorpromazine was with-drawn and the patients were placed onniacin At the end of the period of thisphase of the investigation those onniacin had improved and those onplacebo had become worse. The ethicalexperimenter would then have giventhose on placebo niacin which wasexactly what we did in our second niacindouble-blind study Failure to do this was

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scientifically unsound for more infor-mation would have been gained this way,and morally inept What Lehmann andBan actually did was scientifically idioticand morally reprehensible. It is incon-ceivable that their mentally ill patientswould have agreed to their second stagehad they been in their right minds We donot believe their relatives would haveagreed and no legal guardian couldpossibly have consented If the CanadianMental Health Association associatesitself with such an experiment thenpublic support should be withdrawn.

What happened was this The patientswho had been improved by the minimal(3 g) doses of niacin even though theirtranquilizers had been withdrawn weregiven 20 g a day of methionine Therewas ample evidence that this amount ofmethionine made many schizophrenicsworse and there was none that any hadbeen benefited by it Under Bernard'srules it was a disallowed experimentHowever, as Linus Pauling hasemphasized even supposing one ignoresthe ethics of the experiment and canseparate them from its scientific valuethis was scientific nonsense The 3 g ofniacin were substituting very successfullyfor the withdrawn chlorpromazine, butthere was no reason to believe it couldpossibly cope with 20 g of methionine Itsays much for the ethical insensitivityand scientific obtuseness of the APA TaskForce that this reprehensible experimentseems to be well accepted by theircommittee

In their earlier reports Ban andLehmann were convinced that the in-ability of 3 g of niacin to reverse 20 g ofmethionine disproved a transmethylationhypothesis and so removed a theoreticalrationale for the efficacy of vitamin B3.They no longer follow this line ofreasoning, but maintain that the niacinaggravated the toxicity of methioninecompared to placebo An examination oftheir published data does not supporttheir conclusion There appears to belittle difference for methionine withtranylcypromine was toxic with or with-out niacin

There are several means by whichmethionine could make patients worse:(1) by binding pyridoxine and producinga deficiency of this vitamin, (2) byincreasing homocystine

Thus, Beaton et al (1975) found thatmethionine produced behavioral andsleep cycle disturbances in rats and micewhich were antagonized by I-serine butnot by I-histidine or nicotinamideApparently an increase in methyl groups :_`was not a factor In their experiments j.nicotinamide increased rapid eye move- `;ment sleep in contrast to methioninewhich decreased it

We still believe the transmethylationidea is worth examining although it islikely to be only one possible factor It ,was first proposed by Osmond andSmythies (1952) Kety (1967) was in-terested in this hypothesis, but it always `;seemed to bother him that no trans-methylation hypothesis can ignorevitamin B3 However, with a simplestroke of the pen, Ban and Lehmann

;,

(1975) have solved this problem for their;.colleague who is equally determined ''never to allow additional adequateclinical trials to be carried out by;establishment centers Ban et al state,'

In 1967 Kety formulated the trans-fmethylation hypothesis of schizophrenialjaby shifting the emphasis from the"psychotoxic compound produced byx'faulty transmethylation to the ' biochemical process itself " By this they;hope to entrench Kety as the originator,;of the transmethylation hypothesisHowever, to a biochemist, this statement!.by Ban is meaningless The object of any' ?biochemical reaction is the transforma-,tion of one molecule into another Only";a molecule can be harmful, not the=process of its formation

Pellagra, Schizophrenia, and theQuestion of NAD

The committee as usual finds that: `speculations offered in 1957 for themeaction of vitamin B3 are contradicted bya`other hypotheses considered 13 yearslater In fact, no one knows why vitaminn[33 works and this will remain unknownf

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until research in this area is greatlyexpanded

The argument that schizophrenia andpellagra are not identical is spuriousThere is a wide overlap Many pellagrinsin southern mental hospitals were con-fused with schizophrenia, and aroundthe turn of the last century the dif-ferential diagnosis included pellagra anddementia praecox This is reviewed in achapter in Orthomolecular Psychiatry(1973) which the committee did not read(at least they did not refer to it in theirlong polemic) See also Hoffer (1970)There is no doubt that pellagra producesa schizophrenic syndrome

The committee then zeros in on ournicotinamide adenine- dinucleotide(NAD) studies First, they point out nostudies have ever been published re-lating NAD blood levels to schizo-phrenia But they then fail to add that therelationship between blood NAD levelsand pellagra is not good There are twomain nucleotides: (1) the mononucleo-tides which are inactive as enzymes and(2) the dinucleotide In pellagra eventhough total nucleotides are in thenormal range, there is a significantincrease in the mononucleotide fractionThere are no studies showing how thesesubstances are distributed in schizo-phrenic red cells. Unpublished work byPhilpott (1973) does show that schizo-phrenic erythrocytes in many patients arelower and that a vitamin B3 treatmentimprovement coincided in time withrestoration of normal total nucleotidelevels We would expect that schizo-phrenic red cells contain too muchmononucleotides and too little of thedinucleotide, NAD This has yet to beexamined.

Secondly, they state that NAD cannotpenetrate into cells on a priori groundsMost scientists know that even the best apriori reasons must give way before thefacts Apparently, Ban was once aware ofthis since in 1970 he wrote, "In spite ofthe challenging theoretical considera-tions based on animal pharmacologicalstudies and Hoffer's (1966) positivetherapeutic results, the unsuccessful

attempts to replicate his findings haveresulted in a decrease of interest in thenicotinamide adenine dinucleotidequestion "

The NAD problem was brought into adifferent light, however, by the system-atic studies of Pfeiffer and his collabora-tors (1968) In combining the clinicalwith the electroencephalographicmethod, Pfeiffer and his group were ableto demonstrate that an enteric coatedNAD preparation does exhibit a thera-peutic action Pfeiffer et al 's (1968)findings indicate that the claims aboutthe clinical effectiveness of NAD therapyneed to be further investigated withcontemporary methods."

Recently, Liebow and Rothman (1975)reported that intact digestive enzymescan be absorbed by the intestine andresecreted by the pancreas. Theyspecifically studied chymotrypsinogen, avery large molecule, much larger thanNAD They further report that theintestinal epithelium is permeable to avariety of proteins and they list a numberof references for this observation begin-ning in the year 1958 If such a largemolecule can pass through the intestinalcell walls intact there is no reason whyNAD, a much smaller molecule, shouldnot pass through. And if it can passthrough into a cell there is every reasonto believe it can pass into other cells alsoas needed The problem is to place NADfar enough into the intestine to avoid theenzymes of the stomach and the upperpart of the small intestine This is whyspecial preparations must be used

Thirdly, they falsely state that the NADstudies we published were thoroughlyrefuted by several groups We will nowshow what we did and what these otherinvestigators did

Our StudiesWe used a number of acute and

chronic schizophrenics, not chronicpatients only as the committee statedOur exact words were, "In this studyNAD was given to a wide variety ofschizophrenic patients who had been illfrom six months to 30 years "

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This study was done at UniversityHospital, Department of Psychiatry,Saskatoon, Saskatchewan in 1966 Onepatient had been transferred from amental hospital, Miss A N., the rest wereeither inpatients or outpatients Nonehad been chronically incarcerated inmental hospitals even though they hadbeen ill for a long time

The NAD was a specially preparedenteric tablet in an oily medium Thecontents were designed not to bereleased for two—three hours after theywere swallowed We found that out of 18patients of whom six were muchimproved and two improved beforereceiving NAD, 11 became well in a fewweeks (some in a few days), three muchimproved, and four improved When weran out of supplies of NAD within a fewweeks all the patients reverted to theirearlier state Miss A N , as we reported,was remarkably improved and this waswitnessed by the psychiatrist who hadknown her best, Dr M. Herjanic As longas she was on NAD she remained wellWhen we ran out she relapsed There wasnever any improvement thereafter evenfor a day until she died in the mentalhospital a few years later

We thus used a specially preparedNAD on a variety of acute to chroniccases of whom only one had been achronic mental hospital schizophrenic

There were a few studies where the

Hoffer and Osmond

Preparation a special commercialpreparation

Patients acute and chronic. notchronically incarceratedin mental hospitals

In our report (1966) in reply to Kline wewrote, "Because NAD is hydrolyzedreadily by phosphatases in the digestivetract, NAD given orally probably will beinactive unless it is prepared in a specialform that will carry it into the intestine,where this destruction is minimized Inthe research reported in 'Enzymology ofHallucinogens' the material was sus-pended in a special vehicle and encap -

authors tried to test out NAD. The firstone was a study by Kline et al (1967)Kline used a number of chronic patientswho had been in the hospital for manyyears The committee convenientlyleaves the word chronic out even thoughKline had it in the title of his report. Klinealso used his own preparation of NADwhich was impure and which couldhardly have survived passage through thestomach Although the committeereferred to HOD tests, Kline, in fact, didnot accept the conclusions of the HODwhich showed that the four patients onNAD had marked decreases in HODparanoid, perception, and total scoreswhile four patients on placebo showedno decrease in HOD scores Pfeifferfound that Kline's preparation showedvery slight activity on the quantitativeEEG compared to our preparationGallant et al used the same NAD, but ashe stated used a group of chronicallyincarcerated patients The other three ifstudies are irrelevant since we did not useI V NAD Thus, it is clear that so far no }one has used the same two factors as we =`did, i.e , (1) a good preparation of NAD,(2) a group of acute and chronic caseswho had not been chronic inmates of i i

mental hospitals They were typicalpsychiatric ward patients commonlyadmitted to general hospitals in 1966

The differences in the studies areshown in the following table:

Kline Gallant

his own preparation same as Holler

chronic mental chronic mentalhospital patients hospital patients

sulated in a heavy enteric coat, Canadian}:.Patent #670, 909—1963 It was released;two to three hours after being swallowedEarlier studies by Enzomedic Labora Thiiii

had shown that this preparationrwas active in many patients when:unprotected NAD was not active

"Since 'Enzymology of Hallucinogens'iwas written, we have given 1 g doses,dissolved in water or placed in ordinary}

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capsules, to a schizophrenic patient whohad responded dramatically to theoriginal NAD; there was no clinicalresponse Then she was given 1 g per dayof the original NAD; once more sheresponded and remained very muchimproved for nearly six weeks when,there being no more NAD, she quicklyrelapsed and is still ill

"This difference may explain thefindings of Kline and co-workers whofound no response in 10 chronic schizo-phrenics They used NAD placed insi mple enteric capsules; in addition, itwas 70 percent pure and producedvasodilation (flush) in several cases,indicating that free nicotinic acid waspresent However, on the HOD test,completed by eight of their total group of20 (four on placebo, four on NAD), therewas no change in scores with placebo,but the HOD scores decreased as follows:

Paranoid scores 575 to 3 25Perception scores 14 to 1.75Total scores 63 to40

"It is not possible, therefore, todetermine whether their lack of clinicalresponse was due to a form of NAD thatdid not survive passage in the gut, orwhether they used too little, or whether itwas due to the chronicity of theirsubjects All of our series of 17 werechronic, but only one had been severelyinjured by many years of continuoushospital treatment "

The committee apparently did not readthis addendum

Finally, the committee finds it interest-ing no additional studies have beenreported This is due to the fact we havebeen unable to obtain any more NADThe Kline report effectively killed anyinterest that drug companies might havehad and none have been willing to investlarge sums of money in any furtherstudies If and when we obtain moresupplies we will be the first to renew ourstudies We found it less interesting andmore annoying.

However, whether or not NAD isfinally established as a therapeutic agent

is of little relevance to the pragmaticquestion, does vitamin 133 work. It is ofimmense theoretical significance, butnot of practical value in the megavitaminB3 debate NAD is not nicotinic acid ornicotinamicle even though many psy-chiatrists are not aware they are dif-ferent

The Diagnosis of SchizophreniaIt is not unusual for psychiatrists to

play the diagnostic game if this will savetheir own hypothesis This is a problemwe have encountered since we began ourresearch. In 1953 one of the patientsadmitted into our double-blind control-led experiment was screened in the usualway His psychiatrist diagnosed him to beparanoid schizophrenic and this was inagreement with the clinical director AHas Director of Research also concurredAfter two weeks on medica-tion he was nearly well whereupon hispsychiatrist maintained that sinceschizophrenics cannot recover so quicklyhe was not schizophrenic As a result hedid not follow medication at home andsoon relapsed to be admitted in anacutely paranoid psychotic state re-quiring a series of ECT plus nicotinicacid On decoding we found he had beenon nicotinic acid He remained well for13 years with no medication, relapsedand required two further admissions aftera near-fatal suicide attempt On vitaminf33 he recovered in 1966 and hasremained well ever since. Time sub-sequently removed all doubt aboutdiagnosis.

Recently a recovered schizophrenic onvitamin therapy applied to an eastern IvyLeague medical school He honestlydescribed his illness and recovery fullyexpecting he would not be accepted Tohis surprise he was. The admittingcommittee told him that since schizo-phrenics never recover he could not havebeen schizophrenic This is the game—ifyou recover you obviously have not beenschizophrenic The committee plays thisgame well Wittenborn had such acareful screening system that a fewpatients believed to be schizophrenicwere later rejected Later from this

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purified group he found 24 who as agroup did respond well (half on placebogot worse on tranquilizers), but sincethey did do well he assumes they couldnot be schizophrenic, following thecommittee rule, "if you recover you arenot schizophrenic "

At the bottom of Page 24 thecommittee repeats its false assertion thatCMHA studies were negative We will notrepeat the counter claims which havealready been discussed.

The second paragraph of Page 25 is atotally misleading account of our workThis would have been obvious to anyonewho has consistently and accurately readour reports Our criteria for diagnosishave consistently remained that used bymost psychiatrists The HOD test wasalways an adjunct, never primary Wehave not run any more double blindsbecause having directed four of themthere comes a point where furtherrepetition is wasteful of time and moneyand does not convince One properly rundouble blind which truly reproduced ouroriginal double blinds by Ban andLehmann would have been morevaluable than a dozen double blinds runby us We have never depended uponeither HOD or mauve factor for any ofour double-blind experiments In fact,our first two were completed before themauve factor was discovered and theHOD test developed

The committee then devotes Pages 25to 35 to discussing the HOD which isgratifying as it may arouse interest in ourtest (as it has already done), but is acomplete waste of space since we did notdo HOD testing in any of our double-blind experiments

There are, however, a number of falseassertions about the HOD test such as thestatement it has never been studied forvalidity and reliability Each test kitcontains a manual which carefullydescribes these aspects of the test. Over3,000 test kits have been sold, butapparently not to any member of thecommittee Had they inquired from uswe would have advised them of thepresence of this data They referred toone negative report by Stewart and

Mahood (1963), but did not bother torefer to a subsequent paper when thei ;f+errors and inconsistencies of this paper:;were discussed (Kelm et al , 1965)

As with so much of the committee's ;'Ireport there was a rigorous avoidance ofa searching analysis of all the HODreports The fact that they were able tosfind only one negative report compared 4to over one dozen positive reportsindicates that there has been a rather=widespread use of this simple test

The mauve factor work is reported inan equally biased way In our first papers

z

we reported that the presence of mauve=factor cut across all diagnostic groups,;.=!but the committee tries to leave the::„impression we claimed it as a diagnostic;test invariably related to schizophreniaThus, it is not surprising that "otherworkers (90) (O'Reilly et al ) found themauve factor to appear across diagnostic;':classes " O'Reilly was our colleague andunder our direction set up the laboratory"'to run mauve factor assays at his;.,hospital

The committee's basic premise seems:to be that none of the orthomolecularresearch is of any value Therefore, they"grasp at any research, no matter how;badly done, which supports theirand they call upon any theoretical idea?:no matter how wild which supports;'them This they have done with their'brief examination of the mauve factor re-22search They ignored all the work;reported from Dr Carl Pfeiffer's laborattory relating mauve factor (kryptopyr'role) to loss of pyridoxine and zinc

None of the early workers with mauve=factor had suggested that it was an'=iendogenous hallucinogen because it hadnot been tested The committee antici ' `pated such a conclusion and on a priorBigrounds concluded it was quite unlikely`,it had this kind of activity They also,based this on' Sohler's findings, that it,sedated rabbits This is another example;of the committee ' s propensity to seizeyupon observations to bolster their own, , 'preconceived conclusions RecentlyrWalker (1975) concluded that "kryptop-'yrrole decreased EEG voltage, disrupted`=..synchronization and induced abnormal;

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spiking at a variety of cortical andsubcortical sites Intermittent periodsand low frequency hypersynchronousEEG activity were consistently elicited bykryptopyrrole These waves bear aresemblance to the hypersynchronousEEG pattern associated with hallucina-tory agents such as LSD-25 Markedbehavioral alterations were observedfollowing the initial injection includingataxia, hyperventilation, locomotordepression, and catalepsy Kryptopyrrofecauses major central nervous systemdysfunction and these findings arediscussed in the context of a drug-induced model of psychoses "

In his final paragraph Walker con-cluded, "Hoffer and Osmond haveproposed that mauve factor nowbelieved to be kryptopyrrole representsa metabolic anomaly that is associated inan etiological fashion with certainpsychiatric conditions, particularlyschizophrenia They maintain that thedisappearance of this biochemicalanomaly is statistically associated withpsychiatric improvement The results ofthe present study strengthen the Hoffer-Osmond hypothesis by demonstratingthat the introduction of kryptopyrroleinto the mammalian body is behaviorallyand electrophysiologically disruptive.The abnormal behavioral reactions andEEG patterns associated with kryptopyr-role provided evidence that this com-pound has a serious detrimental effect onnormal brain function "

This report by Walker effectivelydemolishes the committee's speculationthat kryptopyrrole could not be anendogenous hallucinogen It has, so far,not been tested on humans, but in viewof Walker's report we doubt whethermembers of the committee will berushing out to try it out on themselvesWe trust that after digesting our ob-jections to the methionine study they willnot be tempted to use it on unsuspectingpatients

This statement on Page 35 is a typicalcommittee falsehood: "Although theevidence suggests that both mauve testas employed by Hoffer and the HOD testare not reliable for the diagnosis of

schizophrenia these are nonetheless usedalong with unspecified clinical criteriafor the diagnosis of this illness, theinitiation of treatment and the assess-ment of improvement " Each reader willhave to determine the accuracy of theseconflicting views by reading the litera-ture. There is no substitute for readingthe literature oneself

On Page 36 there is another typicalmisstatement Before modified ECT cameinto general use we did use ECT as dideveryone else, unmodified, but when itcame into general use it became part ofthe entire orthomolecular program

Quantitative AspectsThe arguments in the last paragraph

Page 40 and in the first paragraph Page 41have been effectively answered byPauling (1974)

Their discussion on toxicity is bizarreto say the least. If the committee hadfound real evidence for toxicity theywould have shouted it to high heavenHad they treated the toxicity of anycommonly used tranquilizer in the sameway they would be ethically bound to tryand force it off the market j Hoffer hasadequately replied to their biasedreporting It is important to rememberthat as codiscoverers in 1954 of thehypolipidemic properties of nicotinicacid we have had more experience thanany other physician with the potentialside effects and toxic reactions The firstreviews of these aspects were ours,appearing long before any member of thecommittee was even aware of ourvitamin B3 work (see Hoffer, 1962)

ConclusionsOur criticism of the committee and

their report is that: (1) The committeewas in composition biased, failing tocontain anyone who was familiar bypersonal experience with orthomoleculartherapy Not only was the compositionincompatible with fairness, it could notpossibly even seem to be fair (2) Theprocedure used by the committee failedto insure any objectivity or fairness for:(i) they did not obtain any evidence fromanyone using orthomolecular therapy;

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(ii) they selectively examined the litera-ture using the rule that any double-blindstudy or allegedly double-blind study(even if it were not like the Witten-born and Ban studies) was evidence if ityielded negative results while converselyno clinical study if positive wasscientific The four original double-blindstudies from Saskatchewan were suspectsince we did them, so were not evidence;(iii) the report is characterized byfalsehoods, direct and by inference, bybiased statements, by use of briefsentences taken out of context, byomissions which always favored thecommittee's view; (iv) the report waswritten in order to bolster the com-mittee's negative conclusion

Unfortunately, the committee wascorrect in their assumption that mostpsychiatrists who read their report wouldaccept it at face value and would notcheck their references The report hashad a pernicious effect in dampeninginterest in orthomolecular psychiatryWhile this will not hurt any ortho-molecular psychiatrists it will condemnhundreds of thousands of patients to alifetime of tranquilized chronicity

Fortunately, the number of ortho-molecular physicians is increasingrapidly while the families of schizo-phrenics become increasingly knowled-geable about the illness and critical ofthe Establishment's posture

Community psychiatry, which isessentially an expensive system fordelivering tranquilizers to chronicpatients in various shelters, is comingmore and more into disfavor Psychia-trists are sinking lower and lower in bothpublic esteem and in the esteem of theirnonpsychiatric medical colleagues Theprinting and distribution by APA of areport so bigoted and biased as the TaskForce Report can serve only to drive thepsychiatric profession lower in publicesteem

In a recent editorial in the CanadianPsychiatric Association journal W T B.(1975) after summarizing the pros andcons of orthomolecular therapy con-cluded: (1) Nicotinic acid or nicotin-

38

amide when used as an adjunct toconventional therapies such as bar-biturates and ECT as reported earlier byHoffer may have a beneficial effect in thetreatment of some patients sufferingfrom acute early schizophrenia As far asis known, no attempt has been made toduplicate these earlier studies (2) Mega-vitamin therapy has not been demon-strated to be generally efficacious in thetreatment of the vast majority of chronicschizophrenic patients.

He concludes, "Orthomolecular psy-chiatrists should be invited to return tothe forum of conventional psychiatry inorder that they might be given audienceTheir articles should be submitted toconventional journals and should bereceived with the same enthusiasm andcordiality as other submissions, providedthe general criteria of the journal aremet "

This is the first comment in anypsychiatric journal where an attempt ismade to be fair The editorial writer is notfully aware of the degree of misinforma-tion and bias in the committee's report,but he has achieved adequate awarenessto reject the committee's conclusions

Controversy is part of the history ofmedicine and is essential to it if medicineis to continue to advance There willalways be an establishment of ideas, 'some of which will eventually be provenwrong Thus, there will always be acontroversy affecting various parts ofmedicine However, worthwhile thoughit is, there would be a lot less emotionalcontroversy if physicians followed the1basic rule of science, i e , follow thesame procedures and conditions when:attempting to corroborate If this rule;were rigorously followed it would not,matter whether the scientist was positiveor negative about the study But since{this rule is seldom followed it does:matter a good deal If the investigator,has a negative bias toward the originalwork he will conduct his studies in such a'>Dway as to maximize the negative con-clusions and will then discontinue them.tThere are many examples of this from thereports of hostile anti-orthomolecular

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psychiatrists. If they had run their studiesmore scientifically and longer they wouldhave run the risk of seeing positiveconclusions. A scientist with a positivebias may make the same error But ingeneral the error of the negatively biasedpsychiatrist is much more serious In ouropinion the failure to use a treatmentwhich is beneficial is much more seriousto patients than the error of concludingthat a nonactive drug is active For in thelatter case it will soon be shown that thetreatment is ineffective, especially if ithas to compete with other more usefultreatments Destroying a useful treat-ment by sloppy hostile research mayprevent its reintroduction for severaldecades This would insure that largenumbers of patients will have lost theirchance and will be condemned to alifetime of unnecessary ill health

Moss recently (1975) was severelycritical of the UGDP studies on tolbut-amide The results from these double-blind controlled studies indicated thattolbutamide was more hazardous thanplacebo for diabetic patients But Moss isin total disagreement with this con-clusion writing, "No amount of statisticalmanipulation can compensate for theerroneous conclusions that are drawnfrom a study in which one-quarter didnot have the disease, three-quartersshould not have been given the drug, thewrong dose was used and the treatedgroup had twice as much pre-existingcardiovascular diseases " "The value ofany therapeutic agent should be judgedby the benefits that are obtained when itis used properly and not by the harm thatresults when it is used indiscriminately "

Moss pointed out that 23 8 percent ofthe treated sample did not have diabetesaccording to standard criteria, 54 percenthad fasting glucose levels under 130 mgpercent and did not require tolbutamide,50 percent were more than 33 percentoverweight and should have been treatedby a lower calorie diet Only 27 percentof the entire group were proper can-didates for tolbutamide treatment Thedose was constant whereas it is generallyaccepted it should be increased withtime, and base line cardiac risk factors

were twice as high in the treated groupTwenty-five percent of the treated

group had abnormal ECG while only 4percent of the control group showedsimilar abnormalities.

To dramatize his objections Dr Mossposed a number of questions:1 How can one evaluate treatment inpatients who do not have the disease?2 How can one evaluate a drug if only46 percent of the group have hyper-glycemia?3 How can one evaluate a drug ifone-half should not have been given it?4 How can one evaluate a drug whenthe wrong doses are given?

Our objections to the negative thera-peutic trials upon which the committeeleaned so heavily are the same How canone evaluate the benefits of a drug (or ofa treatment program) when only a smallproportion of the groups used were of thekind that could respond, when thetreatment program was not followed, andwhen idiosyncratic criteria for improve-ment were used such as milligrams oftranquilizers required and number ofdays in hospital during which treatmentwas started

Another controversy, this time in-volving the drug propranol, aroused Dr.Lasagna to write, "Some (speaking of theFDA advisory committee) appear tohave gotten hung up on the concept ofthe totally satisfactory paper! The onlytotally satisfactory papers are fraudulent..Every experiment has deficiencies andthe problem is to decide whether thedeficiencies are so great as to render theexperiment totally useless "

The committee has demanded that ourexperiments must be totally satisfactory,but have for obvious reasons notfollowed the same impossible rule fortheir own favorite papers

They are unaware of Dr SamuelJohnson's rule, "nothing will ever beattempted if all possible objections mustfirst be overcome " They demand of usthat our first double-blind experimentsstarted in 1953 should have anticipatedall the newer findings and complicationsdiscovered many years later

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The last controversy concerns DMSO,recently discussed at the third DMSOconference, New York Academy ofSciences, 1974 (see annals New YorkAcademy of Sciences, 1975) On thebasis of flimsy evidence the FDA literallybanned the use of DMSO Arthur LScherbel in his summary of the con-ference stated, "This new policy resultedin the abrupt discontinuation of clinicalinvestigations of DMSO because of theappearance of lens changes in certainanimals that were receiving high doses ofDMSO This decision was made despitethe fact that no eye changes had beenreported in humans receiving DMSO

Among the suggestions he made were"a consulting committee should beappointed by the Food and Drug Admin-istration to evaluate future scientific datapertaining to DMSO At least 50 percentof the members of this committee shouldhave personal scientific knowledge ofDMSO and experience in using it "

Like nicotinic acid, DMSO cannot bedouble blinded Thus Kantor (samevolume) wrote, "as has been pointed outon many occasions, certain biologicalcharacteristics of dimethyl sulfoxidealmost precluded a double-blind study ofits therapeutic effectiveness in manAlmost without exception when it isapplied in concentrations above 10percent to the human skin, there is aburning, stinging sensation and afterpercutaneous absorption, a metabolismto various sulfides These latter appearon the breath; they have a distinctivegarlicky odor True double-blind studiesmay be impossible "

It is our hope that a critical reader whohas followed this narrative and perusedthe appendices will now be in a positionto ask himself those very questions whichit was the duty of the APA Task Force tohave addressed themselves to, about fiveyears ago

The data represented here is of severalkinds and requires thoughtful consider-ation

First of all there are the originaldouble-blind studies undertaken in Sask-atchewan of which there are fourdifferent series: (1) the original study

done at Munroe Wing, (2) a group ofstudies undertaken at the UniversityHospital, (3) Dr O'Reilly's study done atthe mental hospital at North Battleford,(4) Dr Denson's study at North Battle-ford In addition to this, there is a greatdeal of clinical data from clinicians whohave used our approach for several tensof thousands of patients This data is noless important than the double-blindstudies on the grounds of sheer volumealone The belief that double-blind "'studies alone are valuable is held by thenaive, whose knowledge of scientifichistory and methodology is usually <M'

limited and sometimes nonexistent Aswe have shown, many authorities doubt 4

whether the double-blind studies yieldthe kind of information required and '`some believe that they are unethical Aswe shall see, this ethical impropriety hasplayed an important part in the work ofsome of our critics who have tried toreproduce our studies

It seems unlikely that there are anysure-fire scientific methodologies whichwhen properly done are error proof:double-blind studies undoubtedly have a:place, but are not a substitute for clinicalstudies and as a number of authoritieshave emphasized,. clinical studies haveprecedence over double-blind studies Aswe pointed out many years ago, double-blind stuclies, by depriving the patients ofinformation, greatly reduce their interesin and tolerance of a new treatment, thuencouraging errors of the second sor(Hoffer and Osmond, 1961, 1963).

It would seem unwise to begin double-blind studies before one has becomethoroughly acquainted with the use ofthe treatment one is studying Indeed, iis probably not merely unwise but -unethical, because one would knowrtnothing about the possible complica 5'tions In retrospect it appears that ours'initial work in' Saskatchewan may have;erred in this direction However, sinceT ;we continued to do normal clinical=sstudies while at the same time under. '

taking the double-blind ones, we avoidederrors that seemed to have been com L.

mitted both by Ban and Lehmann at,

McGill and by Wittenborn and his

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colleagues in New jerseyPatients are unlikely to participate

freely and willingly in the experimentsunless they believe that those who aredoing them have some faith in what theytare doing Such faith can only beobtained by learning to use a particularinstrument and finding out whether itworks or not It seems likely that ifsomething does not work for a particularinvestigator in clinical studies he wouldbe well advised not to pursue the matterany further. Dr DeLiz (1973) reports thatin the Marlboro study the negative biasagainst the use of niacin was so obviousthat patients took matters into their ownhands and went out to get the vitamin forthemselves. When we first heard of thiswe thought it was an unprecedentedevent, but Dr Shapiro's (Blumenthal etal , 1974) recent findings suggest thatperhaps few double-blind studies escapethis pitfall Patients do not like beinghoodwinked about serious mattersRevelations about the ways of experi-menters over the last decade or so haveseeped through to patients so that wehave heard them say, "then they slippedme a placebo " Science doctors in theirzeal to obtain a sure-fire method ofeliminating bias have simply producedother biases which may be of an evenmore serious kind

In the New jersey studies, for instance,the loss of patient cooperation and trustresulted in patients deliberately breakingthe double blind Apparently this was notseen as very serious because theexperimenters themselves had alreadybroken the double blind due to a peculiarskin condition which seems almostidiosyncratic to New jersey In the Newjersey studies, then, we know that in atleast nine cases the double blind wasbroken, more than 10 percent of thesample Nevertheless, the APA con-tinues to refer to this study as a double-blind study and to puff it with thisfavorable adjective It is nothing of thekind Double-blind studies are likeCaesar's wife, if they are to maintain theirreputation they must be above suspicion.Arthur Shapiro's work suggests that noneare above suspicion, but the New jersey

study was not merely suspicious, butunequivocally broken, according tothose who participated in it There weremany other objections, too, not the leastbeing the small dosage of niacin used,the chronicity of the patients, and thebiased sample—those on niacin hadbeen ill patients 50 percent longer, 58months as against 36 months Neverthe-less, in spite of this, there is evidencethat at least a third of the patientsbenefited in a differential way showingthat for them, niacin had valuableproperties In order to explain thisunwelcome development the Task Forcemembers had the gall to suggest thatthese patients were not truly "schizo-phrenic " This gives the game away Ifyou benefit with niacin, then you are nottruly schizophrenic This is the kind ofscience which the Task Force re-commends to the public This is ashelpful as Kraepelin's view that onlythose who deteriorated completely weretruly schizophrenic According to thosewho did the New jersey study aboutone-third of the patients studied were notschizophrenic because they respondedwell to niacin The question must beasked, how then do we know that any ofthe New jersey patients were schizo-phrenic?

The New jersey study, then, was one ofthose half million dollar flops with whichNIMH has, from time to time, distressedeven its loyalist supporters: whether thisshould be ascribed to bias or in-competence depends upon the evalua-tor's bias Was it worth so huge a sum ofmoney? Indeed, one of us with acolleague whose reputation as a psycho-pharmacologist is widely admired hadbeen prepared to do a similar study for amodest eight thousand dollars someyears before

While the New jersey studies areunusually expensive those north of theborder in Montreal, undertaken byDoctors Lehmann and Ban, were on amore modest scale, but once againexhibit certain curious features. There isno evidence that Dr Ban, who seems tohave been most responsible for theseclinical testings, ever attempted to learn

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how to use megavitamins in the acceptedway by the late 1960s when he began hisexperiments As we have noted, Dr Ban'sexperiments are criticizable on manydifferent levels It was objectionable andimproper that he was allowed to doubleup as a critic and an experimenter andthat he failed to meet undertakings suchas his pledge not to discuss these mattersuntil his experiments had been comp-leted Such actions throw some doubtupon his good faith and make itnecessary to scrutinize his work verycarefully Since this work has beenendorsed by the American PsychiatricAssociation, the Canadian PsychiatricAssociation, and the Canadian MentalHealth Association, their good faith andjudgment must be measured by whatthey have endorsed We have shown thatthere are many technical objections Theevidence is that in one experiment atleast, the experimenters acted with adisregard for the well-being of theirpatients or subjects It is staggering tothink that in the 1970s two reputablemedical associations would stake theirreputations on an experimenter whoseactions in any other context one hopesthey would have condemned

However, before paying attention tothis abominable experiment and theimplication which is attached to it, it isimportant to recognize that few, if any,of the Ban-Lehmann experiments appearto have been double blind In the NewJersey experiments these studies weresupposedly double blind, but as we havenoted, great doubt can be thrown upontheir authenticity since both Dr. Witten-born and Dr DeLiz say that one way oranother a substantial proportion of thosetaking niacin were decoded before theending of the experiment Although itnow appears that very few double-blindstudies are double blind, there is noexcuse for misleading the public, par-icularly when self-praising remarks about' well-controlled double-blind experi-ments" are made by those who shouldknow that these experiments cannot bedescribed in this way In most circum-stances, conduct of this kind is referredto as lying White lies perhaps in a good

42

cause, but lies all the same Those whoclaim to be undertaking confirmatorystudies in matters which affect thewell-being of thousands of patients mustnot be surprised if even such minordeceits as these are brought to thepublic's attention Public money hasbeen spent on these matters, and thepublic has a right to know how well itssupposed guardians have been acting Ifthe guardians acted dubiously over thedouble-blind studies and if, as ProfessorPauling has pointed out, some of theconclusions are sufficiently skewed as tomake one suppose that bias was in-volved, then the public must judge foritself.

But at least one experiment to whichthe American Psychiatric Association,the Canadian Psychiatric Association,and the Canadian Mental Health Assoc-iation have given their approval isunethical, and incompetent, grosslyincompetent In this experiment, Dr Banstates that he withdrew chlorpromazinefrom a group of schizophrenic patientswho had been on it for some time Thesepatients were then given 3 g of niacin per ?

head Another group of patients had thechlorpromazine withdrawn and weregiven a placebo Those on the placebogot worse as one might expect, but those ='-given the niacin not only did not get;worse, the evidence suggests they became rather better This is a most„encouraging finding, particularly today ,when we need to be able to reduce the 1 ?long-term use of chlorpromazine and;i i

si milar phenothiazines as much as;'possible because of tardive dyskinesias aimutisms, and other damaging neurological conditions, which occur mostoften in those who have been on thesesubstances a long time So far; then,there is nothing wrong with this experi-client; indeed it shows that niacin had '

some unexpected uses for chronic rpatients An alert and intelligent clinicalexperimenter would have pursued this_ `lead

It was at this point that Doctors Bang`and Lehmann introduced a new element;which was both scientifically absurd and i

ethically dubious Those who had beenxf

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removed from chlorpromazine and werebeing well supported and even improvedby niacin were then given 20 g ofmethionine per head Not unexpectedlythey became very unwell Dr Ban andDr Lehmann stated that this showed thatniacin did not prevent transmethylationeffects of methionine When DrLehmann was asked about this byProfessor Pauling, at an NIMH meeting,he apparently did not realize how inepthe and his colleagues had been Threegrams of niacin could not possibly beexpected to counteract the effects of 20 gof methionine in addition to preventingthe recurrence of symptoms after stop-ping chlorpromazine At best one can saythat to plunge patients, who had beenimproving somewhat on niacin, backinto madness, which could not possiblyhelp them, and from Doctors Ban andLehmann's account gravely harmedthem, is the kind of unethical experimentwhich since the Nuremberg DoctorsTrials has been universally condemned

If the American Psychiatric Associa-tion, the Canadian Psychiatric Associa-tion, and the Canadian Mental HealthAssociation are so indiscriminating in thekind of experiments which they supportand which they use to discredit ortho-molecular psychiatry, then surely we canhardly be surprised that psychiatry itselfis, according to its leaders, in a state ofconfusion

Confusion is often thought to be one ofintellectual confusion, due to modelmuddles But in this case, moral andethical confusion has been demon-strated, and it is that moral and ethicalconfusion which has fuelled much of theattack on megavitamins and has resultedin otherwise competent people under-taking experiments in a curious waywhich they would condemn in their ownpupils, and would attack most vigorouslyhad orthomolecular psychiatrists beenequally slack and heartless

In recent years political and scientificestablishments have acted as if theybelieved that they were above the lawand above scrutiny As regards politics,this is now becoming unacceptable andwe must hope that the same will apply to

medical and scientific establishmentsPsychiatry, with its knowledge of in-builthuman biases, ought to be particularlysensitive in'this respect; unfortunately,as this report shows, there is no evidencethat our colleagues have succeeded inavoiding those biases which they wouldbe the first to condemn in others

It appears to us that the currentuncertainties and misfortunes in psy-chiatry have been amply documented byits leaders, including Dr John Spiegel,APA President in 1975 We believe thatthese uncertainties resulted in a vigorousand indeed vicious attack on ortho-molecular psychiatry This, no doubt,serves to work off the anxiety andhostility generated by current frustrationsfaced by the psychiatric establishment Itis like kicking the cat or bawling at thechildren because one feels upset and badtempered There is no reason to dignify itwith any of those fine long words whichmake it sound more respectable This is atechnique that Hitler employed regu-larly, and it explains such behavior but itdoes not excuse it. Publicly recognizedassociations of professional people havea duty to examine and correct their ownbiases Failure to do so is especiallyreprehensible among psychiatrists be-cause they claim that this is one of theuseful functions they perform for society.The public may very well ask, who willguard the guardians?

Their GoalWe had President Busse's personal

assurance that the Task Force as well asthe Council was composed of highlyqualified psychiatrists who were familiarwith the scientific method and werecapable of evaluating published litera-ture The reader will judge whether Dr13usse's evaluation and expectations werecorrect We agree that the Task Forcecould have accomplished this task, butthey did not do so Perhaps one day theprofessionals involved in this debate willask themselves why this particular kindof mistake was made and how it can beavoided in future.

The bias of three members of thecommittee was so open that one of us,

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AH, objected vigorously at the beginningof the survey The first evidence of thiswas Dr Morris Lipton's lecture inCalifornia at a public meeting where heopenly stated his strong opposition andbias against the orthomolecular ap-proach He also demanded that thechairman, Dr. Ross MacLean, providehim with more time than was allotted tohim or to anyone else, because he wasthe only critic of orthomolecularpsychiatry

Since three of the five Task Forcemembers made no attempt to hide theirbias against orthomolecular psychiatry,this raises serious questions about theconduct of the American PsychiatricAssociation itself. How could a profes-sional and scientific body allow aninquiry, conducted under its aegis, to beundertaken in a manner which in anyother circumstances it would havecertainly condemned? Would the APAcountenance an investigation of psycho-analysis or community psychiatry using atask force the majority of whosemembers were openly prejudiced againstthese activities? Would the APA attachany importance to the findings of such acommittee, and would anybody besurprised if psychoanalysts and com-munity psychiatrists were unwilling toaccept such a report?

Why then did this Task Force and thosewho appointed it behave in a way whichwas clearly open to criticism and evencensure? It would be poor taste to subjectour colleagues on the Task Force to thatpersonal psychodynamic scrutiny whichSenator Goldwater received about adecade ago from some hundreds of APAmembers However peculiar theseactivities may appear when set out inprint we do not ascribe them either topersonal psychopathology or to badfaith There is no need to when threecommittee members have never deniedtheir bias

Lipton did not reply to a letteraccusing him of being prejudiced andrequesting that he remove himself fromhis position of Chairman Mosher wasquite explicit about his point of viewThe reader can judge for himself whether

his is the stance of an unbiased manWhy then did the American PsychiatricAssociation show such faith in the lack of ,prejudice of those who had not con-cealed their prejudice?

Where important matters are con-cerned even the faintest suspicion of biasis usually sufficient to disqualify thosecharged with fair judgment We infer'from the absence of these customary;safeguards that the main objective of the"Task Force was to defend the establish-ment against our disturbing opinions Asecond and more respectable objectivewas to protect the public against false:hopes and mistaken expectations, formany members of the establishment hadbecome convinced from their deepknowledge of psychiatry that the ortho-molecular claims must be without merit.:Any group with such good ends in mind'>might behave much as the APA did, but,however praiseworthy their intentions,?actions of this kind have been a frequentsource of error in medicine These good!'intentions made the means to be used oflesser importance, so that the APA°establishment became unable to adopt a `.judicial stance other than that of judge :

LynchHowever honorable the goal the mean

employed negated all favorable reports'found in the orthomolecular literature:and led the Task Force to ignore any'supporting evidence even when it'derived, as with Wittenborn, from experiments approved by the committee Howcould this happen? In our opinion the;`:most economic explanation lies in the;,atmosphere and ambiance of Washings;''ton during the early 1970 ' s ='

It is now evident that at few times inthe history of the United States havethose in authority believed more sincere-ly that this gave them license to use any'means to further ends self-evidently'good Bad habits in big governments]spread to little governments The;American Psychiatric Association is the'"little government " of psychiatry in the'U S A In this matter the APA had the":support and cooperation of the NationalInstitute of Mental Health, (1) a hugebureaucratic organ of Big Government?

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which has never disguised its dislike oforthomolecular psychiatry

Perhaps psychiatrists should ask them-selves just how and why, in spite of theirstudy of the mind and heart, they toowere seduced into a ruthless urge toemploy massive authority against min-ority opinion By yielding to this tempta-tion the American Psychiatric Associa-tion became contaminated with thatspirit of intolerance which was abroad inWashington at the time It is now oftencalled Watergate

AppendixWe have made a large number of

serious charges against the Task ForceReport published by the AmericanPsychiatric Association Our main chargeis that the committee had already arrivedat their negative conclusions longbefore they examined the literatureavailable to them and that they tailoredthe report in order to bolster their biasedconclusions As science students we usedto talk about how some students cookedthe data, i e , manufactured the datanecessary to support the conclusion theyknew they would have to reach. This thecommittee did by a selective examina-tion of the literature, by avoiding ref-erences to most of the collaborativereports, by downplaying or ignoring anypositive data in what they consideredreports favorable to their own point ofview, and by so distorting and mis-interpreting data in our original workas to turn our positive conclusions basedupon our observations into their negativeconclusions These they based upontactics such as ripping statements out ofcontext, reporting from tables in amisleading way, and generally con-ducting themselves in such a way that nomatter how hard anyone familiar with theliterature might try it would be im-possible to have even the appearance ofscientific objectivity Scientific dis-honesty is a serious matter, especially inthis case, to the hundreds of thousandsof patients who will be deprived of a

nl Two of the members of the Task Force wereworking for the National Institute of Mental Health.

chance to recover with orthomoleculartherapy

The question of honesty in science hasbeen discussed frequently in Science, apublication of the American Associationfor the Advancement of Science, and inthe public press Thus, Robert C Cowenin the Christian Science Monitor forMarch 26, 1975, opened his report on"Corruption in Science" with the follow-ing paragraph

"Fear, fame and fortune seem to bereplacing the challenge of the unknownas the driving force of much that passesfor scientific research "

There are two main types of corruptionin science reporting Scientists mayreport data in such a way that it cannotpossibly be reproduced no matter howmuch one would wish to do so, or in veryrare cases the data may have beenentirely fabricated And in the secondway, the literature review around whichthe report is built may be presented in amanner calculated, not to provide a fairview of what has been done, but to provea conclusion gained by other meansCowen's strictures against corruption inscience are supported by Marc Lappe inhis report to Science Thus, Lappe wrote,"Those who practice it know that thenature of the scientific enterprise itselfhinges on the scrupulous integrity of itspractitioners "

In a memo to Hoffer dated March 27,1975, Osmond wrote:

"Sometime ago I suggested in a memothat it was not fanciful to suspect that theethics which we saw at work during theWatergate affair had not been confinedto politics My particular concern waswith the behavior of the APA Task Forceand with its Canadian counterpart of Banand Lehmann We know from our ownexperience in Washington that highfederal officials have countenanceddubious behavior as regards our workWe also know that the APA used itshouse organ Psychiatric News to attackour findings while refusing or being verytardy about publishing our rebuttals. Wealso know from very unpleasant personalexperiences that the APA ethics cam-

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mittee was used to attempt to dissuadeus from discussing the megavitamin workpublicly. In the encounter that AH and Ihad with that committee in the fall of1970, it was evident that its members didnot know very much about our manypublished papers They seemed tobelieve that we had reported first to thepublic, a habit only too frequent todaywhich, however, we did not do onprinciple Reporting first to the public isthe scientific equivalent of the politicalleak and is used to steal a march onopponents It seems to have occurred inthe notorious Sloan-Kettering affair

"It is unlikely that so important anactivity as science can be apolitical:apart from anything else its politicalconsequences are so vast, but justbecause politics impinge upon it soheavily, that it is the duty of scientists toinsure that its morals and ethics are noteroded The politicians among scientistshave always been there and some ofthem have been magnificent scientistsIsaac Newton was a Member of Parlia-ment Benjamin Franklin was a marvel-ously adroit diplomat, while BenjaminThompson, Count Rumford, was anextraordinary combination of soldier,spy, traitor, gunmaker, and pure phy-sicist The important thing is thatalthough Newton and Rumford weredifficult and cantankerous men theywere not cheats and they were devotedto science They strove to enlarge truthThere is much evidence that the APATask Force, far from wanting truthenlarged, much preferred that it besuppressed

"Of the one-third of the patients whobenefited significantly from niacin in theMarlboro Study it seems a little bizarre tosuggest that they were not really schizo-phrenic This suggests that those whorespond positively to niacin are therebynot schizophrenic However, if theNIMH study misdiagnosed one-third oftheir cases, why not the other two-thirds?

"Ban's use of large doses of methioninecomes in a similar category but worsesince it actively harmed people who wereimproving on niacin If a man's judgment

is so unsound in one direction can you besure of it in another?

"The failure to report the breaking ofthe double blind at Marlboro was anothererror suggesting bias to even the mostwell-disposed. Not being among the bestdisposed to the APA-NIMH junta I aminclined to take these signs at their facevalue It would be a little improper inpsychiatry not to give one ' s adversariesthe full benefit and courtesy of psy-chodynamic interpretations"

The grand strategy of the committeewas to provide as much support as `possible for the conclusions they hadalready arrived at before they began theirstudies, namely, that orthomolecularpsychiatry had no merit as a treatmentand at its worst was a fraud Once that .strategy had been conceived the tacticsused followed logically, being based tupon the philosophy of the ends justify-ing the means Their ends were to protectthe public from the evils, errors, anddangers they knew were inherent inorthomolecular psychiatry Therefore,any method, no matter how objection-able it might be in another context,would be permissible, even desirable

Inherent in these tactics was thenassumption that they could get away={with it since very few members of the=American Psychiatric Association would`=read the original reports with care anddiligence The committee naturallyassumed that their own status and4prestige as members of an APA sub-;"committee of a research committee`would satisfy the members of the APA::,Unfortunately, they were correct

Several years ago at a press conference'in New York City, arranged by the:American Schizophrenia Association, Drat tiLinus Pauling was questioned about hisviews on ascorbic acid and the common;;cold He was asked by a well-known"

)

science reporter, known for his advocacyof establishment medical views, why if '

ascorbic acid was so good in preventingcolds, was it uniformly rejected by most-physicians? Dr Pauling opened his reply=by stating, "I think I am the only person:who has read my book " He then

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analyzed his conclusions that there wasadequate evidence in the medical litera-ture to warrant research relating ascorbicacid to the cold and that he had made anattempt to draw this to the attention ofmedicine to encourage them to proceedwith these studies We have often feltthat we and other physicians practicingorthomolecular psychiatry must be theonly ones who have read the ortho-molecular literature

Our charges against the committee'sreport are based upon what was writtenin the literature and how it was reviewedby the committee So that each readercan follow our argument in detail andcheck our conclusions we are attachingan appendix It contains the followinginformation:(1) A brief abstract of all the reportswhich we have authored which deal withaspects of orthomolecular psychiatry.We also make a few comments withrespect to the committee's use of thisinformation(2) A brief abstract of all the corrobora-tive reports mostly ignored by thecommittee(3) A reprinting of "On the Ortho-molecular Environment of the Mind:Orthomolecular Therapy" by LinusPauling American journal of Psychiatry131, 1251-1257, 1974 (with permission ofthe American journal of Psychiatry andat a cost of $100)(4) Dr Linus Pauling's Comments on theComments, American Journal of Psy-chiatry 131, 1405-1406, 1974(5) Our comments on the comments byWyatt, 1974, Klein, 1974, and Lipton,1974(6) Comments on Double-Blind (Place-bo) Methodology(7) Efficacy and Toxicity(8) Copies of letters to the American Psy-chiatric Association re Dr. M Lipton'schairmanship of Task Force Report(9) Bibliography.(10) Reading list in Orthomolecular Psy-chiatry(11) Real attempts to corroborate withfailure to confirm original studies.

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SECTION I— Brief Abstract ofOrthomolecular Treatment by

Saskatchewan Group

(1) Treatment of Schizophrenia withNicotinic Acid and Nicotinamide, A.Hoffer, H. Osmond, M. J. Callbeck, I.Kahan (1957),

This was the first major report Wereported that a pilot study to determinedosage, duration of treatment necessary,side effects, and so on was positive andled to the double-blind controlled experi-ment on 30 schizophrenic patients Thiswas the second double-blind experimentever conducted in psychiatry We did thefirst on a yeast nucleotide preparation ayear before The groups receivingvitamin B3 (some of whom received ECT)fared much better than the placebogroup (an equal proportion receivingECT) At the end of one year three out ofnine placebo patients were wellcompared to eight out of 10 on nicotinicacid and nine out of 11 on nicotinamideqi. e , a one-year recovery rate of three outof nine on placebo compared to 17 out of21 on vitamin B3 Follow-up evaluationswere conducted by a trained worker whowas not aware of the treatment code

We were aware that it is impossible torun double-blind experiments withnicotinic acid for the following reasons:(1) It is impossible to prevent or disguisethe flush Even after patients becomeused to it they will now and then have amarked flush, especially in the morning,and will even more often have a pinkglow. They are aware of these reactionsand it is easily seen by any observer (2) Ittastes sour and no allowance can bemade for this For these reasons no claimfor the blindness of any experiment usingnicotinic acid can be accepted unlessthere is proof these factors have beenallowed for We, therefore, used anicotinamide group This form of vitaminB3 does not cause a flush in 99 percent ofthe subjects But the staff were not toldabout this third hidden group Theyexpected that there would be only twogroups, the placebo and the nicotinic

acid group It would be natural to assume `'that every patient who flushed would be''on nicotinic acid and every patient who '

did not would be on placebo, whereas:one-half of the nonflushing patients were'on nicotinamide

In our second double-blind controlled,experiment we used only placebo andnicotinic acid, but we had let it be known`..;that this experiment would ' be run in'exactly the same way as the first By this'ti me we had uncoded the results of the`first and reported them to the clinical ';group

The rest of this paper summarized the? ,results of treatment on 73 other patients:who were compared to 98 cases treated))in the same ward who had never receive&vitamin B3 From the 98 cases not given '

vitamins there were 49 readmissions toahospital averaging 319 days per patientreadmitted, and in 1956 seven were stillin hospital. From the 73 on vitamin B3,there were eight readmissions in theysame interval averaging 234 days perpatient readmitted, and none were i thospital in 1956 i

We, therefore, concluded, when usedin adequate dosages nicotinic acid andnicotinamide materially contribute to therecovery of schizophrenic patients

(2) The Adrenochrome Model and'Schizophrenia, A. Hoffer and H. Osmond'(1959)

After discussing our hypothesis wewrote, "Nicotinic acid and its amide artl•,methyl acceptors which when they are`used in large doses may compete with'j'noradrenaline for methyl groups and sqdecrease adrenaline output This was oncrreason why nicotinic acid was tried forschizophrenia The results for early ';schizophrenia are good ; About 15 percent of our schizophrenic patients'require daily administration of this`vitamin and relapse a few weeks afterstopping it It does not help chroniq-

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schizophrenics even when such massivedoses as 25 g a day are given for threemonths " The committee did not readthis paper

(3) Schizophrenia: A New Approach, H.Osmond and A. Hoffer (1959)

In referring to our treatment we wrote,"This consisted of massive doses ofniacin or its amide ranging from 3 to 25 gdaily " Table 1 from our recent paperoutlines our results. These are that whileniacin seems beneficial in early schizo-phrenia and apparently reduces the rateof relapse (one out of 37 vs six out of 36)when medication is continued, it isusually ineffective in long-continued

illnesses " The committee did not readthis paper

(4) Massive Niacin Treatment in Schizo-phrenia. Review of a Nine-year Study, H.Osmond and A. Hoffer (1962)

This was a general review papercomparing results of adding vitamin B3to standard treatment before tranquiliz-ers came into use ECT was the besttreatment then and about half of thepatients were so treated

The results of treating all schizo-phrenics treated at this ward (MunroeWing, General Hospital, Regina)between 1952 and 1955 were given asfollows:

Number ofGroup N On ECT Number sent to Mental Hospital Suicides

Thus, out of 73 on niacin 66 were ableto remain in the community while out of98 on other treatment 51 were not

readmitted (Chi Sq = P < 0 001)We also showed the cumulative re-

admissions as follows:Number of Readmissions

Group N 1952 .55 1956. 57 195859

Between 1952 and 1955 the readmis-sions accumulated more quickly in thenon-niacin group, but thereafter therelapse rate was nearly the same Wesaid, "It seems from this that niacin keptthe disease in check; but one can hardlyexpect such a protective action tocontinue indefinitely " Most of theoriginal niacin group were not receivingany during follow-up We also reportedthat from our second double-blind studyon vitamin B3, 34 out of 62 had achieveda five-year cure (55 percent) compared to

Days in hospitaltreatment.

Group N admission

four out of 20 on other treatment (20percent) From an earlier study, out of 58treated with niacin (many of whom alsohad ECT) 45 (78 percent) were five-yearcures compared to 34 out of 90 on othertreatment (many of whom had ECT), or38 percent

Finally, we compared treatment resultson three groups treated by otherphysicians, none of whom had anyenthusiasm for vitamin therapy, andsome of whom were actively hostile

Discharge statuswell and much

I mproved

N well onlast evaluationin community

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On other treatment two out of 22 werewell (10 percent), on ECT only 10 out of26 were well (39 percent), while on thecombination of niacin plus ECT 24 out of30 were well (80 percent) None of thepatients were seen by us, but we hadaccess to the hospital and follow-uprecords

We, therefore, concluded, "In ourview it is a useful adjunct in thetreatment of schizophrenia both foracute cases and to reduce the chance ofrelapse; and we hope it will be tested ona fairly large scale with a carefullydesigned follow-up. For with niacin andits amide, unlike the waters of Jordan,one can always try the Abanas andPharphars of the drug companies at thesame time "

(5) Malvaria: A New Psychiatric Disease,A. Hoffer and H. Osmond (1963)

In this paper we discussed the relation-ship of the presence or absence of amauve-staining factor in urine to diag-nosis, treatment, and prognosis Wesuggested the term malvaria for anyperson who excreted this factor Sincethen it has been identified as kryptopyr-role and can be measured quantitativelyWe also reported results of a briefexperiment on 24 retarded children Allwere tested and then started on nicotin-amide using 1 g per 50 pounds This dose,we now realize, was too low The presentrecommended starting dose is 3 g perday We assumed that parents who sawno improvement would not wish tocontinue while those who did notei mprovement would continue

The parents, of course, did not knowthe results of the urine test Out of 16mauve-negative children five remainedon vitamins, whereas in the same intervalout of eight children who were positivenone were discontinued As a classparents of mauve-positive retardedchildren were happier and more optim-istic about the results. Chi Square is 7 5,i e , P < 0 01, this is due to chance

(6) Treatment of Schizophrenia withNicotinic Acid (a 10-year follow-up), A.

Hoffer and H. Osmond (1964).One of the few abstracts which is

correct except the committee got theyear of publication wrong, one of manyeditorial errors They dated it 1963 in thebody of the report and 1964 in theirreferences

(7) Treatment of Organic Psychoses withNicotinic Acid (a single case), A, Hoffer(1965)

A patient with an organic psychosiswho had failed to respond to severalmedications recovered within 24 hoursafter he was started on nicotinic acid andascorbic acid The decision to begin thistreatment was based on a chemical testwhich showed he had mauve factor in hisurine

In a further report, Hoffer (1970a)reported this subject survived 34 monthsafter his inoperable bronchiogeniccancer was established (diagnosed) Thelast radiological examination before hedied showed no recurrence of the cancerThe cause of death at age 76 wasprobably coronary disease Unfort-unately, there was no autopsy Thecommittee ignored the case

(8) Malvaria and the Law, A. Hoffer;(1966b)

One of us (AH) reported that out of 740subjects tested for mauve factor in theirurine, 14 had been charged with a varietyof crimes Of the group, 10 had mauvefactor in their urine This was a very highproportionproportion being similar to the pro-portion of schizophrenics who testpositive When the mauve-positive sub-jects were treated with orthomoleculartherapy most recovered and no longerwere involved in further criminalactivity Detailed case histories weregiven The committee ignored thisreport

(9) Biochemistry of Nicotinic Acid andNicotinamide, A. Hoffer (1967b).

Here one of us (AH) presented abiochemical review of vitamin B3 in-cluding a discussion of side effects andtoxicity There was little evidence it was

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hepatotoxic The fallacy of the abnormalliver function tests was discussed."Nicotinic acid and nicotinamide areremarkably safe compared with thewhole field of chemotherapy" was theconclusion still valid today The com-mittee ignored this paper

(10) The Effect of Nicotinic Acid on the

Frequency and Duration of Re-Hospital-ization of Schizophrenic Patients: AControlled Comparison Study, A. Hoffer(1966)

In this paper one of us (AH) comparedthe results of treatment by other psy-chiatrists who sometimes used nicotinicacid against the results of their standardtreatment on similar patients

Here were the results:

Treatment by N N Total Days inall Psychiatrists N Readmitted Readmissions Hospital Suicides

Nicotinic Acid 128 7.422 0

Other 346 54 491 6

1. The majority of chronic schizo-phrenics were not benefited2 The majority of acute patients given133 responded much better to treatmentwhen these vitamins were included thanthe comparison control group

(11) Nicotinic Acid Therapy and theChronic Schizophrenic, P. O'Reilly(1955)

This is an important paper because ithas been used by opponents as an attackon our work. Dr O'Reilly was then apsychiatrist at the Saskatchewan Hospitalin North Battleford and was in charge ofresearch under our direction We en-couraged him to do this study and helpedhim have it published It was importantfor it confirmed our observations thatchronic patients such as those kept manyyears in the hospital did not respond Wehoped that publication of this reportwould protect us thereafter from therecurrent attack on our work based uponchronic patients; obviously it did notsince even the committee persists inconfusing the reader

O'Reilly referred to three of thepossible mechanisms of action of vitaminB3 including its role as a potential methylacceptor He selected "eleven of themost refractory, regressed, deteriorated

female patients" who had not respondedto any other treatment Tranquilizers hadnot come into use Mean duration of stayin hospital was 16 years They were given3 g per day for eight weeks They werecarefully examined and rated everyweek O'Reilly found that the patientsimproved significantly over an untreatedcontrol group of 43 patients (at 10percent level) in the following areas:1 Sleep improved in all patients2 Appetite increased in all patients3 Directability was better in six.4 Initiative alone was better in five5 Cooperation with routine was better

in four6 Care of personal property was better

in threeNone of the control group showed any

significant improvement.Three patients generally improved and

two histories were given to illustrate this.There was no improvement in delusions,hallucinations, and in other schizo-phrenic features.

O'Reilly concluded, "While this trialdoes not show nicotinic acid to have anyeffect on the schizophrenic process perse, it is felt that nicotinic acid should befurther investigated in a larger trialseries " It is clear that we claimed nosuccess in treating these cases even

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though their behavior was significantlybetter These are patients similar to thosegiven deteriorated, badly prepared NADby Kline et al (1967). The committeedoes not discuss this paper, but erron-eously refers to it among its ECTreferences

(12) Some Schizophrenic Recoveries, A.Hoffer and H. Osmond (1962)

' We described five chronic schizo-phrenics who had failed to respond to

any previous treatment They weretreated with our Phases I, II, and IIItreatment procedures At the time thisreport was compiled three were well ormuch improved Today one of them, LR,is still well, one, CS, refused to cooperatewith vitamin therapy and is todaychronically tranquilized and ill. We haveno report on the others

We also reported the following resultsof treatment achieved by the researchdivision on all patients treated betweenMarch 1, 1960, and March 1, 1961:

To mental hospital and their home

N Much Nsent to NSickI mproved Mental Hospital at Home

We wrote, "Well means that thepatients are as healthy physically andmentally as they were before illnessstruck them They are free of complaintsand function normally at home and inthe community Of 16 patients treatedonly with Phase I, a total of 14 are well ormuch improved These patients were abetter group prognostically than were theother two groups From Phase I I a total of16 patients are well or much improvedTwo went to a mental hospital and one isstill there From Phase III (i e , Phases Iand II failures) three are much improvedThus 33 of 40 treated have to all intents

(13) Nicotinic Acid: An Adjunct in theTreatment of Schizophrenia, A. Hoffer(1963)

Here AH compared readmission dataon all schizophrenic patients treated atUniversity Hospital, Saskatoon, between1955 and 1962 They were all diagnosedand treated by members of the staff notconnected with our research group Allstandard treatments were also usedincluding ECT, tranquilizers, andpsychotherapy Results are shown below:

N N NGroup N Suicides Readmitted Readmissions

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AH concluded, "Although manypatients are so sick they will not recoveron nicotinic acid alone, the majority ofschizophrenic patients who have re-covered as a result of treatment with ECTor tranquilizers will remain well if theyare maintained on nicotinic acid

"Since vitamin B3 is not toxic and iseasy to administer I suggest that schizo-phrenic patients (excluding those chron-ically ill in mental hospitals) are notreceiving the best treatment if thisvitamin is excluded from the therapeuticregimen " Earlier AH had said, "Chronicschizophrenic patients of the type foundin mental hospitals do not respond andthere is no point in giving them thistreatment "

The committee avoided this importantdocument, important since none of thepatients were under our care and at thattime only nicotinic acid or nicotinamide

was used without any other componentof orthomolecular psychiatry

(14) Nicotinamide in the Treatment ofSchizophrenia, R, Denson (1962)

Denson selected from new or firstadmissions and readmissions only thoserequiring ECT Out of 41 cases chosen, 36were able to complete the study Theyrepresented about one-third of the totaladmissions

There were no side effects and thedouble-blind code remained unbroken.At the end of the year there was nosignificant difference, but eight monthslater it was determined that group A haddone markedly better than group B Thecode was then opened and it was foundthat the treatment group had been thegroup doing better

Denson found the following:

Group.

Days inHospital( Mean)

Hospital at 5th and 6th MonthsIn Out

Nicotinamide 1.064 1 16Placebo 1.775 8 11

Significance 0 05 P c 0 01 005 P c 7001

The fifth and sixth months wereselected because one could not expectfive weeks on nicotinamide to exert itseffect forever as Denson put it

(15) Schizophrenia and Suicide, H.Osmond and A. Hoffer (1967).

In this report we discussed the highfrequency of suicide among schizo-phrenics which was about 25 times morefrequent than one would expect in anygeneral population However, the suiciderate for patients treated with ortho-molecular methods was very much less

(16) Comparison of Xanthine Nicotinateand Nicotinic Acid as Treatment forSchizophrenia, A. Hoffer (1969a).

This was a study to determine ifpatients already well or much improved

on nicotinic acid would relapse ifswitched over to xanthine nicotinate. Adouble-blind cross over design was used.Our conclusion was that the nicotinicacid derivative was just as effective inmaintaining the patients

As we have been accused of claimingnicotinic acid was absolutely safe, wewill quote here one of our sentences, "Nomedication is free of side effects andnicotinic acid and nicotinamide in mega-vitamin doses are not exceptional Mostof the side effects are irritating andinconvenient rather than toxic "

(17) Childhood Schizophrenia: A Casetreated with Nicotinic Acid and Nicotin-amide, A. Hoffer (1970)

A single case is discussed

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(18) Megavitamin B3 Therapy forSchizophrenia, A, Hoffer (19716)

This is a general review article trying tocorrect the many errors and biases thenbeing promulgated by the CMHA studiesApparently it had little effect since Banand Lehmann continue to publish as ifthey had not read this paper and recentlyBan was given an award by the CanadianPsychiatric Association for his brilliantwork in disproving our megavitaminclaims

(19) Vitamin B3 Dependent Child, A.Hoffer (1971)

The syndrome of the vitamin B3dependent child is characterized by(1) hyperactivity(2) deteriorating performance in school(3) perceptual changes(4) inability to acquire or maintain socialrelationships

A few cases are given to illustrate theuse of the orthomolecular approach

(20) A Vitamin 83 Dependent Family, A.Hoffer (1971a)

A father and his three children, theyoungest from a second wife, were allvitamin B3 dependent and recovered onvitamin 83 therapy

(21) Orthomolecular Treatment ofSchizophrenia, A. Hoffer (1972)

A review of the development of ortho-molecular psychiatry

(22) A Neurological Form of Schizo-phrenia, A, Hoffer (1973)

A young woman first ill with schizo-phrenia at age 13 developed what wasdiagnosed as a progressive degenerativecerebellar syndrome On nicotinic acid,3 g per day, she recovered

(23) Nutrition and Schizophrenia, A..Hoffer (1975).

A general review article

(24) Five California Schizophrenics, A,Hoffer (1967a)

This was a clinical report of five

California patients who recovered onorthomolecular therapy They had notresponded to any previous treatmentThere was nothing unusual about thisreport except that it set off a chainreaction culminating in our appearancebefore the committee on Ethics of the!American Psychiatric Association inDecember, 1970 Apparently a psychiat-rist who was not willing to identifyhimself complained before the com-mittee This is an example of retros-pective censorship

The committee on Ethics have since::'then not communicated with us andIapparently did not consider our action in `>?publishing a scientific paper unethical

(25) Niacin Therapy in Psychiatry, A.Hoffer (1962)

In this monograph, the first ever`published dealing with nicotinic acid andmental illness, AH described the resultsof treatment as then known, givinghistories of 64 patients treated so the))reader would know the diagnostic and;;treatment orientation

This book contained a special sectionon side effects and toxicity No refer-fence is made to this by the committeewho referred only to the Mosher study, amember of the committee

(26) How to Live With Schizophrenia, A.Hoffer and H Osmond, final writing and-'editing by F. H. Kahan (1966 and 1975)

This is the first book written fopatients and their families consumed byschizophrenia

It provided our perceptual theory ofschizophrenia first elaborated in somedetail by John Conolly about 150 yearsago The first edition treatment sectionwas written in 1965 and represents ourtreatment view then Since this book was'written for lay people we made certainwe were very careful in our recommend -

ations We stated, "If after this treatmenhas been completed you do not improve,it is because you have been sick so long-that the disease has become chronic and '

treatment will have to continue for a long.period of time, either in hospital or at

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home As a rule patients who have beensick for many years will not be helpedwith nicotinic acid alone But if they canbe improved in any way whatever it isbetter to keep them on this treatment "

We also pointed out the need forcontrol of diet, control of infections,control of smoking, adequate sleep, useof medical psychotherapy and otherpsychosocial aids such as OT and RT

The treatment outline in our secondedition contains the more compre-hensive orthomolecular program Wehave been accused by the committee ofbeing shifty because our treatment hasi mproved Using their definition, everymodern psychiatrist is shifty since theyno longer use treatment available in1965 The three phases of treatment arediscussed, but provision is made forjunk-free and allergy-free diets, othervitamins are discussed, and moreattention is given to children Theconcept of vitamin B3 dependency isintroduced as a cause of schizophrenicsyndromes and as a cause of some of thelearning and behavioral disorders inchildren

This book is not a best seller, but hassold over 20,000 copies and continues tosell well

We have thousands of letters fromgrateful parents, spouses, and patients,some of whom wrote that it literallysaved their sanity since it gave them analternative view They no longer wereforced to accept the popular psychiatricview that they, especially parents, hadmade their relative ill They were for thefirst ti me introduced to the medicalmodel of schizophrenia

(27) Controlled Study of OrthomolecularTherapy on Children with Learning andBehavioral Disorders (1967-1974)

This was the final report submitted toMental Health Saskatchewan in 1975 Itis the study reported in paper (19)Thirty-seven children under age 14 (witha mean age of 8 3) with a variety oflearning and behavioral disorders weretreated They were given nicotinamide,1-3 g per day, and ascorbic acid at the

same dose level If and when the patientrecovered the nicotinamide was replacedby identical appearing placebo tabletsThe child was not aware this would bedone The parents were advised aboutthis before they agreed to place the childin the study If and when the patientrelapsed the placebo was discontinuedand the nicotinamide resumed Theparents kept records listing when theyplaced the child back on the activemedication All the children were alsoplaced upon a sugar-free diet Thisclosely resembles Dr B Feingold's dietwhich excludes synthetic additives towhich many of these children react withhyperactivity Manufactured foodswhich contain sugar also contain theseother undesirable additives

Of the 37 children who started theprogram, 21 became normal and 14 werebetter At the final evaluation 18remained normal, five much improved,and the rest were ill or their conditionwas unknown and they were assumed tobe ill That is, 24 out of 37 are well ormuch improved Most of the failures didnot follow the program consistentlychiefly because the parents could notpersuade or force the children to take themedication The vitamin tablets wererather large for children and capsuleswere then not available Only 19 wereplaced on placebo because some werelost from the study and others hadimproved so slowly that we did not wishto expose them to the hazards of arelapse Early in this study it becameapparent that many children who re-lapsed on placebo were set so far backthat it took much longer and higher dosesof vitamins to return them to good healthagain All the patients on placeborelapsed within four weeks, some withintwo For example, one child had re-covered to the point that he waspromoted one grade in school. At thesame time he was switched over toplacebo No one at the school was awareof the study, but in a few weeks theteacher called the parents to inform themthat they had made a mistake inpromoting him and that they were forced

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56

to revert him to his previous statusWhen the parents were convinced of hisrelapse he was placed back on thenicotinamide, recovered, and thereafterhad no further problem in class It wasclear that the ascorbic acid did notprevent relapse

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SECTION II—Brief Abstracts ofCorroborative Reports

It is important to describe briefly allthe corroborative reports The committeereferred to a small number of reports inaddition to those we have alreadydiscussed (#15, 17, 34, 35, 38, 39); listeda number it could not have seen sincethey were never published (#33, 36, 37,40) and they were not present at themeeting

(1) Cyproheptadine: An Excellent Anti-dote for Niacin-Induced Hyperthermia,T. R. Robie (1967).

Dr Robie was the first psychiatrist toreport his corroboration of our work Hedescribed six cases Since then he hasremained an enthusiastic proponent oforthomolecular therapy Lehmann's firsttranquilizer study was conducted on onlyan equally small number of cases Healso remains an enthusiastic proponentof tranquilizer therapy Dr Robie, withover 40 years of experience, observedthat on vitamin B3 therapy his patientsbecame his friends Never before had heexperienced this with schizophrenics

(2) Treatment of Neurotics and Schizo-phrenics Using Clinical and HODCriteria, f• L, Ward (1967)

Fifty-nine schizophrenics were treatedwith orthomolecular methods. Onepatient was worse, five unchanged, and43 (88 percent) were improved and muchimproved This improvement was asses-sed by clinical and HOD score criteriaThe same number of patients felt they

had been helped In a later study ontranquilizers, Borda (1973) found thatonly 21 percent of the patients felt theyhad been helped compared with 66percent of their doctors who concludedthey had been helped There is a betterconsensus for orthomolecular treatment

Ward confirmed our work that non-schizophrenic patients who scored highon the HOD test also responded well tothe therapy He concluded that "massivedose niacinamide or niacin is of benefitin schizophrenia and in variousnonschizophrenic states " As regardsneurotics the committee suggests that allneurotics, not just those who score highon the HOD, do equally well on theorthomolecular megavitamin treatment

(3) Treatment of Schizophrenia withNicotinic Acid, M. Herjanic, B. L. Moss-Herjanic and W. K. Paul (1967).

This paper is ignored by the com-mittee

Four groups were studied:(a) All outpatient schizophrenics seen atone clinic were given nicotinic acid andascorbic acid, 3 g per day of each for sixmonths, plus any other medicationrequired(b) One-third of the patients from onechronic ward(c) A control for group (a) matched forage, sex, diagnosis, duration of illness,and duration of previous hospitaliza-tions(d) Control for group (b).

All other patients on the same ward11

Grout) a

N

21

MuchI mproved

8

Admissions

6 Ss for dads

Mean days

510

Mean perTotal Group

195

Groupc 21 1 10 Ss for 16 ads 776 591

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These results are statistically sign-ificant. On the other hand, groups (b)and (d) did not differ That is, acute andsubacute cases benefited while themental hospital chronics did not

(4) Treatment of Schizophrenia Based onthe Medical Model, D. R. Hawkins(1968)

The committee ignored this paper DrHawkins reported treatment results on315 consecutive patients who applied fortreatment at an outpatient clinic Verystrict diagnostic criteria were used Themajority were chronic Eighty-nine per-cent had previous treatment Many hadmultiple and lengthy periods in hospitalof up to 12 years Almost all had hadphenothiazine and other drug treatmentoften for prolonged periods Some hadover 100 ECT, previous psychotherapy, orpsychoanalysis for up to 20 years A fewfamilies had spent $150,000 (by 1968) onineffectual care

Hawkins concluded, "The majority ofpatients i mproved significantly andprogressively Those in whom the illnessbegan during adulthood showed the mostdramatic response If the onset of theillness was before age 17 the response totreatment was slower and most treatmentfailure occurred in this group of grown-up childhood schizophrenics. Patientswho were either too regressed or ill tocooperate on an outpatient basis weretreated in hospital for an average of sixweeks with a short series of ECT

I mprovement was rated by:(a) Patients' subjective statements(b) Family observations(c) Psychiatric evaluation(d) Decrease in HOD scores

Of the group 71 percent improved Thegreatest response was made by the 70patients who were both alcoholic andschizophrenic

(5) Treatment of Schizophrenic Child-ren, A, A, Cott (1969).

Dr Cott's article ran between pages 44and 60, not 44 to 49 as the committeeerroneously wrote

After describing in clinical detail thediagnostic criteria and treatment pro-gram, Dr Cott presented six detailedcase histories of children he had treatedAs a pioneer in the treatment of childrenDr Cott's views must be taken veryseriously. He concluded, "The responseto the nicotinic acid treatment is slowand in my experience three to six monthsis the minimum time during whichsignificant changes become manifestMost parents have reported that the firstnoticeable change is a slowing of thehyperactivity and attendant on thisslowing, a willingness to learn."

"Although much work and researchwill be required to fill the gaps remainingin our knowledge of schizophrenia, wecan be encouraged with the accomplish-ments achieved in less than two decadesin treating this dread illness We canoffer hope to those who suffer its ravagesand to the parents of children whosepotential is destroyed so early "

(6) Schizophrenia: Responsive to In-tensive Hospital Treatment as Monitoredby the HOD and OIT tests, F. Chiossone,D. R. Hawkins, F. Furfaro, and R. P,Runyon (1969)

Over a 10-month period 140 patientswere admitted into the psychiatricdivision of Brunswick Hospital Center:ECT was given to 85 patients This groupresponded as follows:

unimproved 2improved 118much improved 12very much improved 6recovered 2

The authors concluded, "Intensiveshort-term hospital treatment for schizo-phrenia proved to be highly effective inbringing about substantial improvementin the great majority of patients and thisi mprovement was substantiated by.objective testing " The committeeignored this report

(7) Subclinical Pellagra: Its Diagnosisand Treatment, R. G. Green (1970)

A discussion and presentation of a fewcases to demonstrate the response of

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these patients with learning and be-havioral disorders to vitamin 133 Thecommittee ignored this report

(8) How One Psychiatrist began UsingNiacin, H. L. Newbold (1970).

This is an excellent account, ignoredby the committee, in which a skillfulpsychiatrist describes his history whichled to him becoming an orthomolecularpsychiatrist Most psychiatrists would beunwilling to expose themselves to suchpressure from their antivitamin col-leagues

(9) The Use of Megavitamin Therapy inRegulating Severe Behavior Disorders,Drug Abuses and Frank Psychoses, G.Von Hilsheimer, S. D. Klotz, G. McFall,It Lerner, A. Van West, and D. Quirk(1971)

These investigators treated 32 patientsbetween September 1967 and September1969 in acute psychotic episodes or inthe aftermath of acute crises which didnot appear to be psychotic in nature, notrelated to drug abuse The patients weregiven up to 24 g of niacin per day

"All these patients have respondedwith reduced dysphoria, subjectivereports of improved feeling states,i mproved perception, control of be-havior and general improvement intonus, orientation and appearance ofhealth "

"Several severe psychotic patientsseem to have recovered as a directfunction of niacin therapy " The com-mittee ignored this report

(10) A Report on the Use of Ortho-molecular Therapy in a California StateHospital, E. R. LeClair (1972)

E R LeClair described results oftreating 30 male schizophrenics in a statemental hospital She was permitted to doso after she was able to demonstrate theeffect of orthomolecular therapy on sixpsychotic patients They were too dis-orientated and agitated to participate inpsychotherapy and had failed to respondto the comm i ttee's favorite therapy-tr'anquilizers o iy This was a test project

since, according to the hospital staff,vitamin therapy "has already beenproven not to work " Of the six, threewere in almost constant restraints orseclusion of one kind or another Fivehad been in hospital one month and thesixth for seven They had as a group beenin hospital _ 18 times, averaging 8Ymonths per patient The mean HOD totalscore was 144 5 indicating very severepsychosis The average for all schizo-phrenics is around 70 Each patientresponded They became more manage-able, less agitated, less hostile, lessaggressive They began to talk andbecame more sociable Hallucinationsand delusions diminished These obser-vations by patient, family, and staff wereconfirmed by a decrease in the HODscores to a mean of 4 8 in 2¼ months( Normal scores range from 0 to 15) Fourwere discharged with no tranquilizersand two on tranquilizers, but the doseswere much smaller. After six months onlyone was still on tranquilizers Fiveremained well after discharge The sixthdiscontinued his vitamins and was re-hospitalized three times in 10 months

As each patient was discharged,another was placed on the same pro-gram Eventually another 24 were treatedwith similar results

Another 14 were started, but could notbe continued because one was dis-covered to have a medical problem, sixwere transferred to another hospital, andone was discharged by the court, twowere transferred to a private hospital, inthree patients new physicians would notpermit vitamins to be continued, and inone emesis of niacin and niacinamidewas unavoidable While on vitamins for abrief period, 11 of the 14 showed someimprovement Ten are still in hospital

Summary of Results:Hospital experience before vitamins--

3 43 times for 10 47 months calculatedfor all 30 (per person)

Excluding seven never in hospitalvalues were 4 48 for 13 65 months

Discharge—19 to themselves; seven toparents; four to board and care facility.

it

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Follow-up—When the paper was pre-pared 28 were evaluated. Twenty re-mained on megavitamin therapy Of theeight not on vitamins six had been re-hospitalized one to five times in thefollowing 10 months One committedsuicide and one maintained himself onphenothiazines Three were ordered bytheir physicians to discontinue vitamins.Of the 28, 19 were gainfully employed,five were in board and care facilities, tworetired, and one was dead Five were onwelfare assistance compared to 18 beforetreatment started

The author noted, "A discouragingaspect of the project was the poorreception by many of the hospitalpersonnel The security and com-placence in tradition were apparent Theprogram director, who gave permissionfor the project, experienced many un-complimentary comments from hisfellow psychiatrists Several physiciansalso placed patients on 100 mg to 300 mgof niacin and ascorbic acid. When noimprovement was noted within two tofour weeks, they boastfully made itknown that the 'vitamins did not work forthem ' " Had they done it double blindusing these totally inadequate doses weare certain the committee would havegiven them ample space in their report.The committee ignored this study

(11) A Study of Neurological Organiza-tion Procedures and Megavitamin Treat-ment for Children with Brain Dys-function, S. Krippner and S. Fischer(1972)

Subjects were 100 children diagnosedas suffering from brain dysfunction Theywere divided into four groups:(a) 41 Ss (28 boys, 13 girls) who receivedneurological organization (NO) only(b) 14 Ss (6 boys, 8 girls.) NO only(c) 14 Ss (10 boys, 4 girls) NO andmegavitamin therapy MV(d) 24 Ss (18 boys, 6 girls) NO and MV

For groups (a) and (b) there was nosignificant gain in the neurologicalquotient (NQ), but for groups (c) and (d)there was a significant improvement inNQ

They concluded, "In any event, thefact that megavitamin treatment wasassociated with significant results in thisstudy justifies further research into thistype of therapy " This paper was ignoredby the committee

(12) Clinical Observations on the Treat-ment of Schizophrenia and HyperactiveChildren with Megavitamins, E. L.. Rees(1973)

This is a general outline of treatmentincluding treatment of children allergicto foods

(13) Psychiatric Syndromes Produced byAllergies: Ecologic Mental Illness, H. L.Newbold, W. FL Philpott, and MMandell (1973).

This is one of the first accounts of therole of allergies in producing mentalillness An explanation for schizophre-nics' failure to respond to megavitaminsis now available Why should a patientwho is psychotic because he is con-suming milk to which he is allergic,respond to vitamins?

(14) Pyridoxine and Trace Elementtherapy in Selected Clinical Cases, P.Cutler (1974)

The use of trace elements is rapidlyexpanding

(15) Orthomolecular Approach to theTreatment of Learning Disabilities, A.Cott (1971)

This is a general review paper oforthomolecular treatment based upontreatment of 500 children between 1966and 1971.

(16) An Integrated Community Systemfor the Effecitve Treatment of Schizo-phrenia, D. It Hawkins (1971)

Using a comprehensive treatmentapproach under the medical model, Dr.Hawkins' Clinic treated over 4,000patients At this Long Island Clinic theycarry a case load of 1,500 patients for$300,000 per year Many are chronicschizophrenics with repeated admissionsto hospital. Their results were superior to

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any they had seen with standard psy-chiatric treatment and cost averaged to$200 per year per patient.

One family agency, the Council forYouth Services of the Episcopal Dioceseof Long Island, had become boggeddown with long waiting lists and shortageof staff When they converted to the newsystem, they soon eliminated a waitinglist, doubled their case load, and solvedtheir financial problems The committeeignored this paper

(17) A First Evaluation, M. Williams(1971)

"I was trained in orthodox analyticaltreatment methods and applied these inmy practice for 15 years "

"I discovered that results of strictlypsychoanalytical therapy with or withoutcombined chemical (tranquilizer)therapy produced poor recovery andremission percentages in schizophrenicpatients "

"After three years of using thesediagnostic and treatment procedures(orthomolecular—our note) I have com-piled sufficient case histories upon whichto base my own conclusions My firstimpression was the number of un-recognized schizophrenics Almost 50percent of previously diagnosed neuro-tics were actually suffering from schizo-phrenia History usually indicated life-long problems, and early recognition andorthomolecular treatment, in some casesaccompanied by supportive psycho-therapy, brought about rapid response "

"Chronic (long-standing) schizo-phrenic patients do not respond asquickly or as well However, I have notedmarked improvement in even the mostchronic cases " This report was ignoredby the committee

(18) Clinical Impressions in Early andChronic Schizophrenia and DiagnosticProcedures, M. Williams (1972)

Dr Williams presented three cases toillustrate the response to treatment Thisreport was ignored by the committee

(19) Does Acid Well Water Erode Plumb -

ing Vessels and Sanity? C. C, Pfeiffer(1975)

This is a good paper to illustrate theimportance of minerals in orthomolecul-ar psychiatry

(20) Relationship of Kryptopyrrole, Zinc,and Pyridoxine in Schizophrenics, J,Ward (1975)

This good paper confirms that krypto-pyrrole (KP) is found primarily in patientswho have serious mental disease. It cutsacross all diagnostic group's and can beused to indicate when pyridoxine andzinc are required

(21) Orthomolecular Treatment inDisturbances Involving Brain Function,L. B, Silverman (1975)

On the basis of 400 cases (mostlychildren with learning and behavioraldisorders) treated between July 1972 andApril 1974, Dr Silverman, an ortho-molecular pediatrician, concluded, "Onthe basis of a rather concentratedexperience it certainly suggests to methat whenever medical treatment isindicated, the orthomolecular method isthe first and safest treatment of choice inchildren with perceptive and behavioralproblems associated with minimal neuro-logical difficulties " Several illustrativecases were given

(22) The Schizophrenias: Yours andMine, C. C. Pfeiffer, J, Ward, M. El-Meligi, and A. Cott (1970)

The committee completely ignoredthis i mportant work as they havecontinued to ignore every paper put outby Pfeiffer and his colleagues Theyobviously believe that in so doingPfeiffer's work will go away and they willnot need to deal with it The bookcontains a comprehensive outline ofschizophrenia and its treatment Anumber of new findings have been maderelating histamine levels, kryptopyrrolelevels, and zinc to various schizophrenicsyndromes

(23) A Study of Zinc Deficiency andCopper Excess in the Schizophrenias, C.

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C. Pfeiffer, U. Iliev (1972) See alsoPfeiffer, Iliev, and Goldstein (1973)

Both papers are ignored by thecommittee

(24) Treatment of Drug Addicts inPrivate Practice, A. Vajay (1973)

Dr Vajay treated 89 outpatients inprivate practice between October 1970and December 31, 1971 By then 23 had"graduated" away from drugs and fourmonths later the number increased to 27

This was a chronic group, the mostfrequent ages being 19, 20, and 21Duration of addiction varied from six to84 months Only 17 used one drug Therest were primarily on heroin, butcombined it with three or more otherdrugs None had ever been treated withmethadone, 14 had been treated once,seven, twice, 20, three times, and 34,four times, and five had been in and outfive to 10 times

There was a very high rate of physicalillness, 68 had orthostatic hypotension,50 chronic bronchitis and nasopharyngi-tis, 52 had pustular acne, 48 acutethrombophlebitis of anecubital or dorsalveins of hands, 23 had chronic prostatitis(nine due to gonorrhea), 11 women hadpelvic inflammatory disease (10 hadgonorrhea) Twenty developed hepatitisduring treatment Eight had ulcerativecolitis, one duodenal ulcer, and onechronic asthma

All were also suffering from a variety ofpsychiatric illnesses One was manicdepressive, one epileptic with psychosisfollowing brain trauma, two were organicbrain syndromes, and 35 were schizo-phrenic borderline or pseudoneu-rotic

Twenty-six were given 5 g bufferednicotinic acid, 1 g of ascorbic acid, and 1mg of vitamin B12 plus 15 mg of vitaminB6 by injection every four days. Theywere all started on methadone 40 mg perday for 30 days This was then graduallyreduced until they graduated off it Theyalso received individual psychotherapyGroup therapy was quickly rejected

For such a severely sick group theresults were very encouraging Out of the

27 graduates, 17 were schizophrenic and22 were on megadose vitamins Heconcluded, "in this 14-month program,low-dose methadone is enough formaintenance, that the immediate flushof nicotinic acid successfully replacesthe 'heroin' high and is a useful tool tomaintain motivation and keep thepatient free from craving for heroin "

The committee ignored this paper

(25) Nicotinic Acid Therapy in ChronicSchizophrenia, Sehden and Olson (1974)

These authors treated 14 chronicschizophrenic patients with 3 g per dayof nicotinic acid for 90 days andcompared their progress with 13 untreat-ed patients Every patient had been on aplateau at their current level for sixmonths Of the nicotinic acid group twowere much improved and four mademinimal to moderate improvement Outof the placebo group one was muchimproved and one moderately improvedFor this distribution, Chi Sq = 2 5 Theprobability this is due to chance is about12 percent However, it is a very smallsample Had the sample been twice aslarge with the same distribution Chi Sq.would have been over five which wouldreduce the probability to 2 percent

However, these authors were so con-vinced nicotinic acid could not workthey muddled around in their con-clusion Surely the improvement of sixout of 14 chronic patients who hadshown no change in six months shouldhave alerted them that there might besomething there They could as easilyhave expanded their series This is thereason why the motivation of an experi-menter is important An investigatorwishing to negate findings will run hisexperiments in such a way as tomaximize the negative effect while anexperimenter hoping to corroborate willrun his experiments longer and may thenfind the positive results The firstinvestigator will always quit when he isahead because he minimizes the dangerof being proven wrong by his own dataThe corroborator may also be dis-appointed, but by perserveting heat least

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greatly increases the probability he willbe a party to the introduction ofsomething useful and novel The com-mittee were all hoping to destroy themegavitamin claims They, therefore,conducted their literature review in away designed to maximize this hoped-forevent

(26) Pfeiffer, Sohler, Jenney, and Iliev(1974) confirmed our original des-cription of malvaria (Hoffer andOsmond, 1963) A more appropriate termin our opinion is pyrroluria, the termcoined by Pfeiffer The patient whoexcretes too much kryptopyrrole (here-after KP), i e., has too much in his body,has the following characteristics: (1)white spots in the nails; (2) failure toremember dreams; (3) sweetish breathodor; (4) left upper quadrant abdominalpain; (5) dysperceptive schizophreniaand neurological metabolic symptomsKP combines with pyridoxine and zinc toproduce symptoms of pyridoxine andzinc deficiency Adequate doses ofpyridoxine, up to 3 g per day, and zincwill relieve the symptoms

(27) Pfieffer (1974) In this reportPfeiffer summarized his work leading to adivision of schizophrenics into severalbiochemical types, i e , histapenics,histadelics, and pyrroluriacs Thespecific biochemical treatment for eachgroup is outlined

(28) Cott (1973) Here Dr Cott reportedhis conclusions based upon a series of500 children tested over a seven-yearperiod He concluded that a largenumber of disturbed children and child-ren with learning disabilities can behelped by orthomolecular treatmentThis paper came out after the APA TaskForce Report, but they would undoubt-edly have ignored it since it did notfollow the fad double-blind metho-dology

(29) Mickelson (1975) reported the caseof a 21-year-old male schizophrenic whodid not respond to any of the com -

mittee's favorite treatments includingcounseling,. milieu therapy (threemonths) in a general hospital psychiatricunit, three weeks of day therapy, theusual gamut of major tranquilizers, and aseries of 6 ECT, a rehabilitation program,and frequent visits to a social worker.This was followed by six additional weeksin a psychiatric ward from which he wasalmost forcibly discharged and admissionsoon after to a mental hospital It is clearthat this. unfortunate patient had notresponded and was doomed to the usualpattern of the chronically tranquilizedpatient—the usual revolving doorbetween community and hospital orhospital surrogate

But the parents had read our book,How To Live With Schizophrenia, tooktheir son out against medical advice andhad him sent to an orthomolecularpsychiatrist far from home. On dischargefrom this latest treatment he was greatlyimproved

One would think that most reasonablycurious psychiatrists would become in-terested Dr Mickelson, who carefullyreported how the most persuasivetechniques known including milieutherapy and the other psychotherapieshad failed to do anthing, now falls backon the old, never established notion thatthe patient improved because of theparents' faith in the biochemicalapproach That is, the recovery arosefrom a powerful placebo effect operatingfrom a distance of several hundred miles

(30) Rimland, Dreyfus, and Callaway(1976) completed a double-blind control-led experiment on 16 autistic type child-ren who had shown noticeable behavior-al improvement when given pyridoxine(up to 3 g per day) The patients werealso taking other nutrient supplements.The pyridoxine supplement was replacedduring two separate experimental trialperiods; first by substance A, then by B.The first two authors assigned behavioralratings to the experimental trials afterwhich the third author revealed whichsubstance was pyridoxine. It was ident-ified correctly in 11 out of 15 children

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For the 16th child the judges could see nodifference It was then learned thatpyridoxine had been given for both A andB periods

This is one of the best types of doubleblinds for a group homogeneous withrespect to their response to pyridoxinewas used Secondly pyridoxine, contraryto nicotinic acid, does not give itselfaway by producing a flush

In the spring of 1974 the CanadianSchizophreniaJoundation held its thirdannual meeting It was entirely devotedto orthomolecular treatment and waspublished in the journal of Ortho-molecular Psychiatry, 1974, Decemberissue It is available from the CanadianSchizophrenia Foundation, Regina,Saskatchewan, as a "Primer on Ortho-molecular Treatment "

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SECTION III—Pauling Paper

OPINION AND COMMENTOn the Orthomolecular Environment ofthe Mind: Orthomolecular TheoryBy Linus Pauling, Phi),

The author defines orthomolecular psy-chiatry as the achievement and preservationof good mental health by the provision of theoptimum molecular environment for themind, especially the optimum concentrationsof substances normally present in the humanbody, such as the vitamins. He states thatthere is sound evidence for the theory thatincreased intake of ,such vitamins as ascorbicacid, niacin, pyridoxine, and cyanocobala-min is useful in treating schizophrenia Thenegative conclusions of APA Task ForceReport 7, Megavitamin and OrthomolecularTherapy in Psychiatry, he says, result not onlyfrom faulty arguments and from a bias againstmegavitamin therapy but also from a failureto deal fully with orthomolecular therapy inpsychiatry. Three psychiatrists comment onOr Pauling's presentation

Orthomolecular Psychiatry is theachievement and preservation of mentalhealth by varying the concentrations inthe human body of substances that arenormally present, such as the vitamins Itis part of a broader subject, ortho-molecular medicine, an important partbecause the functioning of the brain isprobably more sensitively dependent inits molecular composition and structurethan is the functioning of other organs(1)

After having worked for a decade onthe hereditary hemolytic anemias, Idecided in 1954 to work on the molecularbasis of mental disease. I read the papersand books dealing with megavitamintherapy of schizophrenia by Hoffer andOsmond (2-4) as well as the reports onBased on a lecture given at a meeting of the AmericanCollege of Neuropsychopharmacology. Palm Springs.California. December 4-7. 1973Dr. Pauling is Director, Linus Pauling Institute ofScience and Medicine. 2700 Sand Hill Rd . Menlo Park.California 94025Reprinted by permission of the American Journal ofPsychiatry, Vol 131, pp. 1251-1257. 1974 (plus a chargeof $100) . Copyright 1974, the American PsychiatricAssociation

studies of vitamins in relation to mentaldisease by Cleckley and Sydenstricker(5-6) and others. In the course of time Iformulated a general theory of thedependence of function on molecularstructure of the brain and other parts ofthe body and coined the adjective"orthomolecular" to describe it (1)

There is no doubt that the mind isaffected by its molecular environment.The presence in the brain of molecules ofLSD, mescaline, or some other schizo-phrenogenic substance is associated withprofound psychic effects Mental mani-festations of avitaminosis have beenreported for several vitamins A cor-relation of behavior of schoolchildrenwith concentration of ascorbic acid inthe blood (increase in "alertness" or"sharpness" with increase in concentra-tion) has been reported by Kubala andKatz (7) A striking abnormality in theurinary excretion of ascorbic acid afteran oral loading dose was reported forchronic schizophrenics by VanderKamp(8) and by Herjanic and Moss-Herjanic(9) My associates and I (10) carried outloading tests for three vitamins onschizophrenic patients who had recentlybeen hospitalized and on control sub-jects The percentage of schizophrenicpatients who showed low urinaryexcretion of each vitamin was abouttwice as great as that of the controls: forascorbic acid, 74 percent of the schizo-phrenic patients showed low urinaryexcretion versus 32 percent of thecontrols; for niacinamide, 81 percentversus 46 percent; and for pyridoxine, 52percent versus 24 percent The possibilitythat the low values in urinary excretion ofthese vitamins for schizophrenic patientsresulted from poor nutrition is madeunlikely by the observation that thenumbers of subjects low in one, two, orall three vitamins corresponded well withthe numbers calculated for independentincidence.

There are a number of plausiblemechanisms by which the concentrationof a vitamin may affect the functioning

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r

of the brain One mechanism, effectivefor vitamins that serve as coenzymes, isthat of shifting the equilibrium for thereaction of apoenzyme and coenzyme togive the active enzyme An example isthe effectiveness of cyanocobalamin(vitamin B12) given in amounts 1,000times greater than normal to control thedisease methylmalonic aciduria (11-14)About half of the patients with thisdisease are successfully treated withmegadoses of vitamin B12 In thesepatients a genetic mutation has occurredand an altered apoenzyme that has agreatly reduced affinity for the coenzymehas been produced. Increase in concent-ration of the coenzyme can counteractthe effect of the decrease in the value ofthe combining constant and lead to theformation of enough of the activeenzyme to catalyze effectively thereaction of conversion of methylmalonicacid to succinic acid

In the human population there may beseveral alleles of the gene controlling themanufacture of each apoenzyme; inconsequence the concentration of co-enzyme needed to produce the amountof active enzyme required for optimumhealth may well be somewhat differentfor different individuals In particularmany individuals may require a consider-ably higher concentration of one or morecoenzymes than other people do foroptimum health, especially for optimummental health It is difficult to obtainexperimental evidence for genemutations that lead to only smallchanges in the properties of enzymes.The fact that genes that lead to large andmore easily detectable changes in theproperties of enzymes occur, as inindividuals with methylmalonic aciduria,for example, suggests that mutations thatlead to small changes also occur

Significant differences in enzymeactivity in different individuals havebeen reported by many investigators,especially by Williams (15) who hasmade many studies of biochemicalindividuality It is likely that thoroughstudies of enzymes would show them tobe similar to the human hemoglobins. A

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few of the abnormal human hemo-globins, most of which involve only thesubstitution of one amino-acid residuefor another in either the alpha chain orthe beta chain of the molecule, differgreatly in properties from normal adulthemoglobin, leading to serious mani-festations of disease

It was in the course of the study of oneof these diseases, sickle cell anemia, thatthe first abnormal hemoglobin wasdiscovered (16) Most of the abnormalhuman hemoglobins, however, differfrom normal hemoglobin in their proper-ties to only a small extent, so that there isno overt manifestation of disease Thereis, nevertheless, the possibility that eventhe small changes in properties of anabnormal hemoglobin associated with amild hemoglobinopathy will have del-eterious consequences An example isthe intolerance to sulfa drugs associatedwith the substitution of arginine forhistidine in the locus 58 in the alphachain or 63 in the beta chain It is likelythat individual differences in enzymeactivity will in the course of time beshown to be the result of differences inthe amino-acid sequences of the poly-peptide chains of the apoenzymes

More than 100 abnormal humanhemoglobins are now known, and thehuman population may be expected tobe similarly complex with respect tomany enzymes, including those involvedin the functioning of the brain Atendency to schizophrenia is probablypolygenic in origin I have suggested (1)that the genes primarily involved in thistendency may well be those whichregulate the metabolism of vital sub-stances such as the vitamins

Some vitamins are known to serve ascoenzymes for several enzyme systems.We might ask if the high concentration ofcoenzyme required to produce theoptimum amount of one active enzymemight not lead to the production of fartoo great an amount of another activeenzyme The answer to this question isthat the danger is not very great. Formost enzymes the concentration ofcoenzyme and the value of the comb

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ination constant are such that most (90

percent or more) of the protein isconverted to active enzyme Accord-ingly, a great increase in concentrationwould increase the amount of mostactive enzymes by only a few percentagepoints, whereas it might cause a greatincrease for a mutated enzyme.

The Orthomolecular Treatment ofSchizophrenia

In the book Orthomolecular Psychia-try: Treatment of Schizophrenia (17) mycolleagues and I pointed out that theorthomolecular treatment of schizo-phrenia involves the use of vitamins(megavitamin therapy) and minerals; thecontrol of diet, especially the intake ofsucrose; and, during the initial acutephase, the use of conventional methodsof controlling the crises, such as thephenothiazines The phenothiazines arenot, of course, normally present in thehuman body and are not orthomolecularHowever, they are so valuable incontrolling the crisis that their use isjustified in spite of their undesirable sideeffects.

Hawkins (18, p 640) stated that hisinitial combination of vitamins for thetreatment of schizophrenia was 1 gm ofascorbic acid, 1 gm of niacinamide, 50mg of pyridoxine, and 400 1. U of vitaminE four times a day Other vitamins mayalso be given A larger intake, especiallyof niacinamide or niacin, may beprescribed; the usual amount seems to beabout 8 gm a day after an initial period of4 gm a day.

The vitamins, as nutrients or medica-ments, pose an interesting question. Thequestion is not, Do we need them? Weknow that we do need them, in smallamounts to stay alive The real questionis, What daily amounts of the variousvitamins will lead to the best of health,both physical and mental? This questionhas been largely ignored by medical andnutritional authorities.

Let us consider schizophrenia.Osmond (19, p 200) stated that about 40

percent of schizophrenics hospitalizedfor the first time are treated successfullyby conventional methods in that they arereleased and not hospitalized a secondtime. The conventional treatment failsfor about 60 percent in that the patient isnot released or is hospitalized againConventional treatment includes adecision about vitamin intake Usually itis decided that the vitamins in the foodwill suffice or that a multivitamin tabletwill also be given. The amounts ofascorbic acid, niacin, pyridoxine, andvitamin E may be approximately the dailyallowances recommended by the Foodand Nutrition Board of the U S. NationalAcademy of Sciences-National ResearchCouncil: 60 mg of ascorbic acid, 20 mg ofniacin, 2 mg of pyridoxine, and 15 I U ofvitamin E Is this amount of vitaminscorrect? Would many schizophrenicpatients respond to their treatment betterif the decision were made that theyshould receive 10 or 100 or 500 times asmuch of some vitamins? What is theoptimum intake for these patients? Ibelieve there is much evidence that theoptimum intake for schizophrenicpatients is much larger than the recom-mended daily allowances By the use oforthomolecular methods in addition tothe conventional treatment of schizo-phrenia, the fraction of patients hospital-ized for the first time in whom thedisease is controlled may be increasedfrom about 40 percent to about 80

percent (19)

Ascorbic Acid

It was reported by Horwitt in 1942 (20)and by later investigators that schizo-phrenic patients receiving the usualdietary amounts of ascorbic acid hadlower concentrations of ascorbic acid inthe blood than people in good health.The loading-test results of VanderKamp(8), Herjanic and Moss-Herjanic (9), andPauling and associates (10) have beenmentioned above In his discussion ofascorbic acid and schizophrenia Herjanic

. (21) concluded:

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The individual variation of the need forascorbic acid may turn out to be one of thecontributing factors in the development ofthe illness Ascorbic acid is an importantsubstance necessary for optimum functioningof many organs If we desire, in the treatmentof mental illness, to provide the "optimummolecular environment," especially theoptimum concentration of substancesnormally present in the human body(Pauling, 1968 (1]), ascorbic acid shouldcertainly be included (21, p 314)

There is, moreover, a special reasonfor an increased intake of ascorbic acidby patients with schizophrenia or anyother disease for which there is onlypartial control About 60 mg of ascorbicacid a day is enough to prevent overtmanifestations of avitaminosis C (scurvy)in most people. However, there areseveral significant arguments to supportthe thesis that the optimum intake formost people is 10 to 100 times more than60 mg These arguments are summarizedin the papers and books of Irwin Stone(22) and myself (23, 24) They constitutethe theoretical basis for the customaryuse of about 4 gm of ascorbic acid a dayin the orthomolecular therapeutic andprophylactic treatment of schizophrenia.

A significant controlled trial ofascorbic acid in chronic psychiatricpatients was reported in 1963 by Milner(25) The study, which was double-blind,was made with 40 chronic male patients:34 had schizophrenia, 4 had manic-depressive psychosis, and 2 had generalparesis. Twenty of the patients, selectedat random, received 1 gm of ascorbicacid a day for three weeks; the restreceived a placebo. The patients werechecked with the Minnesota MultiphasicPersonality Inventory (MMPI) and theWittenborn Psychiatric Rating Scales( WPRS) before and after the trial Milnerconcluded that "statistically significantimprovement in the depressive, manic,and paranoid symptom-complexes, to-gether with an improvement in overallpersonality functioning, was obtainedfollowing saturation with ascorbic acid"(25) He suggested that chronic psy-chiatric patients would benefit from the

administration of ascorbic acid.We found (10) that of 106 of the

schizophrenic patients we studied whohad recently been hospitalized in aprivate hospital, a county-universityhospital, or a state hospital, 81 (76percent) were deficient in ascorbic acid,as shown by the six-hour excretion of lessthan 17 percent of an orally administereddose Only 27 of 89 control subjects (30percent) showed this deficiency Greatdeficiency (less than 4 percent excreted)was shown by 24 (22 percent) of theschizophrenic subjects and by only 1 (1percent) of the controls I have no doubtthat many schizophrenic patients wouldbenefit from an increased intake ofascorbic acid. My estimate is that 4 gm ofascorbic acid a day, in addition to theconventional treatment, would increasethe fraction of acute schizophrenics inwhom the disease is permanently con-trolled by about 25 percent Except forthat of Milner (25), no controlled trial ofascorbic acid in relation to schizophreniahas been made, so far as I know

The requirement of niacin (nicotinicacid) for proper functioning of the brainis well known The psychosis of pellagra,as well as the other manifestations of thisdeficiency disease, is prevented by theintake of a small amount of niacin, about20 mg a day. In 1939 Cleckley, Syden-stricker, and Geeslin (5) reported thesuccessful treatment of 19 patients withsevere psychiatric symptoms with niacin,and in 1941 Sydenstricker and Cleckley(6) reported similarly successful treat-ment of 29 patients with niacin. In bothstudies, moderately large doses of niacin,0 3 to 1 5 gm a day, were given. None ofthe patients in these studies had physicalsymptoms of pellagra or any otheravitaminosis A decade later, Hoffer andOsmond (2, 3) initiated two double-blind studies of niacin or niacinamide inthe treatment of schizophrenia Anotherdouble-blind study was reported byDenson in 1962 (26) In 1964 Hoffer and

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Osmond (4) reported that a 10-yearfollow-up evaluation of the patients intheir initial studies showed that 75percent had not required hospitalization,compared with 36 percent of thecomparison group, who had not receivedniacin Similar estimates have been madeby Hawkins (18, p 585) There are,however, contradictory statements byother investigators The question of theweight of the evidence is discussedbelow in the section on the APA taskforce report

Pyridoxine

Pyridoxine, vitamin B6, is used in thetreatment of schizophrenia in amounts of200 to 800 mg a day by many ortho-molecular psychiatrists Derivatives ofthis vitamin are known to be thecoenzymes for over 50 enzymes, and thechance of a genotype with need for alarge intake of the vitamin is accordinglygreat There is evidence that pyridoxineis involved in tryptophan-niacin meta-bolism

A double-blind placebo-controlledstudy had been made of pyridoxine andniacin by Ananth, Ban, and Lehmann(27) Their experimental population con-sisted of 30 schizophrenic patients: 15were men, 15 were women, their meanage was 41 7 years, and their meanduration of hospitalization was 10 9years They were randomly assigned tothree treatment groups: 1) the combinedtreatment group, which received 3 gm ofnicotinic acid a day for 48 weeks and 75mg of pyridoxine a day during three4-week periods; 2) the nicotinic acidgroup, which received 3 gm of nicotinicacid a day for 48 weeks and a pyridoxineplacebo; and 3) the pyridoxine group,which received 75 mg of pyridoxine a dayduring three 4-week periods and anicotinic acid placebo. In addition,neuroleptic preparations were administ-ered according to clinical requirementsfor the control of psychopathology Theinvestigators reported that "of the tenpatients in each treatment group, sevenimproved and three deteriorated in the

nicotinic acid group, nine improved andone deteriorated in both the combinedtreatment group and in the pyridoxinegroup" (27) They also stated:

Of the three indices of therapeutic effects,global improvement in psychopathology(Brief Psychiatric Rating Scale and NursesObservation Scale for Inpatient Evaluation)scores was seen in all three groups; thenumber of days of hospitalization during theperiod of the clinical study was lower in boththe nicotinic acid and the combined treat-ment group; and only in the combinedtreatment group was the daily average dosageof phenothiazine medication decreasedThus, improvement in all three indices wasnoted in the combined treatment group

However, several side effects were ob-served during the therapeutic trials, indicat-ing that the vitamins used are not completelysafe (27, p 381)

The investigators reached the con-clusion that "on balance, these resultssuggest that the addition of pyridoxinemay potentiate the action of nicotinicacid Thus pyridoxine seems to be auseful adjunct to nicotinic acid therapy"(27, p 381) Hawkins (18) commented onthis work in the following way:

The therapeutic effect was demonstrableeven though the patients had been hospital-ized for an average of 10 9 years, were not onhypoglycemic diets, and the doses of bothpyridoxine (75 mg daily) and vitamin B3 (3gm a day) were considerably below thedosages we routinely prescribe (18, p 638).

Cyanocobalamin

A deficiency in cyanocobalamin(vitamin B12), whatever its cause, leadsto mental illness as well as to suchphysical manifestations as anemia Theanemia can be controlled by a largeintake of folic acid, but the mental illnessand neurological damage cannot Apathologically low concentration ofcyanocobalamin in the blood serum hasbeen reported to occur in a much largerpercentage of patients with mentalillness than in the general population:Edwin and associates (28) determined the

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amount of vitamin B12 in the serum ofevery patient over 30 years old admittedto a mental hospital in Norway during aperiod of one year Of the 396 patients,61 (15.4 percent) had a subnormal orpathologically low concentration ofvitamin B12, less than 150 pg per ml(the normal range is 150 to 1,300 pg perml ) This incidence is 30 times as great asthat estimated for the population as awhole. Other investigators have reportedsimilar results and have suggested that alow serum concentration of vitamin B12,whatever its origin, may cause mentalillness In addition, of course, mentalillness may accompany some geneticdiseases, such as methylmalonic acid-aria, which can be controlled only byachieving a serum concentration ofcyanocobalamin far greater than normal

Minerals and Other Vitamins

There is some evidence that mentalillness may result from deprivation of orabnormal need for minerals and othervitamins (See, for example, Pfeiffer,111ev, and Goldstein [29]) Further work inthis field by psychiatrists and bio-chemists is needed

THE APA TASK FORCE REPORT

In July 1973 an APA task force of fivephysicians and one consultant issued a54-page report titled Megavitamin andOrthomolecular Therapy in Psychiatry(30) In this report the Task Force onVitamin Therapy in Psychiatry purportsto present both theoretical and empiricalreasons for completely rejecting thebasic concept of orthomolecular psy-chiatry, which is the achievement andpreservation of good mental health bythe provision of the optimum molecularenvironment for the mind, especially theoptimum concentrations of substancesnormally present in the human body

Some Errors in the Report

It is mentioned in the report that in thetreatment program of the orthomolecularpsychiatrists "each patient may receiveas many as six vitamins in large dosesindividually determined by the treatingphysician as well as other psychotropicdrugs and hormones whose doses are alsoindividually determined for each patient"(p. 46) The assumption is made by thetask force that the optimum intake ofvitamins for mental health is the conven-tional average daily nutritional require-ment, with growth and development asthe criteria: "In schizophrenia there isapparently an adequate vitamin intakefor growth and development until theillness becomes manifest in the teens orearly adult life" (p 40) Mention is madein the report of the well-known geneticdiseases with both psychic and somaticmanifestations that can be controlled byan intake of a vitamin 100 or 1,000 timesthe usually recommended daily allow-ance, but the possibility that less obviousgenetic differences could result in anincreased individual need for a largerintake of vitamins in order to achievegood mental health, as discussed in my1968 publication (1) and in the earliersections of this paper, is rejected on thebasis of arguments that have little valueor pertinence

One such argument is the following:The two theoretical bases adduced by

megavitamin proponents for the effective-ness of NA therapy (nicotinic acid as a methylacceptor and NAD deficiency) are in factgenerally incompatible, because NAA[nicotinamide), when functioning as a vita-min, is bound to the remainder of thecoenzyme molecule by the nitrogen of itspyridine ring and hence can no longer acceptmethyl groups

Essentially, then, the two views of NA as avitamin precursor of NAD and as a methylacceptor are incompatible, except for thepossibility that there is in schizophreniadouble deficit—both a vitamin deficiencyand a transmethylation defect and thatnicotinic acid has the happy fortune to servetwo purposes simultaneously (pp 40-42)

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There is an obvious error in this taskforce argument There is no incompati-bility between two functions of nicotinicacid; some molecules may engage in onefunction and others in the other A defectin either function might be controlled byincreasing the intake of the vital sub-stance A "double deficit" is not neededThe authors of the report would haveseen the fallacy in their argument if theyhad set up some equilibrium and reactionrate equations, as was done in my 1968paper (1).

The task force expresses an interestingmisunderstanding of the nature of vita-mins, in the following words: "Bycommon definition a vitamin is not onlyan essential nutrient, but it is essentialbecause it is transformed into a co-enzyme vital for metabolic reactions" (p.41) In fact, this is not the commondefinition of a vitamin; it is wrong Somevitamins, including vitamin C, are notknown to be transformed into a co-enzyme This misunderstanding by thetask force may have contributed to themisinterpretation of the evidence for andthe theoretical basis of orthomolecularpsychiatry

Nicotinic acid as a methyl acceptor isreferred to in the report: "From Study No12: nicotinic acid in the dosage of 3000mg per day can neither prevent norcounteract the psychopathology inducedby the combined administration of amonoamine oxidase inhibitor (tran-ylcypromine) and methionine" (p 16) Infact, the molecular weights of nicotinicacid and methionine (a methyl donor)are nearly the same, 123 and 149,respectively Instead of 3 gm, 16 5 gm ofnicotinic acid would have had. to begiven each day to accept the methylgroups donated by the 20 gm ofmethionine that was given each day Thestudy referred to as number 12 (31),which resulted in an exacerbation of theillness of 30 schizophrenic patients whoparticipated in it, has no value as a test ofthe methyl acceptor theory of nicotinicacid Consideration of ethical principlesmay have kept the investigators fromrepeating the study with use of the

proper equimolar amounts of nicotinicacid and methionine.

The Failure to Discuss Ascorbic Acid andPyridoxine

In several places the AM task forcereport mentions the use of 1 to 30 gm ofascorbic acid a day by orthomolecularpsychiatrists There are, however, noreferences to the literature. Milner'sdouble-blind study (25) is not mention-ed, nor is there any discussion of themany papers in which a low level ofascorbic acid in the blood of schizo-phrenics was reported. Neither thegeneral theory of orthomolecular psy-chiatry, as presented in my 1968 paper(1), nor any of the special argumentsabout the value of ascorbic acid ispresented or discussed in any significantway. There is, moreover, no discussion inthe report of pyridoxine and no referenceto the 1973 work by Ananth, Ban, andLehmann (27) on the potentiation bypyridoxine of the effectiveness of niacinin controlling chronic schizophrenia Thetitle of the report, Megavitamin andOrthomolecular Therapy in Psychiatry, iscompletely inappropriate, and the gen-eral condemnation of megavitamin andorthomolecular therapy is unjustified.

Niacin

The report does say that it is possiblethat the other water-soluble vitamins willprove to be more effective than niacin,but it adds:

Nonetheless, the massive use of niacin hasalways been the cornerstone of the theoryand practice of megavitamin advocatesSince this has proved to have no value whenit is employed as the sole variable along withconventional treatments of schizophrenia,the burden of proof for the complex andhighly individualized programs now advo-cated would appear to be on the proponentsof such treatment (p 46)

I shall point out below that theprinciples of medical ethics prevent

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orthomolecular psychiatrists from with-holding from half of their patients atreatment that they consider to bevaluable Controlled tests can be carriedout only by skeptics I now ask whetherthe task force is justified in saying thatthe massive use of niacin has beenproved to have no value when it isemployed as the sole variable along withconventional treatments of schizo-phrenia My answer to this question,from a study of the evidence quoted inthe report, is that it is not justified

The evidence that niacin has no valueis far from conclusive. A beneficial effectof niacin or niacinamide was reported forthree double-blind studies (two by Hofferand Osmond and their collaborators [2,3, 32] and one by Denson [26]) and in 12open clinical trials by other investigatorsreferred to in the report On the otherhand, the report mentions 7 double-blindstudies in which a statistically significantdifference between the niacinamidesubjects and the controls was notobserved

A failure to reject with statisticalsignificance the null hypothesis that thetreatment and the placebo have equalvalue is not proof that the treatment hasno value. The explicit statistical analysisof an alternative hypothesis should becarried out: for example, the hypothesisthat there is a 10-percent or 20-percentgreater improvement in the treatedsubjects than in the placebo subjects Nosuch analysis has been published

In fact, some of the " negative " studiesindicate that the treatment has value.The report states that "Greenbaum [33]reported a double-blind study of 57schizophrenic children who receivednicotinamide 1 gm per 50 lbs of bodyweight or placebo for six months Nostatistically significant differences wereseen in the two groups as a result of thetreatment " (p 11) It is true that nostatistically significant differences wereseen, but that is not the whole truth Theprincipal criterion of improvement in thisstudy was the increase in the score on aclinical scale of observable behaviorcategories The average improvement in

72

the score of the 17 children receivingniacinamide was 4 0 units and that of the24 controls was 2 6 units (there was athird group of 16 children who weregiven a tranquilizer and niacinamide)The children who were given niacin-amide showed a 54-percent greaterimprovement than the children who weregiven placebo The groups were toosmall, however, for the difference to besignificant at the 95-percent level ofconfidence This study does not provethat niacinamide has no value Rather itindicates that niacinamide has greatervalue than the placebo, even though itfails to show this at the customary levelof statistical significance

The Hoffer-Osmond Diagnostic Test

Two-thirds of the report relates toniacin, and one-third to the Hoffer-Osmond Diagnostic Test (HOD) (34),which has no special connection withmegavitamin or orthomolecular psy-chiatry except that it was devised by theoriginators of niacin therapy The reportshould have been given the title NiacinTherapy and the HOD Test, or publishedas two reports, one on niacin and one onthe HOD test It would have been stillbetter for the task force to have discussedmegavitamin and orthomoleculartherapy in psychiatry fully

The Question of Controlled Experiments

The report refers to the low credibilityof the megavitamin proponents, whosepublished results were not duplicated instudies carried out by one of the taskforce members (p 48) The penultimatesentence of the report is, "Their cred-ibility is further diminished by theconsistent refusal over the past decade toperform controlled experiments and toreport their new results in a scientificallyacceptable fashion" (p 48)

I have talked with the leading ortho-molecular psychiatrists and have foundthat they feel the principles of medical

I'.

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ethics prevent them from carrying outcontrolled clinical tests, with half of theirpatients receiving orthomoleculartherapy in addition to the conventionaltreatment and the other half receivingonly the conventional treatment It is theduty of the physician to give to every oneof his patients the treatment that in hisbest judgment will be of the greatestvalue. Some psychiatrists, includingHoffer and Osmond, carried out control-led trials 20 years ago. They becameconvinced that orthomolecular therapy,along with conventional treatment, wasbeneficial to almost every patient Fromthat time on their ethical principles haverequired that they give this treatment andnot withhold it from half of theirpatients The task force is wrong incriticizing the orthomolecular psychiat-rists for not having carried out controlledclinical trials during the last few yearsInstead, it is the critics, who doubt thevalue of orthomolecular methods, whoare at fault in not having carried out welldesigned clinical tests

It is also the duty of a physician to giveto a patient a treatment that may benefithim and is known not to be harmful Theincidences of toxicity and other seriousside effects of the doses of vitamins usedin orthomolecular medicine are low.There is significant evidence that anincreased intake of certain vitamins maybenefit the patient It is accordingly theduty of the psychiatrist to prescribe thesevitamins for him

The Bias of the Task Force

The last sentence of the report reads asfollows:

Under these circumstances this Task Forceconsiders the massive publicity which theypromulgate via radio, the lay press andpopular books, using catch phrases which arereally misnomers like "megavitamin therapy"and "orthomolecular treatment," to bedeplorable (p 48)

This sentence, like others in the reportshows the presumably unconscious biasof the task force "Promulgate" (misused

here) is a pejorative word, and "catchphrases" is a pejorative expression I donot understand why megavitamintherapy and orthomolecular treatmentshould be called misnomers This con-cluding sentence, like many others in thebook, seems to me to have been writtenin order to exert an unjustifiably unfavor-able influence on the readers of thereport.

I have written two popular books, NoMore War! (35) and Vitamin C and theCommon Cold (24) I feel that each ofthem was worthwhile and that neitherwould have been easily replaced by amore technical book. The second book(24) was written because I had dis-covered in reading the medical literaturethat there was much evidence thereabout the value of ascorbic acid indecreasing both the incidence and theseverity of the common cold and thatthis evidence had been suppressed ormisrepresented by the medical andnutritional authorities Since publicationof the book, eight new studies have beenreported Every one of these has verifiedthe value of ascorbic acid The APAreport shows the same sort of negativeattitude as that shown by the authoritiestoward ascorbic acid in relation to thecommon cold There seems to be a sortof professional inertia that hindersprogress

CONCLUSIONS

Orthomolecular psychiatry is theachievement and preservation of goodmental health by the provision of theoptimum molecular environment for themind, especially the optimum concentra-tions of substances normally present inthe human body, such as the vitamins.There is evidence that an increasedintake of some vitamins, includingascorbic acid, niacin, pyridoxine, andcyanocobalamin, is useful in treatingschizophrenia, and this treatment has asound theoretical basis The APA taskforce report Megavitamin and Ortho-molecular Therapy in Psychiatry dis-

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cuss& vitamins in a very limited way(niacin only) and deals with only one ortwo aspects of the theory Its argumentsare in part faulty and its conclusions areunjustified

REFERENCES

1 PAULING, L : Orthomolecular psychiatry Science160:265271. 1968

2 HOFFER. A : Niacin Therapy in Schizophrenia Spring-field. Ill Charles C Thomas. 1962

3 OSMOND. H , HOFFER. A : Massive niacin treatmentin schizophrenia: review of a nine-year study Lancet1:316 . 319. 1962

HOFFER, A., OSMOND, H : Treatment of schizophreniawith nicotinic acidi a ten-year follow-up Acta PsychiatrScand 40:171 . 189. 1964

CLECKLEY, H M., SYDENSTRICKER. V.P., GEESLIN,L.E : Nicotinic acid in treatment of atypical psychoticstates associated with malnutrition JAMA 112:2107-2110. 1939

SYDENSTRICKER, V.P., CLECKLEY. H.M : The effectof nicotinic acid in stupor, lethargy and various otherpsychiatric disorders Am 1 Psychiatry 98:83 .92. 1941

KUBALA, A L., KATZ, M M : Nutritional factors inpsychological test behavior .1 Genet Psvchol 96:343-352. 1960

8 VANDERKAMP, H.: A biochemical abnormality inschizophrenia involving ascorbic acid Int J NewerPsychiatry 2:204-206. 1966

9 HERJANIC, M„ MOSS-HERJANIC, B L : Ascorbic acidtest in psychiatric patients J Schizophrenia 1:257-260.1967

10 PAULING. L., ROBINSON. A.B., OXLEY. S S., et al.:Results of a loading test of ascorbic acid. niacinamide,and pyridoxine in schizophrenic subjects and controls, inOrthomolecutar Psychiatry: Treatment of SchizophreniaEdited by Hawkins. 0.. Pauling, L.. San Francisco. W HFreeman and Co . 1973. pp 18-34

it ROSENBERG, L.E.. LILLJEOVIST, A-C, HSIA. Y.E:Methyimalonic aciduria: metabolic block localization andvitamin 812 dependency Science 162:805 . 807. 1968

12 LINDBLAD, 8., OLIN P.. SVANBER G. B.. et al : Methy-Imalonic acidemia Acta Paediatr Scand 57:417-424.1968

13 WALKER, F.A , AGARWAL. A B., SINGH. R : Methyl-malonic aciduria: response to oral 0 12 therapy JPediatr 75:344. 1969

14 ROSENBERG, L. E.. LILLJEOVIST, A-C, HSIA, Y E ,et al.: Vitamin 8 1 2 dependent methylmalonicaciduria:defective 812 metabolism in i cultured fibroblasts.Biochem Biophys Res Commun 37:607-614. 1969

15 WILLIAMS. R.J.: Biochemical Individuality Npw York.John Wiley B Sons. 1957

16 PAULING, L , ITANO. H A.. SINGER. S.J et al.: Sicklecell anemia. a molecular disease Science 110:543 .548.1949

17 HAWKINS. D PAULING, L. lads.): OrthomolecularPsychiatry: Treatment of Schizophrenia San Francisco.W H Freeman and Co 1973

74

18 HAWKINS, D : Orthomolecular psychiatry: treatment ofschizophrenia Ibid. pp 631673

19 OSMOND. H.: The background to the niacin treatmentIbid. pp 194 . 201

20 HORWITT. M.K.: Ascorbic acid requirements of in-dividuals in a large institution Proc Sec Exp Blot Med49:248-250. 1942

21 HERJANIC, M : Ascorbic acid and schizophrenia. inOrthomolecular Psychiatry: Treatment of SchizophreniaEdited by Hawkins. D., Pauling, L.. San Francisco. W HFreeman and Co 1973 pp 303-315

22 STONE. I: The Healing Factor: Vitamin C AgainstDisease New York. Grosser and Dunlap 1972

23 PAULING L : Evolution and the need for ascorbic acidProc Nall Acad Sci U S A 67:16434648. 1970

24 PAULING. L : Vitamin C and the Common Cold SanFrancisco W H Freeman and Co . 1970

25 MILNER. G.: Ascorbic acid in chronic psychiatricpatients: a controlled trial Br J Psychiatry 109:294-299.1963

26 DENSON, R ; Nicotinamide in the treatment of schizo-phrenia Dis New Syst 23:167172. 1962

27 ANANTH. J.V., BAN. T A., LEHMANN, H.E : Potentia-tion of therapeutic effects of nicotinic acid by pyridoxinein chronic schizophrenics Can Psychiatr Assoc 118:377.382. 1973

28 EDWIN, E , HOLTEN. K . NORUM, K R , et at : VitaminB12

ndhyp77689 inoss inmental diseases Acta Med

Sca

29 PFEIFFER. C.C., ILIEV. F . GOLDSTEIN, L.: Bloodhistamine, basophil counts and trace elements in theschizophrenias, in Orthomolecular Psychiatry: Treatmentof Schizophrenia Edited by Hawkins, D.; Pauling. L..San Francisco W H Freeman and Co 1973. pp 463-510

30 Task Force Report 7: Megavitamin and OrthomolecularTherapy in Psychiatry Washington. DC. AmericanPsychiatric Association. 1973

31 ANANTH, .1.V., BAN, T.A . LEHMANN, H E . et al :Nicotinic acid in the prevention and treatment of meth-ionine . induced exacerbation of psychopathology inschizophrenics Can Psychiatr Assoc J 15:15-20. 1970

32 IdOFFER. A . OSMOND, H., CALLBECK. M J., andKAHAN, I : Treatment of schizophrenia with nicotinicacid and nicotinamide J Clin Exp Psychopathol 18:131158. 1957

33 GREENBAUM, G H C.: An evaluation of niacinamide inthe treatment of childhood schizophrenia Am JPsychiatry 127:89-93. 1970

34 KELM, H.: The Hoffer-Osmond Diagnostic Test IHODIiin Orthomolecular Psychiatry: Treatment of Schizo-phrenia. Edited by Hawkins. D Pauling. L. SanFrancisco. W H Freeman and Co . 1973. pp 327.341

35 PAULING, L.: No More War! New York. Dodd. Meadand Co .1958

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SECTION IV— Letter To The Editor

Dr. Pauling Comments on the Comments

Sir: I believe that the comments madeby Drs Wyatt, Klein, and Lipton on mypaper "On the Orthomolecular Environ-ment of the Mind: OrthomolecularTheory" (November 1974 issue) help toclarify the question, and I thank the threeauthors for their illuminating discussions.

In my article I concluded that thegeneral condemnation of megavitaminand orthomolecular therapy by the APATask • Force on Vitamin Therapy inPsychiatry (1) is unjustified Wyattconcluded that the principles of theorthomolecular hypothesis are reason-able and might be testable, but that thereis no good scientific evidence as yet thatmegavitamin therapy is beneficial Kleinpointed out that society needs to knowwhether a treatment is effective ordeleterious and that there is an un-pleasant likelihood that orthomolecularmethods will continue -to be used inpsychiatry without adequate scientificassessment He mentioned his belief thatonly programmatic centers can developthe large-scale, adequate, and timelycomparative factorial treatment studiesnecessary to answer the many complexquestions in the field of psychiatric care.Lipton discussed some of my criticisms ofthe task force report He mentioned theneed for further evidence only incident-ally, but I think that he would agree withWyatt, Klein, and me that further studiesshould be made

Much of Klein's comment dealt withthe question of scientific inference Myconclusion, derived from the publishedstudies, is that there is evidence (al-though it is far from overwhelming) thatan increased intake of some vitamins,including ascorbic acid, niacin, pyri-doxine, and cyanocobalamin, is useful intreating schizophrenia and that thistreatment has a sound theoretical basis

Reprinted by permission from the American Journal ofPsychiatry, Vol. 131, pp 1405

. 1406, 1974. Copyright 1974,the American Psychiatric Association

In the task force report it is stated thatthe massive use of niacin "has proved tohave no value when it is employed as thesole variable along with - conventionaltreatments of schizophrenia " (1, p 46).One of my criticisms of the task forcereport is that this statement cannot besupported

Klein stated that "one cannot prove anegative assertion, i e , that a drug is nodifferent from placebo." I gave thefollowing brief discussion of thequestion:

A failure to reject with statistical signifi-cance the null hypothesis that the treatmentand the placebo have equal value is not proofthat the treatment has no value The explicitstatistical analysis of an alternative hypo-thesis should be carried out: for example, thehypothesis that there is a 10-percent or20-percent greater improvement in thetreated subjects than in the placebo subjectsNo such analysis has been published

My statement was so brief that Dr.Klein misunderstood it. His discussion ofthis point began as follows:

Insofar as I understand his exposition,Pauling seems to be saying the following:Consider an experiment that finds that a drugis 30 percent more effective than placebo inthe samples studied, but that the 30-percentdifference could easily have arisen fromsampling fluctuations One has no way oftelling this 30-percent sample difference froma true zero-percent population differenceTherefore, the null hypothesis of no dif-ference in the sample populations cannot beinvalidated Pauling says one should alsomake a test against the possibility that thereis a true 10-percent or a true 20-percentpopulation difference

That is not what I said Let us considera study in which niacin is given to asample of 20 subjects taken at randomfrom a given population and placebo isgiven to a sample of 20 from the samepopulation Let us assume that 10subjects in each sample improve The

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conclusion might be drawn that niacinhas no greater value than placebo It ison the basis of studies such as thishypothetical one that the task forcereported that niacin has proved to haveno value. My question was whether astudy such as this has shown, at a certainlevel of confidence (e g , the customary95-percent level), that there was less than10-percent or less than 20-percent greaterimprovement in the niacin sample thanin the placebo sample

Reference to statistical tables showsthat, because of possible sampling errors,this hypothetical experiment does noteliminate at the 95-percent confidencelevel the hypothesis that, relative toplacebo, niacin increases by as much as50 percent the fraction of subjects whoimprove If niacin and placebo were infact equivalent, studies of much largersamples would be needed before it couldbe proved with statistical significancethat niacin has little value. As I pointedout, no such analysis has been made tojustify the statement made by the taskforce about niacin I have not made athorough statistical analysis of the niacinstudies that are described as givingnegative results, but the rough cal-culations that I have made indicate thatthey do not reject at the 95-percentconfidence level an effectiveness ofniacin as great as that claimed by theproponents of megavitamin therapy

Klein wrote that "one further problemis Pauling's incomprehensible accept-ance of very minimum differences thatlack statistical significance as solidevidence of therapeutic efficacy " I feelthat this remark distorts the facts I havesaid that there is evidence that mega-vitamin therapy has value It is notnecessary that the results of a study besignificant at the customary level ofp 05 (which is quite arbitrary) in orderto constitute evidence There are recog-nized methods for combining the resultsof several independent but similarstudies with low statistical significanceinto a result with higher statisticalsignificance I have criticized the taskforce for making strong statements that

are not supported by the evidence I donot think that my paper contains anyincorrect or unduly strong statements

In this connection, Klein stated that hewas baffled by my having appraised astudy (2) which both he and I consider tobe a poor one that contains methodo-logical errors A main reason for myinclusion of this study was that one of itsauthors was a member of the task forceAnother reason for mentioning it wasthat it is pertinent to orthomoleculartherapy in psychiatry but was notmentioned in the task force report It wasa double-blind study and deserved to bementioned both in the task force reportand in my article

I pointed out that derivatives ofpyridoxine are known to be coenzymesfor over 50 enzymes and that the chanceof a genotype with need for a large intakeof the vitamin is accordingly great. I alsostated that there is evidence thatpyridoxine is involved in tryptophan-niacin metabolism I described the study(2) and quoted the statements made bythe investigators about their results aswell as a comment by Hawkins I did notappraise the study myself; Klein errs insaying that I did I quoted the statement,"On balance, these results suggest thatthe addition of pyridoxine may potenti-ate the action of nicotinic acid Thuspyridoxine seems to be a useful adjunctto nicotinic acid therapy" (2), which wasmade in an article that was coauthoredby a member of the task force but wasomitted from the task force report.

Both Klein and Wyatt discussed myreference to the work of Greenbaum (3),who reported no statistically significantdifferences in a double-blind study ofschizophrenic children receiving niacin-amide or placebo Klein stated that Ipointed out that the children givenniacinamide showed greater positivegains on a critical scale than the controlsubjects, although not at a significantlevel He also pointed out my statementthat the study "indicates that niacin-amide has greater value than theplacebo, even though it fails to show thisat the customary level of statistical

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significance " Klein responded to thiswith the following statement:

This seems utterly incorrect The merefact that one sample had a bigger effect thananother sample does not justify the statementthat "niacinamide has greater value thanplacebo," since this is a statement thatgeneralizes to the population relationship

Klein is wrong in suggesting that mystatement or argument is incorrect,although of course it may have seemedutterly incorrect to him. First, I did notstate that niacinamide has greater valuethan placebo; what I said was that theGreenbaum study indicated that niacin-amide has greater value than placebo,even though it failed to show this at thecustomary level of statistical signifi-cance Even if the study had indicated agreater value for niacinamide at thep < 05, p <01, or p < .001 level, I couldnot have said simply that the studyproved niacinamide has greater value. Icould state only that it indicated this at acertain level of statistical significance.There is nothing holy about the 95-percent level of confidence. A study mayprovide evidence whether or not itreaches this conventional level

Greenbaum 's paper (3) permitted onlya rough estimate to be made of the pvalue for this comparison of his niacin-amide and placebo subjects. The value of37 given by Wyatt (obtained from

Greenbaum) corresponds to p < 18 by aone-tailed test The value of p (one-tailed) is pertinent to the question ofwhether the samples showing higherscores for niacinamide ; than for placebosubjects correctly represent the popula-tion from which they were drawn orwhether they represent a statisticalfluctuation associated with the selectionof the samples from the population.There is an 18-percent chance that such afluctuation would occur; that is, accord-ing to this calculation, it is five times aslikely that niacinamide would give betterresults than placebo in the wholepopulation than that the two are equiva-lent Greenbaum's observation. mightsi mply be the result of a sampling error..

Both Wyatt and Klein criticized my

statements about the ethical questionsassociated with experiments on humanbeings I see no reason to change myopinion on this matter

REFERENCES

1 Task Force Report 7: Megavitamin and OrthomolecularTherapy in Psychiatry Washington. DC. AmericanPsychiatric Association. 1973

2 ANANTH, J.V , BAN, T.A., LEHMANN, H.E : Potentia-tion of therapeutic effects of nicotinic acid by pyridoxinein chronic schizophrenics Can Psychiatr Assoc .1 18.377-382. 1973

3 GREENBAUM, G H C.: An evaluation of niacinamide inthe treatment of childhood schizophrenia Am JPsychiatry. 127:89.93. 1970

Linos Pawling, Ph.0Menlo Park. Calif

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SECTION V—Hoffer and Osmond'sComments on R. J. Wyatt's Comment

(1974) on L. Pauling 's report:

On The Orthomolecular Environment ofthe Mind: Orthomolecular Theory

We wonder why Wyatt bothered towrite his comments since they are merelyopinions lifted holus bolus from the TaskForce Report Since he makes exactly thesame errors it suggests he did not botherto read the original reports His criticismsare these:(1) That H Osmond in a brief back-ground paper on orthomolecular psych-iatry did not reprint the massive data wehave published in a large number ofpapers since 1957(2) That we did not again repeat all thisdata in our suicide paper where werestricted it to show how orthomoleculartreatment markedly decreased thesuicide rate(3) That we exaggerated the safety ofvitamin B3. He referred to a report byChinaglia that five out of 14 patientswere taken off vitamin B3. He referred tothe Ban-Lehmann studies showing theneed for phenothiazines was apparentlyincreased and to Wittenborn's pigmentstudies Nowhere does he refer to themassive evidence available in the litera-ture showing that vitamin B3 is muchfreer of toxic reactions than any tran-quilizer He does not refer to the hugecoronary study where out of severalthousand cardiovascular cases on nicot-inic acid no cases of acanthosis nigricanswere reported, nor that in no one else'sseries has such a large proportion of theseries had these innocuous skin changesHe does not refer to Wittenborn's groupwho found no increased need for pheno-thiazines, thus refuting Ban and Leh-mann

Wyatt thinks the fact we have reportedno further double blinds in 10 years isdata against the efficacy of ortho-molecular therapy He is unaware thatwe (1961, 1963) have been very critical ofdouble blinds from a theoretical andpractical point of view We made a

carefully calculated decision not to doany more If psychiatrists are going todisbelieve our four double blinds, whyshould they believe another hundred ifwe were disposed to present them?

His economic argument is totallyfallacious since it is comprised of:(1) the number of visits to a psychiatristwhich are required much less frequentlywith orthomolecular therapy; (2) feweradmissions to hospitals; (3) recovery tothe point they are able to pay substantialincome tax as lawyers, doctors, and soon We challenge Wyatt to show us aseries of schizophrenics who have re-covered to this degree on tranquilizersalone

Wyatt reports that three studies onacute cases failed to show significanti mprovement with niacin or niacin-amide An examination of the threereferences showed the following One ofthem was a paper by Meltzer et al , whoused NAD (which is not the same aseither niacin or niacinamide and whichhas different dose requirements). Thesecond paper is a study by Ananth et al.on chronic patients only In the title ofthis paper it is clearly shown that this wasa study on chronic patients The lastreference is to a nonpublished report. Ina brief communication by McGrath alarge number of acute and chronicpatients were treated with niacinamideonly, but only one-third of this groupwere acute Thus, on close examinationof Wyatt's statement one finds that hisstatement "there are three studies (12,16, 21) in which acute schizophrenicswere given niacin or niacinamide" istotally wrong. He is also contradicted bya recent editorial in the CanadianPsychiatric Association Journal 20, 97-100, 1975

Comment on D. F. Klein (1974)We totally disagree with Klein's thrust

which seems to be that only when the

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scientific community has accepted anidea is it a useful fact He ignores thehistory of medicine which shows that alarge number of very useful treatmentscurrently acceptable were exposed to asmuch criticism for as long as is ortho-molecular psychiatry There have beengaps of 40 years and more in medicinebetween a discovery and its applicationIn addition, he presents no evidence thepsychiatric and scientific establishmentare the same Very few psychiatrists arescientists, nor do they claim to be soVery few bother to read original material,being content to read erroneous reviewssuch as the one produced by the APATask Force committee

Since the first double-blind compari-son experiments in psychiatry wereconducted under our direction using adesign which is still considered the wayone does these experiments, we find ithard to understand how Klein can fail toaccept conclusions from our first doubleblinds while accepting the so-calleddouble blinds of Wittenborn and Ban andLehmann The studies he favors were atbest semi-blind, but it would bethoroughly dishonest to consider themdouble blind when patients were soeasily identified by the flush

If Klein were motivated to use hisposition as Director of Research to repeatour work as described, i e , similarpatients, the same treatment, and thesame method of evaluation, he would domuch to settle the controversy Action,not good advice, is required

Comment on Lipton (1974)Lipton's arguments are what one would

expect from one of the most violent andbitter opponents of orthomolecular treat-ment His arguments are, as they havealways been, irrelevant and trivial,especially his views on toxicity Asclinicians who have used megadoses ofvitamins since 1952, we are in a strongerposition to judge their relative toxicitythan Lipton who has not yet given anymegavitamin treatment to patients Everyyear we are confronted with cases ofjaundice, blood dyscrasias, tardive

dyskinesia, thought blocking, and at-tempted suicide (many successful), sex-ual impotency, and a variety of neuro-logical disorders in patients referred to uswho have already been on tranquilizersfor many years Every year we have todeal with intelligent patients immobili-zed by their constant tranquilizer medi-cation, oral or parenteral, who are totallyunproductive We would rather deal withthe occasional case of nausea andvomiting, with the ubiquitous initialvasodilatation produced by nicotinicacid, with the occasional allergy to thetablets, and with the infrequent benigncase of hyperpigmentation The undesir-able side effects of vitamins are minorirritants and have never caused deathThe undesirable side effects of thephenothiazines and their toxic reactionswould require a volume to report and todescribe There can be no comparisonbetween the undoubtedly toxic tran-quilizers which the committee accepts asthe best that modern psychiatry can offerfor schizophrenia and the minor sideeffects of vitamins Perhaps this is whyLipton does not present any comparabledata for toxicity as he does so frequentlyfor efficacy

His concluding statement is mistaken.There is, on the contrary, increasingevidence that vitamin therapy now usedover 20 years for some patients has notonly not caused any harm to the patient,but has instead so sharply reduced thedose of tranquilizer required that eventhese toxic drugs can be used with safetyThe final result of many years oftranquilizer medication has been theproduction of the perfect human con-sumer, of welfare, of nursing support,medical support, community psychiatry,and with no hope of ever being anybetter Has Lipton ever studied thefantastic costs to patient and communityof perpetually chemically producedtranquility—of the perfect chemicalstraight jacket?

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SECTION VI—Comments on the Double-Blind (Placebo) Methodology

We will summarize the ideas of thosewho are not enamoured with double-blind techniques as the only ones avail-able to physicians This we do toillustrate that there is a good deal ofopposition toward accepting placeboexperiments (all double-blind experi-ments must eventually begin with onecontaining a placebo) as the only validmethod for judging the efficacy oftreatment or of drugs Since the com-mittee accepted only experiments theyconsidered to be double blind, evenwhen they were not, these ideas sum-marized here provide an attack upon thecommittee's basic notion. It was thiserroneous premise that permitted themto ignore a vast amount of clinical datacorroborating orthomolecular therapyThe onus remains with them to presentdata proving that the double-blindexperiment really is an effective methodfor sorting efficacious from noneffectivetreatments We will begin with a fewquotations from Claude Bernard, thepioneer in the development of clinicalcontrolled experimentsBernard, Claude. An introduction to thestudy of experimental medicine. Trans-lated by H. C. Greene, first published1865. Available from the MacMillan Co.,1927, New York.

"It is therefore clear to all unpre-judiced minds that medicine is turningtoward the permanent scientific path Bythe very nature of its evolutionaryadvance, it is little by little abandoningthe region of systems, to assume a moreand more analytic form and thusgradually to join in the method ofinvestigation common to the experiment-al sciences "

"These men (talking about system-atizers) start in fact from an idea which isbased more or less on observation andwhich they regard as an absolute truth.They then reason logically and withoutexperimenting and from deduction to

so

deduction they succeed in building asystem which is logical but which has nosort of scientific reality Superficialpersons often let themselves be dazzledby this appearance of logic; and dis-cussions worthy of ancient scholasticismare thus sometimes renewed in our day "

"Men who have excessive faith in theirtheories or ideas are not only ill preparedfor making discoveries but they alsomake very poor observations "

But it happens further quite naturallythat men who believe too firmly in theirtheories do not believe enough in thetheories of others So the dominant ideaof these despisers of their fellows is tofind other's theories faulty and to try tocontradict them The difficulty forscience is the same They make experi-ments only to destroy a theory, instead ofto seek the truth At the same time theymake poor observations because theychoose among the results of theirexperiments only what suits their objectBy these two opposite roads men arethus led to the same result, that is, tofalsify science and the facts "

"It is said that coincidence may play solarge a part in causes of statistical errorsthat we should base conclusions only onlarge numbers What a physician needsto know is whether his patient willrecover and only the search for scientificdeterminism can lead to this knowledgeBut when determinism increases, statis-tics can no longer grasp and confine itwith a limit of variations There we leavescience for we are forced to invokechance or an occult cause to regulatephenomena. I therefore refuse toacknowledge that science has a place formen who make criticism their specialty,as in letters and in the arts To be reallyuseful criticism in every science must bedone by men of science themselves andby the most eminent masters."

"Pure contradiction would amount toan accusation of lying and we should

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avoid it because happily scientific falsi-fiers are rare As such cases moreoverhave no connection with science, I neednot offer any precept on the subject Iwish merely to point out here thatscience does not consist in proving thatothers are mistaken; it can be a profitablework for science only insofar as we showhow he was mistaken."

"Physicians often pride themselves oncuring all their patients with a remedythat they use. But the first thing to askthem is whether they have tried doingnothing, i e , not treating other patients;for how can they otherwise knowwhether the remedy or nature curedthem From all this I conclude thatcomparative observation and experimentare the only solid foundation for experi-mental medicine "

Atkins, A. Conduct of a controlledclinical trial, British Medical journal 2,377-379, 1966.

"If there are problems—ethical,scientific and even mathematical—associated with controlled trials it never-theless remains the case that thistechnique holds out greater promise foradvance in therapy than any yet devisedMore important, however, is it thatrecognition of the scientific basis uponwhich such trials are constituted willinsure so far as is possible that theundesirable state of affairs prevailing inmedicine during the first half of thiscentury will never be repeated to theextent of producing so many false trailsand so many unnecessary and unworthymodes of therapy "

Baird, K, A. Medicine's Domination bythe Control Worshippers. CanadianDoctor, page 27, 1968.

"The Establishment in CanadianMedicine insists on the method ofcontrols, especially what Gilder called'one of the fetishes of experimentalmedicine the double-blind clinical

trial ' Editors refuse new and promisingwork unless accompanied by an 'adequ-ate series of normal controls,' except anoccasional article from the right source,if in fine with what is 'accepted' by the'authorities ' One editor stated over hissignature that 'case reports would not beconsidered as evidence!'

"An American when told about a newidea usually asks, 'What is it?' but theCanadian asks, 'Who is doing it?'However, one American editor said hismagazine never reported clinicalmaterial not accompanied by suitablecontrols Concerning a disease known tobe always fatal within five years, wouldhe not report 10 cases who lived 10 yearswith a certain treatment, but wouldpublish five cases if the other five hadbeen allowed to die in the acceptedmanner? Absurd, you say! Control-worshiPpers are a bit absurd! But thereare signs of rebellion against theirretarding progress any longer

"In science a controlled experimentmeans every variable is held steadyexcept that being studied This isimpossible in clinical medicine! In theaverage 'controlled' clinical observationsare the following equally balanced?Nutrition, smoking, drinking, sexual ormarital adjustments, pregnancy, pre-vious medication or treatment, desensit-ization or immunization, differences insocial classes (affecting precautions,exposures, cleanliness, natural vac-cination from exposure, plumbing),blondness, or brunetteness, size, bodybuild, mental type, inheritance, etcHow controlled is an experiment whichassumes none of these affects the result?

"The value of the so-called double-blind study is much questioned today bymany thinking writers, who suggest thefollowing: It is not a foolproof mechani-cal means of insuring a correct interpret-ation of result It may mislead as well aslead The objectivity of the double-blindstudy is a medical illusion It is time thatthe double-blind approach be preventedfrom developing into a triple-blinddisaster The use of the double-blindtechnique does not guarantee thesanctity of the trial "

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Baird, K. A, Assessment of Reports ofDrug Trials. Canad. Med. Ass. ). 90,1279, 1964.

"The insistence in recent years on'blindness' or 'double blindness' in eval-uating the effect of therapy is an insult tothe intelligence of the average clinician.Most new drugs today provide sympto -

matic relief and are not curative. Theultimate observation is made by thepatient, who alone knows whether or nothe is relieved of his subjective symptoms.Relief due to psychotherapy and sug-gestion is nonetheless relief

"Use of a placebo is based on theassumption that the placebo has noeffect or that its psychotherapeutic effectwill equal that of the drug being tested.Neither assumption is necessarily true Inthe Proceedings of the Royal Society ofMedicine (The Placebo and the ClinicalTrial, 57: 67, January, 1964) JamesParkhouse points out that the physicianhimself cannot escape being a placebo tosome extent: but that in any case, Oneof the first things to be realized,therefore, before embarking lightheart-edly upon the use of a placebo is that farfrom clarifying the issue it may merelyadd confusion '"

Ban, Thomas, A. Methodology andPitfalls in Clinical Testing of Psycho-pharmacological Drugs, Chemotherapia9, 223-230, 1964.

"The asylum clinician has such greatadvantages in regard to the observationof the action of these medicaments thatit is a neglect of opportunity if he fails tolead and instruct the whole medicalprofession in this respect In private orout-patient practice, and even inordinary hospitals and sanataria, theresults of any mode of treatment areliable to be vitiated by variations of dietsand habits of life, which are entirelybeyond the ken of the physician In thehospital for the insane, on the contrary,the diet and habits are under almostabsolute control, and observation on theresults of treatment should be muchmore reliable "

"Bigelow considers the administration

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of placebos in the clinical evaluation ofpsychotropic drugs in a number ofinstances a source of error He arguesthat unless the placebo is administered insuch a fashion that an observed emergentcan be clearly linked either to theplacebo, the test substance, or both,then obviously administration of theplacebo has been fruitless and anyconsideration of the validity of the givenresult merely because placebo was givenis unwarranted. Moreover, he claimsanother pitfall arises from the necessitythat the placebo itself has to be rigidlycontrolled. If orally given it must havephysical characteristics analogous to theactive medication and it has to beadministered in the same fashion withidentical procedures as the real drug.

"From a theoretical point of view, inhuman beings where transaction ofprocesses are present, a double-blindcontrolled study seems to be essential toeliminate the bias that might be intro-duced through feedback mechanismsbetween the observed and the observer(11) However, in Batterman and Gross-man's experiment the double-blindmethod for some unknown reasonobscured the presence of an actuallyexisting pharmacotherapeutic propertyof the drug which arose when theyswitched to a single-blind placebo trial.Furthermore in Uhlenhuth's experimentthe therapist's attitude broke through thedouble-blind experiment and Hoffer andOsmond (8) argue that the double-blind method, when the group understudy is not homogeneous, may obscurethe presence of significant differences

"It is really unfortunate that thestatistical method also has its own pitfalls(5) Some of these were expressed byHuntsman by the following: 'the prestigeof mathematics is so great that manypersons forget that even in mathematicalhands, probability, chance and randommean ignorance They come to think thatin the alembic of mathematics chance insome way becomes certainty They takegreat care to select random sampleswithout realizing that insofar as a samplehas been random, they don't know how it

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was selected (9) A more severe criticismwas launched in the Lancet by Wienerquite recently (1962) (14) According tohim, many clinical investigators 'becausethey are unduly sensitive or insecureregarding their lack of mathematictraining and knowledge habitually handover all their data to biometricians foranalysis in order that their papers mayinclude the appropriate tests, standarderrors and so on In that way they havecome to depend more and more onmathematicians who have no knowledgeor understanding of the subject tointerpret their findings, instead of relyingon their own experiences and commonsense ' Wiener concludes that mathe-matics is a poor substitute for accurateobservations, reliable experimentation,and common sense "

Bellak, L, and Chassan, J, B. AnApproach to the Evaluation of DrugEffect During Psychotherapy: A Double-Blind Study of a Single Case. J. Merv.Ment. Dis. 139, 20-30, 1964.

"There has long been abroad in theland of clinical research the notion thatcomparisons between groups of patientsis the sine qua non of statistically validscientific clinical research, and that thestudy of the individual case must berelegated at best to a status of intuitionand the clinical hunch, not capable ofstatistical testing and validation Forreasons that have been discussed in somedetail (5, 6) this view is seen to lackvalidity in its own right It has unfortun-ately tended to perpetuate a basicallysuperficial methodology as a uniqueprototype for science in clinical researchwith mental patients "

Cotzias, G, C. New Eng. J. Med.Limitations of Controlled Double-blindStudies of Drugs. New Eng. J. Med, 287,937, 1972.

"In double-blind evaluations of drugsneither the patient nor the physician canknow what is being administered; suchstudies are also called controlled whenthe patients are randomly assigned to aplacebo and a drug-receiving group. Theprotocol is formulated at the beginning

of the study and must be followedmeticulously to the end It wouldobviously be absurd if these types ofstudies should become the law of theland "

Cromie, B. W. The Feet of Clay of theDouble-Blind Trial. Lancet 2, 944-997,1968.

"After generations of doctors haveaccepted without question the opinion ofthe great names in medicine, a changehas come about so that little or nocredence is now given to clinicalobservations even by experienced in-vestigators. This change in official at-titude is probably a step in the rightdirection, but one wonders whether thependulum has not swung a little too far,allowing a blind acceptance of double-blind trials without a critical evaluationof their shortcomings and their ability tomislead as well as to lead "

Dinnerstein, A. J., Lowenthal, M., andBlitz, B. The Interaction of Drugs withPlacebo in the Control of Pain andAnxiety, Perspectives in Biology andMedicine, 10, 103-117, 1966,

"For scientists attempting to under-stand the action of analgesic andpsychoactive drugs, it is suggested thatthe simple double-blind study is not anadequate experimental design. A givendrug may produce opposite directions ofeffect on pain or anxiety in differentemotional and instructional contexts. Itmay produce opposite directions ofeffect in different subjects within thesame objective context. The simpledouble-blind study, employing a singleset of instructions and subjects treated asa random variable, is thus inadequate inthat it provides no hint concerning thedegree to which the observed drug effectis dependent on contextual, instruction-al, and subject variables."

Feinstein, A. R. Clinical Biostatistics IX.How do we measure "safety and ef-ficacy?" Clin. Pharmacol, and Therap,12, 544-558, 1971.

"My purpose in this essay is to show

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that our act of faith is a delusion Themethods do not exist There are nosatisfactory standard procedures forassessing the safety and efficacy ofdrugs Despite general acceptance, theexisting techniques are oversimplified,naive, and grossly inadequate for theneeds of clinical medicine

"These intellectual maladies of clinicaltherapy cannot be cured merely by thefurther application of inappropriatestatistical theories, by 'crash' programsand bureaucratic fiats, or by recom-mendations from scientists who have hadlittle or no personal responsibility for thecontinuing care of patients The pro-blems arise in clinical activities, and canbe best perceived and solved by con-noisseurs of those activities

"The public will continue to demandregulations that assure the safety andefficacy of pharmaceutical therapy andregulations will inevitably be created inresponse to this demand Without modif-ication of current procedures, however,the regulations will succeed in replacing'clinical experience' that is scientificallyunspecified by 'scientific' statistics thatare clinically worthless If academic andpracticing clinicians want these regula-tions to be both scientifically meaningfuland clinically sensible, the clinicianscannot continue to evade their ownparamount responsibilities while com-plaining about the work done by thestatisticians, pharmaceutical companies,and federal personnel to whom theresponsibilities have become allocatedby default "

Feinstein, A. R. The Need for HumanisedScience in Evaluating Medication. TheLancet 2, 421-423, 1972.

"These principles of biometric sciencehave proved suitable for the experiment-al goals and data encountered with theanimals or agricultural crops for whichthey were developed However, they donot deal with scientific problems inselecting the type of information that isto be appraised in the therapy of sickpeople In particular, biometric methodsdo not contain provision for evaluating

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the complex, crucial data that distinguisha person from a dog or a field of wheat.

"The treatment of patients requiresattention to at least three issues thatbecome paramount in experiments wherethe 'material' is a person: (1) of themany things that can happen when aperson is treated, which will be chosen asthe indexes of accomplishment; (2) fromthe many changes observed in theseindexes, how do we rate each change forits desirability as good or bad; (3) how dowe combine these multiple individualratings of desirability into a single ratingthat represents the final decision? Thecontrolled, statistical randomised pro-cedures do not currently provide data toanswer these questions

"There are many scientists in academicor government advisory positions todaywho seem to prefer a 5 percentimprovement rate which seems scientifi-cally 'pure' to a scientifically 'impure'rate of 68 percent

"Fortunately, of course, aspirin hadbeen used for decades before develop-ment of our current scientific doctrinesMillions of people already knew aboutaspirin's many benefits and recognised itshazards as relatively infrequent andslight Aspirin has been appraised anddeemed beneficial by an empiric butbalanced scheme of assessment that issometimes called 'common sense 'Aspirin might never be approved ifsubjected to the unbalanced assessmentsused in modern therapeutic science.

"A different problem in balance relatesto evaluations performed by expertsusually chosen from the ranks ofacademic scientists and clinicians work-ing full-time at a university or otherresearch institute An academicianseldom sees the patient or the patient'sfamily at home, and seldom follows apatient for an extended period The totalpicture of human therapy—with all itseffects on performance, convenience,anticipation, family, and economics—will not be regularly seen by an academicspecialist.

"The evaluation of all the humanisticdata associated with therapy will there-

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fore require additional judgments fromsources outside the academic or govern-ment enclaves These sources will in-clude full-time practising doctors,patients, and others who are familiarwith the total picture These 'consultants'may not be connoisseurs of currentdoctrines in science, and may not speakthe magisterial language of statistics, butthey can often provide experience,wisdom, and common sense in asituation for which contemporaryscience is inadequate This type ofconsultative judgment will be especiallynecessary in evaluating over-the-countermedications in which doctors do notparticipate and for which all of theanticipation effects occur in the patient

"Until the methods of science aremade satisfactory for all the importantdistinctions of human phenomena, ourbest approach to many problems intherapy will be to rely on the judgmentsof thoughtful people who are familiarwith the total realities of human ail-ments Human testimony and humanjudgments are not objective; they maynot be precise; and they are oftenfallible At this stage in the developmentof human science, however, our primarychallenge is to assemble information thatis meaningfully human, even if scientifi-cally imperfect We shall advance theprogress of neither science nor humanityby obsequious adherence to scientificdoctrines that provide quantitative glitterand 'statistical significance', while de-humanising our data, confusing oursensibility, and diverting our attentionfrom the people who are the only propersubjects for the study of mankind "

Glick, B. S., and Margolis, R. A study ofthe influence of experimental design onclinical outcome in drug research. TheAmer. J. Psychiat. 118, 1087-1096, 1962.

"Those studies which included withintheir structure the double-blind,placebo-controlled technique showedsignificantly lower clinical improvementrates than those which did not.

"Long-term studies showed significant-

ly higher clinical improvement rates thandid short-term studies, demonstratingthat duration of therapy, as well asdegree of 'blindness', may be a verymeaningful variable in determiningclinical outcome

"Duration of therapy was significantlyrelated to degree of 'blindness' in thatonly one of 11 double-blind studies waslong term and only four of 16 single-blind studies were short term

"Long-term, single-blind studiesshowed appreciably higher clinicalimprovement rates than did short-term,double-blind studies The very meagernumber of long-term, double-blindstudies (1 only) and, to a lesser extent, ofshort-term single-blind studies preventedus from differentiating between degree of'blindness' and duration of therapyregarding their relative impact onimprovement rates Thus, no clear-cutcertain evidence could be adduced eitherto support or nullify the contention thatthe double-blind, placebo-controlledmethod is, per se, a necessity for the'accurate' clinical evaluation of a drug.

"We were unable to demonstrate ageneral decline in improvement rateswith the passage of time Thus we couldnot validate the commonly held belief ofa progression from an initial over-enthusiasm to a later realism in thesubjective evaluation of a drug "

Lasagna, L. The Impact of ScientificModels on Clinical Psychopharmacol-ogy: A Pharmacologist's View. Seminarsin Psychiatry 4, 271-282, 1972.

"A third general area is the worship ofthe controlled trial. Having spent a lot oftime in my life arguing on behalf of thecontrolled trial, I think I know its valuesas well as its limitations I am sorry thatso many people have overbought theconcept of the controlled trial and thatother valid ways of acquiring evidencehave been neglected L-dopa is anexample of how a drug can be rated asineffective on the basis of poor double-blind controlled trials, several of whichwere done early in its history. Becauseinadequate dosages were used for in-

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adequate periods of time, there was nosignificant effect. It was on the basis ofuncontrolled trials of L-dopa (as well ason all the beautiful logic and experiment-al data that preceded it) that one came tothe conclusions, and rightly so, that thisdrug was a dramatic therapeutic ad-vance We have only to remind ourselvesthat all sorts of highly important psycho-active agents such as barbiturates,meprobamate, chlorpromazine, imipra-mine, etc , were discovered by waysother than the formally controlled trial "

Lasagna, L. The nature of evidence.Triangle 11, 145-152, 1972.

"(a) 'Anecdotal' or 'uncontrolled'observations. Usually these phrases areused in a pejorative sense, despite thefact that such observations constitute theoldest method for studying drug actionsand remain a mainstay even today Thepoint too readily forgotten is that theyare in fact not 'uncontrolled' The controlconsists of what the observer believeswould have occurred in the absence ofthe drug

"(d) The comparative randomizedtrial. This approach is relatively new. Theso-called trial in the Book of Daniel inthe Bible or the famous trial by JamesLind on H. M.S Salisbury on citrus fruitsand scurvy are really not modern trials inthe strict sense! For example, Lind'sexperiment would be criticized todaybecause of a difference in baselinevariables in his therapeutic groups Hetook two patients very sick with scurvyand purposely assigned them to the citrusfruit diet, which he suspected would bebeneficial The therapeutic results weredramatic, but the supersceptic couldhave accused him of using a populationthat was destined to irnprove becausethey had nowhere to go but up! (Theycould have chosen to die, of course, butsuch trivial points have been known to becompletely ignored by a superscepticwith blood in his eye )

"There are many ways in whichcontrolled trials can go wrong One cancome to the conclusion that no dif-

ference exists between treatments be-cause the population has been chosen inthe wrong way, because the numbers aretoo small, because the observations weretoo sloppy, or because the patients failedto take their medication If a new drughas been compared against placebo, onemay erroneously conclude that the drugis inefficacious, since the errors sug-gested above will tend to 'prove' the nullhypothesis

"(h) Professional judgment and themarketplace. Popularity among thepublic or among physicians is nottantamount to worth On the other hand,there are interesting examples of drugsthat have sold well despite an absence ofadvertising, or compounds that havefailed despite a good deal of advertising,and suggest that the physician or thepatient is not completely devoid ofdiscriminatory ability It is generallyassumed that expert 'anecdotal' judg-ments are better than non-expert'anecdotal' judgments, despite the factthat there are some compelling instanceswhere the practising doctor has discover-ed truths that the experts failed torecognize.

"Schneller has recently suggested thatexperts in the science of clinical investi-gation are not the same as experts in theart and science of treating patients Hestates: 'For the one kind of expert todominate the drug usage of the other islike a Sebring race driver setting theoperating regulations for New York Citytaxicab drivers'

"It is my contention that three or fourwell-done trials by people who are expertin a field, with conclusions that aresimilar, is enough to demonstrate that adrug has effectiveness. The accumula-tion of thousands of patients oftenserves, I believe, merely to providepsychological comfort.

"Weiner has suggested that for drugsused for a long time with apparentsuccess and without evidence of signifi-cant toxicity, the burden of proof shouldbe on those who claim that such drugs donot work 3

"It is quite possible that the new

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developments in regard to 'substantialevidence' are carrying us farther andfarther away from the real-life situationsin which drugs are ultimately to beapplied. Certainly most drugs are notgiven under the circumstances of double-blind technique, obtaining informedconsent, hospitalization, the avoidanceof other simultaneous therapies, theapplication of drugs by experts, etc "

Plutchik, R,, Platman, S, R., and Fieve,R. R. Three Alternatives to the Double-Blind. Arch, Gen, Psychiat, 20, 428-432,1969.

"This double-blind method has beencriticized on several grounds. First, inmany cases drugs produce side effectswhich are easily noticed by the evaluat-ing psychiatrist These effects immedi-ately eliminate his blind condition andenable his expectations to begin to affecthis judgment Since differential sideeffects are an almost universal con-comitant of any therapeuticallyefficacious drug, it is practically impos-sible to keep an observant psychiatristreally blind to the medication beingused

"A second argument against thedouble-blind technique is that it createsa highly artificial situation which haslittle relevance to the clinical setting inwhich any drug would actually be used.The cold, impersonal evaluation ofchanges is not typical of clinical contactIn the language of stimulus samplingtheory, such evaluation has little'ecological validity' 5"

Clearly there is a growing recognitionthat the double-blind technology is onlyone of a number of methods for testingdrugs and that it has so many errors andbiases that it ought to be used sparinglyand with scepticism It will never replaceclinical judgment although it may con-tinue to serve to allay the anxiety ofeditors and government officials whoneed reassurance their decisions will not

be criticized in the future The double-blind technique is most cherished bythose professional people who havethe least contact with patients It is rareto find clinicians who enjoy doing doubleblinds, believe the results of doubleblinds published by others, or defendthem in any public debate

It is unlikely that double-blind experi-ments really are double blind for evenwhat appears to be a simple task ofpreparing placebo tablets, similar inevery respect to tablets containing theactive medication, may be extraordinar-ily difficult Joyce (1968) remarked thatin none of the 20 clinical trials he hadbeen involved in had the first attempts ofthe manufacturer at identical formula-tion been successful Hill et al (1976)studied 22 pairs of agents used inpublished double-blind controlledexperiments A panel of four observersfound only five pairs so closely matchedthey were indistinguishable, but in sevenpairs all four observers detected obviousdifferences This is not very encouraging,but even worse is the fact that themedication may cause changes in theperson which are easily distinguishableSome agents discolour the urine (rif-ampin or riboflavin), stain the linen(p-aminosalicylic acid), or produce phy-siological reactions such as the flush(vasodilation) of nicotinic acid

Hill et al concluded, "it may be verydifficult to produce indistinguishablepreparations for use in 'double-blind'trials and that as a consequence suchstudies are often not double blind at all "They add, "The facts that stand out arethat, unless the organization of the studyis appropriate, the interpretation of theresults may remain in doubt and that the'double-blind' study is an idol which mayand often does have feet of clay "

We have presented our views in severalpublished papers Our conclusions arosefrom our experience with double-blindexperiments which we began in 1952,long before most psychiatrists had theslightest idea what the method was Wehave not been able to find any double-blind study in psychiatry which preceded

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ours Dr. A Shapiro in his extensivesearch of the placebo literature has notbeen able to find any one either, at leasthe has not been able to support by anyreference to the literature his thoughtlessstatement made in a letter to JAMA thatwe were not the first We are still waitingfor his statement admitting his errorwhich he seems reluctant to make

Rather than prepare a new discus-sion we will reprint a major portion of ourpaper, "Some problems of stochasticpsychiatry," J Neuropsychiatry 5, 97-111, 1963, as well as the paper, "ATheoretical Examination of Double-Blind Design" by A Hoffer, Can Med.Ass. 1 97, 123-127, 1967

The reader should note that our paperswere written and published long beforethe APA Task Force Report 7 on mega-vitamin therapy was published It doesnot appear that in their inadequateexamination of the megavitamin litera-ture they recognized the importance ofour objection to the methodology bywhich they came to set such storeHowever we need not be surprised by thisomission for as we have noted here, DrThomas Ban, one of the Task Forcemembers, apparently shares our sceptic-ism when not engaged in his Task Forceduties

A Theoretical Examination of Double-Blind Design

A Hoffer, MD,Ph D,F.APA,CRCP.[C],

Saskatoon, Sask

Recently an eminent surgeon wrotethat A Bradford Hill's contribution to thedesign of controlled experiments was

Director, Psychiatric Research. Psychiatric ServicesBranch, Department of Public Health, located atUniversity Hospital. Saskatoon. SaskatchewanSupported by the Psychiatric Services Branch, Depart-ment of Public Health. Saskatchewan, and by theDepartment of National Health and Welfare. Ottawa(Mental Health grant )

Reprint requests to: Or. A Hoffer. BOO Spadina CrescentEast. Saskatoon. Saskatchewan.Reprinted by permission of the editor of the CanadianMedical Association Journal

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equivalent to Fleming's discovery ofpenicillin.2 This statement by a surgeon,who freely admitted that the double-blind method had no place in surgicalresearch, indicates how convinced somephysicians are that this method willprevent serious errors in the developmentof new treatments, and will lead us tonew heights in therapeutic discoveryAccording to Atkins, every therapeuticdiscovery made before 1945 was made byresearchers of Nobel calibre such as Lind,who discovered that oranges and lemonscould cure scurvy Since we have double-blinds, we need no longer depend uponthese sporadic occurrences of geniuses todiscover even better therapies We needno longer breed Harveys, Pasteurs,Ehrlichs and Flemings

I wish I could agree with this optimisticview It is my thesis that controlledexperiments are not new, that they goback certainly to Lind, that our Nobellaureate colleagues have always usedcontrolled experiments, that the onlything new is the "double-blind", and thatthis double-blind addition has created somany new difficulties and errors that itshould be re-examined carefully andrigorously.

A surprising number of youngerscientists are convinced that controlledexperiments are new in medicine. Thismay be a reflection of our ignorance ofmedical history and the rapid adoptionby governments, grants and editorialcommittees of the false idea that onlydouble-blind clinical experiments arecontrolled experiments A double-blindexperiment is one in which neither thepeople evaluating the results of treat-ment nor the subjects being evaluatedknow whether they have been given aninert substance or a substance shown inprevious pilot experiments to be activeOne may compare two active sub-stances, but, in the end, reference mustbe made to the placebo for base-lineactivity

To equate double-blinds with a con-trolled experiment leads many to assumethat once an experiment is "blinded" noother controls are required. It is moreaccurate to talk about comparison

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experiments since one treatment iscompared to another Comparisonexperiments may be open, single-blind,double-blind, or if you like, multiple-blind.

Comparisons between treatments havebeen made by physicians for centuriesThe history of discovery in medicine isthe history of trial and error, andrecognition of error indicates that com-parisons have been made. A controlledexperiment was reported by Pare in theseventeenth century when he comparedthe effect of crushed onions on burns byapplying them to only half the body Lindin 1747 compared the effect of twooranges and one lemon per day on twoscorbutic patients against the effect ofstandard treatment in 10 cases. Only thetwo recovered Claude Bernard frequent-ly discussed the need for controlledexperiments and, of course, men likePasteur and Ehrlich performed onlycomparison experiments Claude Bernardpointed out that a comparison group (hisword) should provide an estimate of thenatural remission rate Any treatmentmust do better than this if it is to haveany value in medicine

Theoretically the double-blind methodis designed to test the efficacy of a drugfree of the influence of bias in theobserver and faith in the patient It isassumed that bias and faith confound theresults of other kinds of comparisonexperiments.

Since, as far as I know, no experimentshave been recorded which prove orsuggest that the double-blind doescompensate for these variables, it ispossible to examine it only theoretically,as we are in the presence of a standardclinical method which has never beencalibrated or subjected to the hard test ofexperiment Since what were probablythe first two double-blind experiments inpsychiatry were conducted under mydirection, we have had nearly 14 years ofcontinuous experience with it I am,therefore, to some degree responsible forthe present popularity of the double-blind method.

There are several theoretical ob-jections to the use of the double-blind

There are, of course, ethical and practi-cal difficulties as well

1. Role of Probability TheoryProbability theory was invoked as a

way not only of randomizing groups, butof determining the significance of afinding; that is, a statistical test wasmade to see if the results observed couldhave by chance occurred with aninactive drug. But no clinical trialsatisfies two of the basic theorems uponwhich probability theory is based Thismatter was recently discussed by Hog-ben.15 Probability theory was developedpartly as an aid to English noblemen,who wished to win at the gaming tablesin Monte Carlo According to Hogben, "acalculus of probability is relevant to thereal world (a) only in so far as it specifiesfrequencies of observable occurrences inan indefinitely protracted sequence oftrials, (b) only if also such occurrencescollect a sequence wholly devoid oforder " Neither one of these essentialconditions is present in clinical trialsWhen one gambles with dice, it ispossible to use dice manufactured toprecise standards One can assume that aman one thousand years from today whothrows these dice by carefully prescribedtechniques will come up with the sameprobabilities, i e the dice have beenmade invariant; but every biologicalphenomenon is subject to minor andmajor cyclical changes Since humanobservation beyond one life span isdifficult, it is hard to measure changesover decades or centuries, but it is prettyclear we do not live in the same world asdid our grandparents Biological pheno-mena are subject to remarkable evolu-tionary and geophysical drifts It is,therefore, possible to specify phenomenarigorously, but not to ensure an in-definitely protracted sequence of trials.Nor are our sequences wholly devoid oforder Perhaps these considerationsworried Sir Ronald Fisher, because,before his death, he expressed to hisstudents great concern about thedirection clinical trials were taking 13

One of the assumptions in probabilitytheory is that the population from which

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the sample is drawn is homogeneous Butin psychiatry, where diagnosis is highlysubjective and, therefore, imprecise, it isimpossible to have homogeneous groups.Double-blind studies have been reportedusing antidepressants for treating depres-sion The matched groups containedendogenous depressions, schizophrenicswho were depressed and neurotic depres-sives When heterogeneous groups areused, the therapeutic response is sovariable that the response of the treatedand control group depends too much onthe random distribution of differentclasses of patients in them No provisionis made for this in the double-blindcontrolled design

2, Control of BiasIt has been assumed that not knowing

whether a patient is receiving drug orplacebo will reduce or eliminate bias Ifthe code remains unbroken and theexperiment remains truly blind, this isprobably true But the double-blindintroduces serious new biases of its own,which may be even more misleading.

There are at least three major variablesin any therapeutic program. The first isthat feeling of trust or faith the patienthas in his doctor and, therefore, in histherapy The second factor is the faith orconfidence the physician has in himselfand in the line of therapy he proposes touse. The third factor is the therapy. Thebest results are obtained when all threevariables are set at their optimum level.If he has little faith in the doctor, thepatient may or may not follow therecommended treatment This may ex-plain why a large proportion of patientstear up the prescription very soon afterthey leave the doctor's office. Thepatient's faith must sustain him until thetreatment begins to work It can be extra-ordinarily great I know several patientswhose faith in their doctors remainsintact even after 10 years of therapy withno improvement.

The doctor's faith in his medicationmust also be maximum. This does notmean that he need be deluded about theresponse to therapy. The doctor with

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faith will encourage his patient topersevere, he will hold out the promise ofrecovery or improvement, he will mini-mize nontoxic side effects, he will notproduce many iatrogenic side effects andhe will remain interested and enthusias-tic If he has no faith in a medication hewill be more apt to discourage thepatient, to use improper dosage sche-dules, to maximize side effects and todiscontinue treatment too early Boththese forms of faith, positive or negative,influence the therapeutic result, butsince in office practice physicians do notuse therapies of which they disapprove,the negative factors are seldomoperative

The double-blind technique makes itdifficult to sustain these two variables attheir optimum level It is hardly likelythat a doctor will have as much faith in anew drug as he does in drugs with whichhe is familiar, and when he is forced towork in a double-blind way his faith andenthusiasm are reduced to a very lowlevel. It has been our tradition forcenturies to abhor the use of placebo ortrickery For centuries doctors havecondemned quacks. In the Middle Agesthe only difference between quacks anddoctors was that while the doctors weremore honest, the quacks were moreintelligent Quacks knew their remedieswere no good and so sold atmosphere,displays, catharsis and other trappings ofnonmedical faith Doctors used similarremedies which were no more thera-peutic, but they did have faith in theirefficacy In the end the doctors wonbecause therapies in which we can justlyhave great faith developed

Serious ethical problems are raised bydouble-blind techniques which furtherreduce faith If severe toxicities shoulddevelop, one may have to break the code(and ruin the experiment) or run thegrave risk of harming the patientConversely in order to ensure that sideeffects are not missed, the physician maysearch for side effects in all his subjectstoo diligently and markedly increaseiatrogenic side effects.

If the doctor is unenthusiastic about

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the therapy, it is certain the patient willknow it and his faith and enthusiasm willbe dampened Thus two of the basicingredients of the therapeutic process areset at very low levels

There are undoubtedly drugs which intheir natural setting, i e combined withoptimum faith and hope, are very good,but which without these human factorsare nearly inert The double-blind isbound to destroy these compounds andso deprive us of valuable safe medica-tions To survive these serious limitationsof the double-blind, the drug must bepowerful and nonspecific It may be saidthat the double-blind works best forcompounds where it is least needed, e.g.for penicillin or nicotinic acid forpellagra

When a biochemist wishes to test therate of reaction of an enzyme which hasan optimum temperature of 370 C., hewill not get very far by putting hisreacting vessel in a deep freeze. Byrunning a double-blind we are, in effect,placing the therapeutic process in a deepfreeze

To confound double-blinds even more,it is doubtful if more than a smallproportion of these experiments arereally blind Hardly ever does the designof the study ensure that at no time willthe code be broken by doctor or nurseobservers In many psychiatric wardsthere is a tradition among nurses whichensures that every attempt will be madeto break the code. Nurses are no worsethan doctors and, like doctors, they alsohave ethical problems about giving theirpatients a placebo They will chew, taste,swallow the tablets, suspend them inwater, pound them with a hammer,throw them against the wall and stampon them They will study the fluidcharacteristics of the coded liquid insyringes and see how it mixes with bloodwhich may flow back into the barrel. Itseems the double-blind not only reducesfaith to an undesirable low level, butbrings out petty larceny in all of us

An example of severe bias in medicalreporting was recently described byVogel et al.10 In 1960 Astin and Rossireviewed the literature on the effect of

glutamic acid on intellectual perform-ance These authors were so convincedthat only double-blinds should be usedthat in their survey they ignored 25clinical studies By their selection ofpapers they were able to prove thatpositive results were obtained withclinical non-blind studies, whereas con-trolled studies usually showed glutamicacid to be inert In fact, when all studieswere included and errors in reading theoriginal papers were corrected, it turnedout that both non-blind and blind studiesyielded similar positive results

Do Double-Blinds Establish GoodTherapies and Destroy Bad Ones?

If Atkins2 is correct, our present era ofdouble-blind methodology should becharacterized by a substantial increase ingood (i.e effective) therapies and by amassive reduction in poor or ineffectivetreatments Perhaps this is true in someof the other branches of mediGine, butunfortunately it seems not to havehappened in psychiatry. Apparently thedouble-blind has not replaced our needfor the Pasteurs, Bantings and Flemings

Not only should our era be remarkablysuccessful in developing new therapies,but one should be able to ascribe thesechanges to the double-blind method.

TABLE 1

The Relationship of Clinical Trials and theIntroduction of New Therapies into Psychiatry

A "Good"therapies

Double-blind Not blind1 Acceptable None Tranquilizers

Anti-tensionagents

Antidepressionagents

Modified ECTPenicillin for GPINicotinic acid for

the psychosisof pellagra

2 Not acceptable Mega " -nicotinicacid for

schizophreniaMega-thyroid for

schizophrenia

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B Poortherapies

1 Acceptable None PsychotherapyGroup therapyFamily therapy

2 Not acceptable None None

'Mega—this refers to doses which are much abovethe usual range required to control deficiencies Theseare 3-250 per day for nicotinic acid or nicotinamide and200 mc0 or over of tri-iodothyronine or its equivalent

I have listed in Table 1 the treatmentsmost frequently used in psychiatry Itwould be useful if specialists in otherbranches of medicine would perform asi milar exercise.

Not all new therapy in psychiatry hasbeen developed as a result of double-blind methodology On the other hand,we have a large number of very effectivetreatments including tranquilizers, anti-tension chemicals, antidepressant drugs,modified electroconvulsive therapy(ECT), penicillin for general paresis of theinsane (GPI) and nicotinic acid foreradicating pellagra psychosis

Chlorpromazine, first introduced byDelay and Deniker,12 was found byLehmann and Hanrahanl7 to reducemarkedly psychomotor excitement Thehundreds of double-blind studies onchlorpromazine have added hardly any-thing to our knowledge of chlorproma-zine. In fact, only a couple of years agonearly one million dollars was spent in awell-designed double-blind study whichsuggested that chlorpromazine was a bitmore active in controlling overactivitythan starch This study was appropriatelyreported as "the million-dollar fizzle "

Reserpine was introduced intoAmerican psychiatry about the sametime Kline16 in the.first study showedthat it improved 22 percent of 200patients with chronic psychosis to thepoint where they could be discharged. Itwas subsequently found that 86 percentwere improved.3 At this point it may beuseful to lay at rest another myth aboutclinical testing It has become a cliche inpsychiatry that any new tranquilizer mustbe used very quickly because with timethe real value of the drug will have been

proved to be nil, i e the initial flush ofenthusiasm will have waned If true, adrug company could become wealthy bysi mply putting out a new placebo with anew name every year backed by enthus-iasm-creating factors Apparently drugcompanies have not considered thismethod This myth was examined byGlick and Margolis,14 who reported thatit was false They examined reportedrecovery rates of the same drug over afive-year period and found no evidenceof a decline in therapeutic efficacyTherapies replace each other if there arereal advantages, one over the other Thusinsulin coma therapy was replaced bytranquilizers because tranquilizers work-ed more quickly, were cheaper andrequired less skill in their administrationIt is still debatable whether the long-term effects are any better, and I suspectthat the use of insulin coma may wellcome back Similarly, chlorpromazinedisplaced reserpine The rule is not thatdrugs are forsaken because they losetheir efficacy, but that they are replacedby other more effective or less toxictherapies

Two good therapies for schizophreniawere developed by double-blind techni-que which are not yet accepted One isnicotinic acid therapy that we have beenusing since 1952 We have completedthree double-blind controlled studieswith follow-ups going back 14 years. Our10-year cure rate is 75 percent comparedto our comparison control rate of 35percent The other is high-dose thyroidtherapy developed by Danzigerll andLochner, Scheving and Flach.l8 Finally,there is one good therapy for alcoholism,LSD, which will never be double-blinded

All the "poor" therapies were develop-ed by non-blind studies, but are accept-able to most psychiatrists Thus it is clearthat therapies in psychiatry have beendeveloped by clinical studies and havereceived little help from double-blindstudies Non-blind studies have develop-ed treatment methods which are poor,i e can be improved, but they have alsogiven us excellent therapies which haverevolutionized the treatment of psychia-tric patients Double-blind studies have

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not led to the development of a singleuseful psychiatric therapy, and evenwhen this method has been used as withnicotinic acid, the results have not beenaccepted

Double-blinds are considered essentialfor clinical testing for many reasonsFirst, we have been confronted with alarge number of new treatments andnaturally it is important to know whichones are best for certain classes ofpatients The clinical trials commonbefore 1945 did lead to many polemicsbetween originators and their detractorsIt appeared to many scientists, especial-ly those having no responsibility fortreating patients, that the double-blindwould settle these issues Over and over Ihave observed that the most enthusiasticsupporters of double-blinds are somestatisticians, psychologists and otherswho never have done, nor will do,clinical experiments themselves, andphysicians like deans and chairmen whoorder their junior men to perform themUniformly the physicians who are res-ponsible for evaluation and treatment aremuch less enthusiastic about themethod.

A second reason is that men given theresponsibility of receiving and vettingresearch grants believed that this methodor design would help in deciding whoshould receive a grant. The NationalHealth Grant application forms all con-tained a question concerning the statis-tical design to be used. It soon becameclear that no one could hope to receive agrant unless the double-blind methodwas described Whether it was eventuallyused is a different matter In any event,research workers are intelligent andeasily conditioned, especially when thecarrot of grant support is dangling beforethem.

When the work was done, journalsrefused to accept papers unless theydescribed double-blind experiments, andsoon the journals blossomed forth withself-congratulatory titles such as "acontrolled study of Drug X," etc Andfinally, drug houses discovered thatwhen government agencies wanted datathey wanted only a certain kind of

data—i e double-blind data In fact,many drug companies are now deludedinto thinking double-blinds are not sobad after all; but then they do not haveto run them They merely have to findothers who will

A beautiful example of circular logicwas used to bolster the double-blindtechnique. It is common knowledge thatdrugs, said to be effective when testedsingle-blind, turned out to be no betterthan placebo when double-blinded Itwas, therefore, assumed that since thedouble-blind was infallible this provedthat these chemicals really were inactiveIt seems not to have occurred to theseworkers that since the double-blind hadnot been validated, or calibrated, itmight be a dud method In other words,one could just as logically assume thatany method which could not demon-strate efficacy in drugs known to beactive must be of little value

This view was supported by Glick andMargolis,14 who discovered that double-blind experiments are of short duration,while single-blind experiments are oflong duration The double-blind is sodifficult to operate that it must be ashort-term experiment If it ran for a longtime, all the difficulties would be greatlyincreased Since most psychiatric illness-es are chronic, it seems inappropriate torun short-term experiments

In 1865 Claude Bernard wrote, "Thesemen [talking about systematizers] start,in fact, from an idea which is based moreor less on observation and which theyregard as absolute truth They thenreason logically and without experi-menting and from deduction to deduc-tion they succeed in building a systemwhich is logical, but which has no sort ofscientific reality Superficial personsoften let themselves be dazzled by thisappearance of logic; and discussionsworthy of ancient scholasticism are thussometimes renewed in our day "

CONCLUSIONS

I suggest that since the double-blind method for testing drugs has neverbeen rigorously tested in the laboratory,

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i e. has never been validated or cali-brated; is not based upon mathematicaltheory acceptable even to mathematic-ians; sets two important therapeuticvariables at unreasonably minimumlevels; is ethically questionable; cannotbe used for comparing small hetero-geneous groups; and has not led to thedevelopment of any useful new thera-pies, at least in psychiatry, it should bere-examined seriously to see if theseimportant flaws can be corrected

Other studies critical of double-blindcontrolled experiments are given in thelist of references 4-10, 19

SummaryControlled experiments may be con-

ducted without the use of double-blindtechniques, which themselves inducenew difficulties and errors In view oftheir wide acceptance as an indispen-able tool in therapeutic trials, double-blind techniques should be critically re-examined because their value has neverbeen rigorously tested in the laboratory,they are based upon unacceptablemathematical theory, they diminish theeffectiveness of two important variablesin any therapeutic situation (the faith ofthe patient and the doctor in thetherapy), they are ethically questionable,they cannot be used for comparing smallheterogeneous groups, and they have notled to the development of any useful newtherapies, at least in psychiatry

ResumeDes experiences controlees peuvent

etre effectuees sans recourir aux me-thodes a double iconnu, lesquelles fontnaitre de nouvelles difficultes et intro-duisent de nouvelles erreurs. Etant donneleur emploi generalise, comme outilindispensable Bans les essais therapeuti-ques, it serait bon de reexaminer dans unesprit critique les methodes A doubleinconnu. Leur valeur n'a jamais eterigoureusement mise A 1'epreuve enlaboratoire; elles sont basks sur unetheorie mathematique inacceptable;elles reduissent I'efficacite de deuxvariables importantes dans une situation

therapeutique quelconque (la confiancemise, et par le malade et par le medecin,clans le traitement Iuimeme); elles sontdiscutables sur le plan de I'ethiqueprofessionnelle; elles ne sont d'aucuneutilite pour comparer de petits groupesheterogenes et, enfin, elles n'ont jamaispermis de mettre au point une thera-peutique utile, du moms en psychiatrie

REFERENCES

1 ASTIN_ A W . and ROSS. S : Psycho) Gull 57:429.1960

2 ATKINS. H : Brit Med 1 , 2:377. 1966

3 BARSA..1 A . and KLINE. N S JAMA. 158. 110.1955

4 BELLAK, L.. and CHASSAN..I B New Ment Dis139: 20. 1964

5 CHASSAN..1 B : Psychiatry. 20: 163. 1957

6 Idem Biometrics. 15: 396. 1959

7 Idem: Psychiatry 23: 173. 1960

8 Idem: Behavr Sci 6: 42. 1961

9 Idem: Psychopharmacologia (Berlin). 4: 78. 1963

10 (dem: Intensive or single-case design in drug evacuation:some preliminary experience Paper presented at theSecond Annual Meeting of the American College ofNeuropsychopharmacology. January. 1964

11 DANZIGER. L : Dis Nery Syst 19: 373, 1958

12 DELAY, J , and DENIKER. P : Thirty-eight cases ofpsychoses under prolonged and continuous chlorpro-mazine treatment Paper presented at Congres desmedicins alienistes et neurologistes de France et des paysde langue lrancaise. 50e session. Luxembourg. July21-27. 1952

13 'FISHER. R : Personal communication. 1964

14 GLICK, B S., and MARGOLIS, R : Amer .1 Psychiat118: 1087. 1962

15 HOGBEN, L : Statistical theory: The relationship of pro-bability, credibility and error Allen El Unwin Ltd .London 1957

16 KLINE. N S : Ann N Y Acad . Sci , 59: 107. 1954

17 LEHMANN. H. E . . and HANRAHAN G E : A M AArch Neural Psvchiat 71: 227 1954

18 LOCHNER. K H., SCHEVING. M R_ and FLACH. F F :Acta Psvchiat Scand . 39 413 1953

19 McLAUGHLIN, B E . CHASSAN. 1 B and RYAN. FComer Psvchiat 6' 128 1965

20 VOGEL W et al : Psycho) Bull . 65: 367. 1966

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SOME PROBLEMS OF STOCHASTICPSYCHIATRY

A. Hoffer* and H. Osmond**

Hogben (1957) reminds us that probab-ility theory was developed to benefitnoble English gamblers who hoped toincrease their winnings at the tablesThese early statisticians were dealingwith man-made objects (dice, wheels,cards, etc.) built to certain exactspecifications of size, symmetry, density,hardness, etc Hogben writes "a calculusof probability is relevant to the real world(a) only insofar as it specifies frequenciesof observable occurrences in an in-definitely protracted sequence of trials,(b) only if also such occurrences collect-ively constitute a sequence wholelydevoid- of order " The calculus ofprobability was first used in physics andchemistry and later adopted by scientistswho work with plants, animals andhumans One of its earlier applications tohuman affairs was in insurance wherelarge numbers of individuals or incidentswere involved.

Psychologists who develop tests forintelligence personality and aptitudealso applied a variety of forms ofstatistical analysis, and they seem tohave been useful here, but they have notalways found statistical methods to bemore effective than clinical methods,Meehl (1954), Sydiaha (1959) Hogben'ssharp criticism and the fact the statisticalanalyses are not always very enlighteningwhen applied to clinical matters raises animportant question To what extent is thereal world in which we live, work,become ill and die of a kind that can beanalyzed accurately and objectively bymethods which some statisticians believecan do just this? In other words, are themeasuring devices which they would

We are indebted to Professor Hogben for this useful,accurate and inclusive term. stochastic for those whoare not conversant with it, the shorter O.E.O. definesStochastic (now rare or obsolete) from Greek to aim ata mark. guess Pertaining to conjecture

• Director, Psychiatric Research Unit, Department ofPublic Health, located at University Hospital, Saska-toon, Saskatchewan.•• Onet Cottage, Milford (near Godalming) England.Received for publication: May 17, 1962'

have us use more helpful than misleadingon balance?

It is hardly surprising that clinicianshave joined in the general fashion andpsychiatrists too now cherish thesemathematical devices. Only a few yearsago those authors of medical papers whoused statistics would explain such termsas "standard deviation" or "X degrees offreedom" for the uninitiated Today,authors sometimes present statisticsonly, no longer bothering to include thedata from which they were derived. Thisincreasing interest in statistical methodshas undoubtedly been fostered by therediscovery of what has long beenknown, and has indeed been the stock intrade of quacks since time immemorialThis is that the simple act of givingsomething or doing something no matterwhat it is often produces astonishingeffects on patients Some proceduresmay be started or some drug prescribedand the patient improves When thisoccurs without any consensus that theprocedure produces its benefits or thedrug its effects by some means under-stood by the profession at large, thisbenefit is often called the placebo effect.

This refers to reactions which may bebeneficial or harmful by chemicals"believed" to be inert We use "believed"because the inertness of a substance canonly be established empirically There isno reason why the purest starch shouldnot be harmful to some people andbeneficial to others These reactions maybe termed positive or negative placeboreactions. In a recent paper, Hoffer andOsmond (1961), we have noted thatsome people do not respond withappropriate- physiological or psycho-logical 'changes to compounds longknown to be active, and half jesting wehave termed these obecalp reactions,(placebo in:.reverse) The possibility thathuman subjects can react positively oradversely to drugs raises serious issues.The chief of these is whether the "blind"studies of a classical kind are applicableto drug effects After many years ofrelatively uncritical acceptance byscientists but private resistance from

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clinicians, statisticians themselves andclinicians have raised these questions 4,5, 11, 13, 18, 19, 20 This problemrequires urgent and immediate examina-tion by all scientists working with humansubjects Unless this is done, research inthese matters may be seriously hamperedbecause scientists are being encouragedto use inappropriate methods whichnevertheless have received generalassent. It is already apparent that somegranting agencies make this new fashiona necessary preliminary for gettingmoney for research, yet as we shall show,it is at least possible that double-blindstudies will as often indicate that anactive compound is inactive as theconverse

Grayson (1961) has given an admirablyclear account of the views of those whouse double-blind techniques to test newdrugs in psychiatric practice At asymposium on Chlordiazepoxide hecriticized severely papers given there andelsewhere According to him, no studycan be termed confirmatory unless itincludes: (1) a controlled group ofpatients; (2) an objective evaluationprocedure; (3) compliance with statis-tical requirements

Dr S Cohen voiced a different sort ofdissent saying, "I would rather see a dirtystudy by Fritz Freyhan than a cleandouble-blind study by many other in-dividuals " He added that dirty studieshad shown certain chemicals to beeffective many years ago and thatclassical double-blind studies in VeteransAdministration Hospitals had merelyconfirmed what was already well-known.

The clinician and the statistician wereat logger-heads, the statistician statingbluntly that he alone was correct, andthe clinicians expressing a dour un-willingness to give up their ways whichthey believe have worked AlthoughGrayson did not actually say that allerrors could be resolved by using theclassical double-blind experiment whichhe had described, he clearly implied this,but in company with most other theoristsin experimental design, he had neglectedpatients' failure to react to chemicals

which are known to be active in mostpeople 15 We will therefore see whathappens to his sort of experimentaldesign which is so highly recommendedby theorists today when one does takethis into account.

Treloar (1939) describes two classes oferroneous inference (A) where insignifi-cance is found when there is in fact a realdifference, (B) where significance isclaimed when none in fact exists Class Aerrors lead to valuable procedures oractive pharmacological substances beingeither ignored or improperly discarded,thus increasing or prolonging humansuffering unnecessarily Class B errorslead to the use of ineffective treatmentswhen better may be already available orcould perhaps be devised In addition,they may result in wasteful and expensiveinvestigations in the future Treloarbelieves that Class B errors are moreharmful to the progress of science

Treloar states that the price foravoiding one sort of error must be toincrease the chance of the other sort It isa matter of debate which class of errorhas the graver consequence formedicine It is by no means certain thatTreloar's verdict holds equally in everyscientific situation, for sometimes errorsof the second sort (mistaking a positiveresult for a negative) may be by far themore serious The great blood-lettingepidemic of the eighteenth centurycertainly shows that harm results whensignificance is claimed where noneexists Generally speaking, unless thetreatment itself is dangerous littledamage is done; even if a particularmedicine does no good it at least givespatients, their relatives and doctors, afeeling that something is being donewhich may tide them all over a difficulttime If, however, insignificance isalleged when in truth the treatment orsubstance is effective, then we run acertain risk of not discovering an insulinor penicillin That this is no idle notioncan be shown by the fact that it actuallyhappened with penicillin itself ErnestAugustin Clement Duchesne in 1897

wrote his doctoral thesis on antagonisms

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between microbes and moulds. (SeeM.D of Canada, January 1961). He con-cluded "Furthermore, it seems from someof our experiments, unfortunately toofew in number and which ought to berepeated again and checked, that certainmoulds (penicillium glaucum) inoculatedinto an animal simultaneously withextremely virulent cultures of certainpathogenic microbes (8. coli and Ebar-thella typhosa) are able to attenuate thevirulence of such bacterial cultures to aremarkable degree It is to be hopedtherefore that in pursuing the study ofthe facts of biological competitionbetween moulds and microbes—merelyoutlined by ourselves and to which wehave no claim other than rendering herea very modest contribution—the dis-covery of further facts directly useful andapplicable to prophylactic hygiene andtherapy may be attained " Duchesne'swork passed completely unnoticed at thetime and was soon forgotten

It is therefore particularly importantnot to jump to hasty negative con-clusions, because it frequently happensthat an initial substance which either hasside effects or is not notably potent canbe a stepping stone to something bothsafe and potent What has saved usefulsubstances and procedures in the pasthas often been simply the faith of a fewcommitted people There is a real dangerthat the rash pontifications of dedicatedmethodologists may be enough todestroy the faith at a crucial moment

Model ErrorThere is another kind of error which

has crept into psychiatry in evaluatingthe results of therapy from a long-termpoint of view. This kind of error has beendirected against the evaluation of theshock treatments, especially ECT andinsulin shock therapy Penrose and Marr(1943) evaluated insulin shock then beinggiven in the Province of Ontario, andconcluded that the outcome of thistreatment, as measured by the number ofpatients in hospital at the end of four andfive years, was no different from thosewho had not received it They therefore

inferred that it was pointless to useinsulin as a treatment for schizophrenia.Clinicians, however, seem to have paidno attention to their advice for ifanything, more deep insulin was givenafter their paper than before it. Insulinwas not discarded until safer and simplertreatments such as the phenothiazonesbecame available The clinicians' re-luctance to relinquish insulin is some-ti mes used as an example of obstinateand supercilious behavior, but it mightalso mean that those who work closelywith patients were better able to assesswhat had happened than statisticiansworking with data

In our particular example, the clinic-ians may have been well advised tocontinue to use insulin, for we believethat the statisticians made a seriousmistake which has gone unnoticed fornearly 18 years They did not askthemselves relevant questions about thekind of illness which they were exam-ining In other words, they used thewrong sort of model with which todetermine whether treatment wassuccessful or not. There are at least threekinds of models which are useful forthinking about diseases and their treat-ment The first is that of a single attackPneumonia is such a disease. Often inthese cases, the body is overwhelmed bythe intrusion of the foreign organism but,having thrown off the assault, it seems tobe resistant to any recurrence of thesame disease

A second class of disease is one inwhich there is a phasic course of theillness with exacerbations and remis-sions. Such a disease is, for example,arthritis.

A third kind of model is where thedisease is continuously present andunless adequately treated, may lead toquick death For example, perniciousanemia or diabetes mellitus In assessingthe response to treatment, one mustknow which model is most appropriatefor a particular disease Schizophrenia,being a very variable disease, may followany one of these three models andtherefore the type of evaluation must be

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I-z

quite different for each case. If schizo-phrenia were like pneumonia and wereproduced by a massive attack from asingle organism, then one would expect aspecific treatment to quickly vanquishthe organism, and if four or five yearslater another attack produced a relapse,one would not state that the originaltreatment had been ineffective. Onewould merely be disappointed that thedisease had recurred and would give thesame treatment again. If schizophreniawere an illness like arthritis, even whenthere was a good response to treatment,one could never be quite sure that thiswas not one of those natural remissionswhich do occur

The third model, the chronic disease,is the easiest to work with, especiallywhen one has a treatment which is quitespecific This is because here treatment isfollowed quickly by remission and ceas-ing treatment results in recrudescence ofthe illness and this can be repeated untilthe investigator is certain that a relation-ship exists between treatment and re-mission

It is clearly possible to treat a largegroup of patients, to have a goodremission of symptoms and to find aftersome months or years have passed thatall or many of them have relapsed Andsince with the control group of patients,there would also be remissions andexacerbations, it is likely that in an illnessof this kind, regardless of treatmentgiven, the same proportion of patientswould suffer relapse four or five yearslater without further treatment

If schizophrenia is a chronic diseaseand most people think it is, then it wouldbe unreasonable to expect any treat-ment, however successful at first, tocontinue to exert a beneficial effect foran indefinite time after that treatmenthad been stopped If schizophrenia is achemical disease, then one would expecta response to treatment resembling thatof other biochemical diseases

For the last nine years we have studiedthe effects of massive nicotinic acid andits amide on schizophrenic patients. Wehave found that those patients who have

98

been. given ECT and nicotinic acid show avery small number of readmissionsduring the first few years after dischargecompared with those who have not hadthis vitamin, but the protective actiononly seems to last for about two to threeyears. After this, those patients who havebenefited greatly from nicotinic acidslowly begin to relapse. An account ofthis in which the data is given in detailhas been published by C. C Thomas in abook entitled Niacin Therapy in Psychia-try A similar group of schizophrenicpatients given ECT but no nicotinic acidhad a remission rate of 50 to 60 percentwithin the first one to two year periodsafter discharge, but over the next four,five or six years this did not greatlyincrease Those not receiving nicotinicacid had a downward concave curve

FIGURE1

90'-

0 00 " COMPARISON4- GROUP

W 4O-C NICOTINIC

ACID GROUP

u :0

while those who had it show an upwardconcave curve This data is showngraphically in Figure 1

Curve A represents the proportion of98 patients who required readmission tohospital over a follow-up period of aboutnine years At no time did any of thesepatients have nicotinic acid or its amideThe 73 patients shown in curve B weretreated with nicotinic acid as well as theother treatments used in curve A. Thesignificance of the difference between

1950 1954

YEAR

1950

Number of schizophrenic patients readmitted at leastonce during a follow-up period

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these groups depends upon which year isselected after discharge As it happens,with these patients the differences aresignificant for all years, but if curve Bcontinues to follow its trend and curve Aremains stable, then in a few years' timethe same proportion of patients will havebeen readmitted from each group Onecould perhaps select a ten-year follow-upand show no difference whatever thenSuppose we had known nothing aboutour patients' progress during this decade,and had undertaken our follow-up at theend of it, we might have well concluded,quite erroneously, that niacin was use-less. Our statistical conclusions would becorrect but wholly misleading In thesepatients, nicotinic acid was given for atleast one, and sometimes for severalyears It exerted a protective effectagainst recurrence of schizophreniawhich was sustained long after it hadceased to be given Other substancesmight work in much the same Way, butbe of a kind which could only be given ina hospital. Insulin coma treatment seemsto be of this type. We have still to beconvinced that the many able clinicianswho reported on the successful use ofinsulin were all self-deluded. As we havealready noted, psychiatrists using insulinin the treatment of severe schizophreniadiscontinued its use only upon thedevelopment of other treatments whichwere almost as effective as ECT, re-serpine and tranquilizers, and whichwere simpler, safer and easier to ad-minister Some mental hospitals still useinsulin and report upon it favourably

Since it is possible that this misunder-standing originated in Penrose and Marr'spaper, it should perhaps be carefully re-examined for it has had great influenceand not determining what had happenedhistorically is important Their error layin the first, second and third years aftertreatment It is quite possible that therewere significant differences here whichescaped them The selection of thefourth and fifth years was quite arbitrary,indeed Penrose and Marr give noadequate reason for choosing this timerather than some other Statistical errors

of inference of the second sort are morelikely to occur unless proper follow-upassessments are used

One of us (H 0 ) has been involvedrecently in an interesting example of anerror of the second sort in connectionwith a study of ololiuqui Osmond25made the first psychiatric study of thepsychotomimetic properties of ololiuqui,long known as the chief narcotic of theAztecs 28 After a series of self experi-ments with increasing doses of ololiuqui(Rivea Corymbosa) seeds, he reporteddefinite and an unexpected kind ofactivity, i.e , psychological changes andapathy followed by a marked feeling ofwell-being This report was received withsome excitement and studies of itspsychological properties and attempts toisolate the active fraction began

Investigators at Lexington 2l ran aclassical double blind study, and Kinross-Wright22 conducted a single blindexperiment. Neither found any con-vincing evidence that ololiuqui was apsychotomimetic agent It now appearedthat Osmond had made a serious errordue to his somewhat subjective method.The chemical studies were more pro-ductive In 1960, Hofmann (discoverer ofLSD-25 and psilocybin) reported at asymposium in Australia that he hadisolated an indole alkaloid, lysergic acidamide from Rivea Corymbosa (ololiuqui).Further, he had consumed a smallquantity of this alkaloid and had experi-enced a reaction similar in many respectsto one Osmond had experienced in 1954Hofmann's report was received with greatskepticism by some chemists who statedthat they had been unable to find thesealkaloids in ololiuqui and assumed thatthis meant that no one else could findany Lysergic acid alkaloids had untilnow been found only in some fungi andnot in higher plants, so this claim ofHofmann's was doubly exciting. Taberand Heacock30 corroborated Hofmann'sclaim and have isolated lysergic acidamide (L A ) as well as other substancesSince L.A. is known to be a weakpsychotomimetic, the original work ofOsmond is now verified It seems clear

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from this that even very competent andexperienced investigators are notguaranteed success by using methodswhich are often discussed as if they alonecan guard against error

There is another matter, not illustratedby the ololiuqui example but which is,we think, important. This concerns theway in which scientists perceive eachother Is it better for science if scientiststry to corroborate each other or try todestroy other scientists' work? Althoughone might suppose that either methodwould yield much the same results, thereare great practical differences It may bethat in psychiatric research a number ofthose ostensibly engaged in it do notknow that the effort of corroboratinganother's work is frequently as onerous asthat of original discovery It is indeed forthis very reason that men who do this areso highly regarded by their fellowscientists It seems proper to ask our-selves what motives are likely to be thebest for undertaking a task which is of thehighest importance, calls for greatexertion and yet which lacks the specialspice and excitement of original dis-covery Much must surely depend uponthe attitude which one scientist hastowards another. It has long been ourtradition, rarely broken, for scientists toaccept their peers as being men ofhonesty and integrity although alwaysbeing ready to disagree with theirinferences and their conclusions unspar-ingly Polemic has been the life blood ofscience, but generally speaking,character assassination has been less wellregarded. Attempts to corroborate mustbe persistent, cautious, sustained andonly after determined attempts to cor-roborate would a negative report bemade. No such report should ever bemade unless the procedure originallydescribed had been used with exactnessThis still seems to be the best method tous We believe that one should have faithin the resourcefulness, skill and honestyof other research men combined with arigorous and prolonged investigation oftheir claims and readiness to disagreewhen necessary. Unfortunately another

attitude seems to be not uncommon inpsychiatric research where the discovereris often assumed to be foolish, brash,crack-potted and even a little crooked atti mes

Some behave as if they believed thatthe best attitude towards their fellowresearchers was one of suspicion or evenhostility They do not act as if they wereattempting to corroborate or confirmanother's work, but to disprove it orexpose some trick or stupidity Thisattitude is common among certain kindsof inspectors whose function is to findevidence for misdeeds and here it isdoubtless proper, but is this an attitudewhich we can afford to foster in thescientific community of psychiatric re-searchers? For with a negative andinspectorial attitude the scientist, sup-posedly trying to confirm original work,may be tempted to publish findings as arefutation of that work without theinfinite patience, care and zeal exertedby the original discoverer In effect, alack of trust in the integrity of a fellow-scientist may lead to one giving up thesearch far too soon. In this way, sciencecan be done great disservice and patientsdamaged Readers of psychiatric journalswill come across many examples of thiskind of study in the literature of the lastdecade Indeed, some researchers seemto make an occupation of " inspecting"

other people's claims and failing tovalidate them after cursory efforts,thereby establish for themselves a reput-ation for "soundness." At times onewonders if this is not becoming a moreacceptable way of being recognized as apsychiatric researcher than by attempt-ing the onerous task of new discovery.We think it may be important forresearchers to enquire whether they areconforming to those customs which havebeen found useful and productive inother branches of science In contrast toEngel, 6 we hold that one of the scientist'smain tasks is to question the ideas andinferences of other scientists 14, 15, 27Discussion, polemic, satire are entirelyproper here Let us have the strongestdisagreements, but no ad hominem

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attacks, character assassinations, im-putations of dishonesty or incompet-ence, and above all no inspectorcomplexes Eminence in science isconferred by one's peers, it does notdescend on a man simply because he isthe head of an institute, a department, asection or a laboratory It inheres in menand women, not in the position whichthey chance to hold in an organizationResearch does not require superscientiststo decide what is and what is not; thescientific method and the passage oftime will do that soon enough There isthe even greater danger that the in-spectors will insinuate themselves intothe councils of fund-granting bodies andwith their passion for neat, clean and tidyexperiments do psychiatric research un-told harm Indeed, they may alreadyhave done some. What has happened isthat a confusion of function has arisen. Itis far easier to be a capable inspectorthan to be a good judge of what is likelyto be a valuable research and to increaseour knowledge It happens that it is thismore difficult function that is neededmost

The Relationship of the Experiment to theInvestigator

Foulds8 surveyed the literature ondouble blind studies He found thatsignificantly more double blind studiesshowed drugs to be ineffective Fox,9surveying a different set of studies, cameto the same conclusion Fox collectedmany reports on treatment, and byselection reduced them to a series ofpapers which he divided into those heconsidered had used acceptable methodsand those which had not Each classifica-tion was further sub-divided into twosub-groups In one, the results suggestthat a therapeutic drug was significantlybetter than chance (or faith). In theother, negative results were foundPapers with adequate controls (compari-son groups) in which adequate statisticalanalyses had been used were classified asacceptable This is what Fox found

Kind of Study Therapeutic Claims

Chi Square = 8.54, i e , the nullhypothesis was disproven In otherwords, there was a significant differencein the conclusion of the two kinds ofpapers

But Glick and Margolisl0 found thatthe duration of clinical studies con-founded these results Although doubleblind studies showed significant dif-ferences less frequently they were moreoften brief studies. Only one out ofeleven double-blind studies was oflong duration. But 12 out of 16 singleblind studies were long clinical studies(Chi Square = 8 ca ) Long-term studiesmore often reported clinical improve-ment than short-term double blindstudies They stated "there is no validtheoretical or scientific reason whydouble blind studies must be short-termor even placebo controlled or why singleblind studies must be long-term or non-placebo controlled " Finally from theirextensive review of the literature, theseauthors could find no support for thecommon belief that initial enthusiasm fora particular drug is always followed by alater realism and a more sober evalua-tion

Why, then, do people who carry outorthodox clinical studies seem to getbetter results than investigators who rundouble blind studies?

(1) Fox considers that authors may bereluctant to write and editors even morereluctant to publish negative results Thismay have once been true, but Fox's owncollection of papers hardly suggests thatthis is so now We have found few signsthat authors are unduly sensitive oranguished by negative results, rather thereverse Indeed, one sometimes has thefeeling the investigators have become sointerested in method that the success orfailure of a research is equated with anicety of design rather than with new

AcceptableNot Acceptable

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discovery(2) We believe that double-blind

studies may prove drugs ineffective, i e ,have large errors of the second kind

(3) What has usually been muchneglected is the impact upon theinvestigator and thus on his staff andpatients of the particular design fol-lowed Barber in a witty study has dealtwith this in a general way 2

In any therapeutic study a variety ofcontrols are required It is not, of course,true that a controlled study is always onewhere a comparison group is usedControlled studies are used in all thesciences In biochemistry, a controlledexperiment is one in which majorvariables such as temperature, pressure,concentration, pH are set at steady levelswhile other variables are allowed tofluctuate But in clinical practice"controlled" has come to mean the use ofa comparison group 18

It would be moreaccurate to call these studies comparisonstudies for such studies with two or moregroups may ignore important variablessuch as drug dosage, its relationship tomaximum need, etc In fact, comparisonstudies may be nearly uncontrolled andthose without a comparison may be verymeticulously controlled

One of the main variables whichpsychiatric investigators have tried tocontrol has been called faith, suggestion,placebo effects, etc Mathematicianshave implied that the classical double-blind study will in fact do this Themathematician may be correct, but hedoes not concern himself with the levelat which faith is "controlled " A chemist,for instance, can control temperature atfreezing or at boiling point It makeslittle difference statistically unless one isinterested in temperature as a variableand not as a constant The chemist willtherefore select that temperature whichis most efficient for obtaining hisparticular objective.

One may perhaps excuse the statist-ician for his lack of understanding aboutfaith as a variable, but we can hardlyexcuse those investigators who follow hisrecipes so blindly

For faith can be made constant at alow level or a high level, yet the doubleblind technique usually sets it at aconstant low level But faith is animportant ingredient in any therapeuticprocess, and if this is so, why not set it atthe most effective level? Indeed asdoctors, we are ethically bound to do justthis, particularly when so far as thestatisticians are concerned the results arethe same so long as the faith level isconstant The investigator then wishes toshow that faith plus a drug is significantlybetter for a patient than faith plus aplacebo As Hogben and Wrighton aptlypoint out, this is not usually donebecause "The reason is that cookery bookrecipes will commonly prescribe as theappropriate null hypothesis the onewhich commends itself to the math-ematician for reasons which have no-thing to do with the operational intentionof the scientific worker "20

The mathematician little interested infaith except to exclude it, cannot knowthat human nature being what it is,doctors prefer to know what theirpatients are getting and that there issome therapeutic benefit And this iswhere we run into a major problem,because it is so difficult to ensuremaximum but equal faith for both groupswith double blind studies This difficultyis readily explained on operant con-ditioning theory

One important ingredient for main-taining a satisfactory relationshipbetween doctor and patient is whatamounts to positive reinforcement of thedoctor himself by what appears to besuccessful treatment When a doctorgives medicine to a patient and thepatient seems to benefit, this reinforces(encourages) the doctor who heartensand supports the patient to continuetaking the medicine Such encourage-ment may in itself minimize side effectsBeing reinforced by his success with onepatient, the doctor will use the treatmenton others with even greater confidence,and so a fruitful combination of medi-cine and faith develops On the otherhand, if many patients fail to respond, or

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if there are side effects which disturbboth patients and doctor, then thedoctor's habit of giving that particulartreatment will be extinguished quickly;indeed, it is something of a joke amongthose who often use new drugs that if oneof them is to be successful, it is essentialfor the first few patients to do well, forthis produces enough reinforcement toensure continuing trials It is obvious thatthe reverse can occur A clinician mayhave negative reactions to an active drugand his faith in the drug can be as quicklyextinguished Originators of newer treat-ments are often sustained by theirhypotheses But the fact remains thatclinicians have introduced many treat-ments which work

This suggests strongly that in clinicalstudies without control groups, due toreinforcement, active drugs will be useduntil replaced by something provenbetter; while the giving of inactive drugswill be quickly discontinued It followsfrom this that clinical studies are those inwhich the doctor's habit of giving thedrug has been reinforced Studies ofshort duration are those in which thehabit has been extinguished The factthat studies are long suggests then thatthere has indeed been therapeutic bene-fit Long studies may indeed be an indexof therapeutic benefit One could arguethat non-specific remedies have beenused for centuries However, suchremedies are not altered until better onescome along and many "non-specificremedies" have been found to containgreater or less quantities of active drugs

The finding by Fox and Foulds may bedue to this 8, 9 It is at least possible thatthe use of drugs or treatments for longperiods of time is a better index of theirtherapeutic efficiency than any measuresyet available, for were this not so, theiruse might have been discontinued longago in the manner which we havedescribed This should at least beconsidered by those planning clinicaltrials

EpicrisisIf this is as obvious as we have

suggested, why then has it gone un-

remarked for so long? It has, of course,been discussed repeatedly in the past,but possibly in recent years clinicianshave become intimidated and muddledby the formidable mathematics and thei mposing words which methodologists sooften use Kluver*** (1931) warned elo-quently almost one-third of a century agoagainst applying refined mathematicsinappropriately Like a great brandy, hispapers read even better after a fewdecades We can only urge the stoch-astically inclined to meditate upon hisideas, but we cannot resist whetting theirappetites with a few lines from his paper

"We must start from the facts andsomehow find the tools adequate fortheir investigation If we find in psycho-logy that certain dynamic systems,certain behavior units, exist to which wecannot do justice by pointing out the fewmathematical relationships known atpresent; if, at the same time, there seemsto be no hope whatever for increasingour knowledge of these relations or ofrelations found by other exact methods;then even the description of thesebehavior units by means of these 'exact'methods (not to mention a thoroughscientific treatment) is inexact since thetools are totally inadequate In suchcases a 'type ' may be far more 'exact '

than an equation Only one who thinksabout method as something divorcedfrom the facts and from the material athand will doubt this statement Inclosing we would like to call attention tothe fact that physicists inform us thatthere are scientific procedures whichenable us to test the validity of aproposition by reference to a singleobservation "

It may be that our old and discreditedmedical standby, the single case, willone day become respectable againOthers preceded Kluver with sensiblewarnings, none more eloquently thanClaude Bernard whom Hogben quotes aswriting almost a century ago, "Bydestroying the biological character ofphenomena, the use of averages in

From Methods in Social Science. Page 184 Analysisand typological method Rice Ed 1931 University ofChicago Press

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physiology and medicine usually givesonly apparent accuracy to the results If,for instance, we observe the number ofpulsations and the degree of bloodpressure by means of the oscillations ofamanometer throughout one day, and ifwe take the average of all our figures toget the true or average number ofpulsations, we shall simply have wrongnumbers In fact, the pulse decreases innumber and intensity when we arefasting and increases during digestion orunder different influences of movementand rest; all the..biological characteristicsof the phenomena disappear in theaverage If we collect a man's urine toanalyze the average, we get an analysisof a urine which simply does not exist;for urine when fasting is different fromurine during digestion A startling in-stance of this kind was invented by aphysiologist who took urine from arailroad station urinal where people of allnations passed, and who believed hecould thus present an analysis of averageEuropean urine! Aside from physical andchemical, there are physiologicalaverages, or what we might call averagedescription of phenomena, which areeven more false Let me assume that aphysician collects a great many in-dividual observations of a disease andthat he makes an average description ofsymptoms observed in the individualcases; he will thus have a description thatwill never be matched in nature So inphysiology, we must never make averagedescriptions of experiments, because thetrue relations of phenomena disappear inthe average I acknowledge myinability to understand why results takenfrom statistics are called laws Certainexperimenters, as we shall later see, havepublished experiments by which theyfound that the anterior spinal roots areinsensitive; other experimenters havepublished experiments by which theyfound that the same roots were sensitiveThese cases seemed as comparable aspossible; here was the same operationdone by the same method on the samespinal roots Should we therefore havecounted the positive and negative cases

and said: The law is that anterior rootsare sensitive, for instance, 25 times outof a 100? Or should we have admitted,according to the theory called the law oflarge numbers, that in an immensenumber of experiments we should findthe roots equally often sensitive andinsensitive? Such statistics would beridiculous, for there is a reason for theroots being insensitive and anotherreason for their being sensitive; thisreason had to be defined; I looked for it,and I found it; so that we can now say:The spinal roots are always sensitive ingiven conditions, and always insensitivein other equally definite conditions"Hogben comments, "Against this back-ground of lucid exposition (1865), it is atfirst difficult to understand why it shouldnow (1954) be necessary to challenge theclaim of the statistician to prescribe thedesign of experiments in general and ofthe clinical trial in particular In my view,such claims are acceptable only if werelinquish the standards of intellectualrectitude of an earlier generation "18And again, " In short, statistical theory istemporarily, at least, in the quicksands.Nothing less than a transvaluation of allvalues is in process For my part, I havereluctantly come to the conclusion thatthe statistician will emerge in the endwith a very much chastened view of whattraditional methods can accomplish Ifthere proves to be any enduring basis fora stochastic calculus of judgments, weshall be able to define its proper terms ofreference clearly only after we havecleared the site from an overgrowth ofprescriptions which can certainly nolonger claim the universal assent ofprofessional mathematicians " And, "Ifwe then concede every claim put forwardfor such devices as the Chi Square testand others of its kind till recentlyprescribed by most professional statisti-cians without misgivings, we may stillentertain misgivings about how far thequestions for which they claim toprescribe the method prerequisite to acorrect answer tally with what theclinician and the biological researchworker do want or should most want to

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know in the context of the clinical trialIn stating my own view about this, Iapproach the topic with the admittedpreoccupations of my main professionallifework as an experimental biologist Inthat capacity, I see the assessment ofremedies as the disclosure of a specificstimulus-response nexus; and I mean bycontrolled experiment no less exacting anundertaking than as stated in my openingparagraph." Hogben and Wrighton2Osummarize their point of view in thisway:" (1) Hitherto it has been customaryto assess the claims of therapeutic andprophylactic measures in statistical termsby recourse to tests which invoke aunique and so-called null hypothesis,namely that the procedures comparedare equally efficacious (2) This pro-cedure has no bearing on the operationalintention of the trial, viz to find out howmuch advantage accrues from sub-stituting one treatment for another. (3)Within its more restricted domain, thecredentials of any significance test whichtakes within its scope only one hypo-thesis have now to meet the criticismthat it takes into account only one sort oferror, viz that of rejecting the hypothesis.when it is true (4) A procedure whichjustifies assertions of so limited andconditional a scope may be a usefulself-disciplinary convention; but itsclaims to rank as an instrument ofstatistical inference are no longer accept-able "

It may be however that there issomething about statistical experimentswhich Bernard, Kluver and Hogben haveall failed to appreciate. We shall attemptsome sort of empirical test One of ourearlier arguments could perhaps beturned against us—in the form that sincemany people use and are enthusiasticabout the statistical methods they mustbe effective We noted that doctors usecertain medicines and procedures forlong periods of time because these resultin their being reinforced by their patients'betterment and tend to relinquish thosewhich do not result in improvement Indouble blind studies, those who under-take them seem to be reinforced (re-

warded) by the elegance or cleverness ofthe design rather than by any real orsupposed benefit to patients Suchstudies as Fox's scholarly enquiriesshowed that they are their own reward,but in our present climate they reap inaddition a harvest of praise from critics,like Dr Grayson, who admire the newmode and scorn the old If learningtheory is any guide, these self-rewardingstudies will continue until there is amarked change of medical opinionregarding their worth.

Some other test than this is neededWe could enquire for instance how oftenelaborate statistical manipulation andthe methodological refinements nowconsidered essential for good psychiatricresearch, have played a large part inthose developments of the biologicalsciences which have done so much toimprove the human condition in the lastcentury Few would disagree that Nobelprize winners are a fair sample of thosewho have made great discoveries.According to Stevenson's (1953) surveyfifty-eight Nobel prizes were given fordiscoveries in the biological sciencesbetween 1900 and 1950. Table 1 showshow they were distributed.

TABLE 1

Distribution of Nobel Winnersby Discipline 1900-1950

Discipline Number

Immunology and Bacleriologv 10Physiology 12Anatomy and Pathology 4Biochemistry 18Genetics and Embryology 3SurgeryOpthalmology and Otolaryngology 2Therapeutics 8

Total 58

It appears from Stevenson that onlyone (Muller) made any extensive use ofstatistics, and this was in genetics Noneof them referred to statistics in their mainwork None of the eight prize winners intherapeutics used the double blind

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method now thought to be so indispens-able This can hardly be becausestatistics are new; Calton and Pearsondid much of their valuable work in thelast quarter of the nineteenth century,Fisher (1925) in the first quarter of thetwentieth Statistics of this kind are asold as bacteriology and immunology andfar older than biochemistry founded byGowland Hopkins about 1912 In spite ofits recent origin biochemistry in whichstatistics play a very small part heads thelist with eighteen prize winners, almostone-third of the whole It seems from thisempirical test that statistical expertisehas little to do with original discovery.Those who put their faith in it shouldconsider these findings before becomingtoo over-bearing and insistent that their'sis the only path to truth

Let there be no misunderstanding Wedo not imply that stochastic theoryshould dispense with statistics or thatscientific methodology should be neg-lected It is and must continue to be avaluable aid which can ease the burdenof discovery and speed its confirmationand acceptance. But sometimes it hasbecome a straight-jacket, even a coffin,imposing harmful and fatal limitations onthose delicate tendrils of enquiry whichare among the most precious growths ofscience Clinical trials should be donecautiously and with modest expecta-tions We should not be too keen todiscard or deride substances or treat-ments which experienced clinicians sayhelp their patients They may, after all,be right

REFERENCES

1 ABRAMSON. H A'. The use of LSD in psychotherapy

2 BARBER B : Science. 134:596. 1961

3 CAFFEY, E. M . and KLETT C ..l : Dis Nery Syst22:370 1961

4 CHASSAN. 1 B : Psychiatry. 23:173. 1960

5 CHASSAN. 1 B : Behavioral Science. 6:42. 1961

6 ENGEL. G L Perspectives in Biol 6 Med 4:386.1961

7 FISHER, R. A.: Statistical Methods for ResearchWorkers. Oliver & Boyd. Edinbourgh. 1925

8 FOULDS. G : 1 Ment Sc : 104:259. 1958

9 FOX B : J Ment Sc 107:493. 1961

10 GLICK, B S., and MARGOLIS. R : Am .1 Psychiatry.118:1087. 1962

11 GOLDMAN. D : in Biological Psychiatry Ed. J HMasserman Grune & Stratton. New York. 1959

12 GRAYSON, H : Dis New Syst 22:52. 1961

13 Group for the Advancement of Psychiatry Report 42.May. 1959 104 East 25th Street. New York 10. N V

14 HOFFER. A : Perspectives in Biol 6 Med . 4:492, 1961

15 HOFFER, A and OSMOND. H : J Neuropsychiatry.2:221. 1961

16 HOFMANN, A ; International Symposium on theChemistry of Natural Products Abstract of Papers.Australia. 1960

17 HOFMANN. A . and TSCHERT ER. H Experentia 16:414. 1960

18 HOGBEN. L : The Medical Press. 232. October 13, 1954

19 HOGBEN, L.: Statistical Theory: The Relationship ofProbability, Credibility and Error George Allen and UnwinLtd London. 1957

20 HOGBEN. L., and WRIGHTON R : Brit J Soc Med689 .117 1952

21 ISBELL. H Personal Communications to H Osmond.1957

22 KINROSS-WRIGHT, V J.: NeuropsychopharmacologvProc 1st Int Congress. Amsterdam. 1959. p 453

23 LUCY J CLANCY, J.. HOFFER, A., OSMOND, H..SMYTI-IIES, J . and STEFANIUK. B . Bull Menn Clinic.18 147. 1954

24 MEEHL, P E.: Clinical Vs Statistical Prediction U ofMinn Press. Minneapolis. 1954

25 OSMOND H : J Ment Sc 101:526. 1955

26 PENROSE. L S and MARK. W B'. .1 Ment Sc. 89:374. 1943

27 POLANYI. M The Lancet. 1:921. 1956

28 SCHULTES. R. E : A Contribution to our knowledge ofRivea Corvmbosa Botanical Museum of HarvardUniversity- 1941

29 SYDIAHA. D : J Applied Psychology 43:395. 1959

30 TABER. W A., and HEACOCK. R A : Can J Micro-biol B.137. 1962

31 TRELOAR, A E.: Elements of Statistical ReasoningJohn Wiley 6 Sons. Inc New York 1939

32 STEVENSON, L G.: Nobel Prize Winners in Medicineand Psychology. 19014950. Henry Schuman. New York.1953

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SECTION VII—Efficacy and Toxicity

The double-blind controlled methodfor testing efficacy is only one of anumber of possible tests In spite of itsoverwhelming popularity, especiallyamong professors, editors, and civilservants; there is a large and growingbody of scientific opinion that it hasmany inherent errors and should be usedwith great scepticism and its limitedconclusions accepted with extreme re-luctance When it comes to a matter oftoxicity no double blinds are recom-mended. This is too serious a matter tobe left in the hands 'of double-blindmethodologists We do not know of asingle drug taken off the market becauseof double-blind human trials We believethis double standard tells us much aboutthe validity of the double blind Forserious matters such as toxicity it isignored For efficacy, obviously con-sidered much less serious, it is recom-mended

How then are we to judge the relativetoxicity of drugs? We cannot demandanimal type toxicity trials where thelethal dose is determined by finding outhow much will kill half the subjects Weare forced to fall back on the number and

intensity of undesirable side effects andreactions which would be very toxic andeven lethal if allowed to continue

Children, Drugs, and Vitamins—A Matterof Ethics, A. Hoffer, M.D., Ph.D.

When Dr H Osmond read Dr BRimland's megavitamin study on a largeseries of sick children, it occurred to himthat it lent itself to an examination ofefficacy as against toxicity. Efficacywould be the improvement due to thedrug while toxicity would be the termapplied to any worsening of the con-dition Relative efficacy would be theratio of one to the other Thus if drug Ahelped 50 percent of a sick populationand made 10 percent worse, its relativegroup efficacy would be 5 If it helped 25percent and deteriorated 25 percent, itsrelative group efficacy would be 1Obviously the drug with highest relativeefficacy would be the one best used formost sick children.

Rimland (1972) reported results whichmake it possible to rate a large number ofcompounds. His Table 2 is here re-produced:

No PossiblyDefinite Helped a

TABLE 2

SomeImpr Def.

Made aLittle

MadeMuch Efficacy

Drug Name Total Effect little Total Helped Total worse Worse Total Index

Dexedrine 172 30 18 48 25 19 44 27 53 80 0 5Aventyl 35 16 5 21 3 3 6 5 3 8 08Benedryl 151 47 45 92 13 21 34 12 13 25 1 3Compazine 49 15 16 31 5 2 7 4 7 11 06Deana) 73 30 16 46 10 7 17 8 2 10 1 7Dilantin 204 69 36 105 18 39 57 21 21 42 1 3Mellaril 277 60 61 121 57 44 101 31 24 55 1 8Stelazine 120 25 27 52 20 20 40 16 12 2B 1 4Thorazine 225 49 50 99 25 33 58 39 29 68 0.8Valium 106 28 16 44 9 22 31 17 14 31 1 0Ritalin 66 7 10 17 10 12 22 9 18 27 0 8Phenobarbital 52 11 10 21 3 7 10 7 14 21 0 5Ataraz/Vistaril 51 15 12 27 3 6 9 11 4 15 0.6Mysoline 10 0 2 2 1 3 4 2 2 4 1 0

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Rimland wrote, "Table 2 shows for thetotal group of children that certain of thedrugs (e g , Dexedrine) seem to impairbehavior more than they help, whileother drugs (e.g., Mellaril) are moreoften beneficial than harmful. Half of thedrugs appear to have harmed more thanhelped, and even Mellaril was reportedto have helped only about one-third ofthe 277 children on whom it was tried."

We have added the relative efficacynumbers calculated by dividing thenumber of children who were definitelyhelped or showed improvement by thenumber of children made a little worse ormade much worse

Rimland states: "It is interesting tocompare the drug results in Table 2 withthe results of our so-called 'megavitamin'study The megavitamin study involvedseveral hundred children who were givenlarge amounts of vitamin 'C' and certainof the B vitamins, especially niacin, B6,and pantothenic acid The vitamins weregiven for a three-month period, followedby a one-month 'no-treatment period.'Evaluations of change were made byeach child's parents and his physician

"Table 3 shows that the vitamins arenot only far more likely to help than thedrugs—they are also far less likely tocause any kind of harm—behavioral orphysical.

"The findings in Table 3 are of specialinterest in view of the criticism of ourvitamin study commonly made by peoplewho do not understand the experimental

design of the study. The study made useof an unusual design in which clusters ofchildren, grouped by a computer in termsof their similarity on Form E-2, werecompared on their response to treat-ment. The computer grouped the child-ren with no information on their responseto the vitamins. The criticism was thatour positive results might stem from thefact that many parents would be inclinedto overrate the vitamins because theywant so badly to see their child improve.This criticism is not valid, but if it werevalid, the same spurious effect should beseen in the parents' assessment of thedrugs It is not. Since there is clearlymuch more improvement reported forthe vitamins than for the drugs, theargument must be rejected that ourvitamin findings reflect only wishfulthinking by the parents (As indicated inour primary report on the megavitaminstudy, the finding of significant between-cluster differences in response to thevitamins leads to the same conclusion[Rimland, 6]).

"I predict that in a few years the use ofhigh dosages of vitamins will be acommon-place method of treating—andpreventing—various disorders, includingespecially the so-called 'mental' dis-orders. There is a very common mis-conception to the effect that anyone whoeats a normal diet will not requireadditional vitamins That may (or maynot) be true in most cases, but it iscertainly not true in all cases."

TABLE 3

Comparison of Parent Ratings of Effectiveness ofAll Drugs, Best Drug (Mallard), and Vitamins

NoDef

PossiblyHelped a Some Def

Made aLittle

MadeMuch Efficacy

Treatment Total Effect Little Total I mpr Helped Total Worse Worse Total Index

All drugs 1591 402 324 726 202 238 440 209 216 425 1 0(Avg Drug) 100% 253 20 3 45 6 12 7 14 9 27 7 13 1 13 6 26 7Best Drug 277 60 61 121 57 44 101 31 24 55 1 8I Mellari8 100% 21 7 22 0 43 7 206 158 364 112 87 199

High dosage 191 20 37 57 41 86 127 4 3 7 18 0Vitamins 100% 104 19 4 298 215 450 665 21 1 6 37

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Thus it is clear that the megavitaminapproach not only helped more childrenthan the best single drug, Mellaril, butalso had an efficacy index 10 times ashigh, chiefly because it produced so fewside effects

This then is the background for one ofDr Osmond's memos entitled "Children,Drugs, and Vitamins—A Matter ofEthics," which follows:

"You will see that Bernie R has nowdone this piece of computation with veryinteresting results What I hope we shallbe able to do is to underscore the factswhich this very simple approach hasmade so very clear. All drugs may donothing much, some good or some harmThe clinician aims at getting as muchbenefit as possible and as little harm.One would suppose that a rationalapproach would be to start with the bestbet which would clearly be that whichdid most good and least harm Because asubstantial proportion of all these sub-

. stances came into the 'nothing much'category, we need only study the worseand improvement categories There is noreason why a drug should not have a 50percent much worse or a 50 percentmuch better split, but none of these did.Clearly when this is likely to happen onemust be very alert to deterioration andwherever possible discriminate betweenthose who are likely to be benefited andthose who are likely to be harmed

"Bernie's figures allow us to constructa sort of rough cost-benefit approach. Ishall exclude the no-change cases al-though they too could be examined andshould be examined in a longer article.

"Where change occurs, Mellaril andthe vitamins apart, it is as likely to be forthe worse as for the better. This appliesto both categories of improvement andworsening. With Mellaril the chances are2:1 in favor of improvement I am a poorstatistician but go by Sir Ronald Fisher'srule, as told me by Leonide Goldstein,that in medicine the kind of statistics youneed are those that don't requirestatistics Mellaril looks better to me thanthe assembled drugs

"However, when we come to thevitamins, the chances of being definitely

helped are three times that of Mellarilwhile the chances of being made muchworse are less than 1:25 If oneconcentrates on the definitely helped-much worse figures and compares Mell-aril and vitamins and uses the product ofthese two categories, on my reckoningthe vitamins are 12 times as effective asMellaril, because they are (roughly) threeti mes more likely to produce definitehelp and four times less likely to doharm

"I do not know that medicines haveever been assessed in this way before,but it seems to me that an examination ofthis and other medical procedures inthese terms would be possible and mightthrow a very different light on drug andother treatment effectiveness. My math-ematical knowledge is so poor that I mayhave made some gross blunder here, butI am inclined to think that I have notdone so There are times when lack ofsophistication allows one to recognizeissues which would otherwise be ob-scure

"As far as the patient and his/herfamily, what they are concerned with is acost or risk-benefit which can be assessedfairly simply To make that reasonableassessment, which NIH urges upon us asa right for all patients, one has to havesome way of assessing and presenting theinformation available I do not doubtthat there are more elegant and efficientways than those which I have suggestedhere, but since at this moment, so far as Iknow, no method of this kind is ingeneral use, mine can stand untilsuperceded It has much bearing when itcomes to measuring the nature andextent of improvements in medicine,surgery, etc over the years

"My own eye operations are examplesof this (cataracts); 25 years ago or so theodds were not very much better than say50 percent definite improvement against50 percent complete loss of vision Theoperation itself was frightening, some-ti mes very painful, psychotic episodeswere not infrequent, and occasionallyoperation on one eye might result incomplete blindness in both. Today theodds in favor of restoring vision are about

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99:1, and the odds on losing one's visionhave become miniscular In other words,the benefits have increased greatly andthe risks have been as greatly reduced

"There have been many similar situa-tions, but in my experience medicalmatters are rarely presented in thismanner Were this done it might make iteasier for us to discriminate among thevarious treatments available and allowdoctors, patients, and their families togauge realistically where the best courselay This approach would also draw ourattention to those illnesses in which thecurrent natural history has been insuf-ficiently investigated for us to be able tomake a reasoned and reasonable decisionregarding the chances that treatment willhelp rather than hinder " (B Rimland,"Recent Research in Infantile Autism," ).Operational Psychiatry 3, 35-39, 1972 )*

One of the most dangerous side effectsof tranquilizer therapy is a conditionuntil now considered irreversible, tardivedyskinesia. Kunin (1976) referred to it asa prolonged and sometimes permanentextrapyramidal syndrome present in upto 50 percent of patients older that 50who have been on tranquilizers overthree years Over 2,000 cases have beenreported in the world literature bymid-1973 An FDA bulletin in May 1973advised caution in the use of tran-quilizers It acknowledged that thesymptoms appear to be irreversible insome patients and that there is no knowntreatment

Modern psychiatry would collapsewithout tranquilizers It is the main basefor so-called "community psychiatry "Tranquilizers are very helpful when usedin moderation wisely and as an adjunctto orthomolecular psychiatry It is desir-able to prevent the toxic side effects ofwhich tardive dyskinesia is one of theworst

Ironically the solution may have comefrom orthomolecular principles Kunin(1976) was spurred to investigate thecause of tardive dyskinesia by findingthat 10 percent of his schizophrenic

Reprinted from the Huxley Institute . CSF Newsletter.April. 1974. Vol 1. No 2

patients already were afflicted and by areport that tranquilizers bind manganesefirmly (this is called "chelation") andcould cause a manganese deficiencyManganese is found in high concentra-tion in the extrapyramidal system Itappeared likely that, by leaching mang-anese out of these parts of the brain,tranquilizers caused tardive dyskinesiaVery soon after, Kunin was consulted bya young man who complained ofdyskinesia due to fluphenazine enanth-ate. This condition had not cleared withprevious medication. However mangan-ese chelate 10 mg three times per daycleared it in two days In his report hegave details of 15 cases These areKunin's conclusions:1 Fifteen cases of withdrawal andtardive dyskinesia were treated withmanganese chelate, and 10 of these withniacin or niacinamide also2 Review of frequency of occurrenceand mechanisms of cause and treatmentin drug-induced dyskinesia are discussed.3 There are four cases (27 percent) ofdramatic and almost immediate cure,after manganese treatment In nine othercases (60 percent) definite improvementoccurred in two to five days. Only onecase was unresponsive to manganesetreatment4 In one case unresponsive to mangan-ese, niacin therapy was dramaticallysuccessful, associated with almostcomplete cure in a matter of hours5 In eight of nine other cases in whichniacin was used it was associated withsignificant elevation of mood and clear-ing of sensorium In seven of seven casesthat also were treated with niacinamidesimilar clearing of sensorium was notedand, in two cases, significant improve-ment in extrapyramidal symptoms6 It is concluded that manganeseappears to be of value in many cases oftardive and withdrawal dyskinesia7. It also appears that manganese maybe of value in preventing the occurrenceof tardive and withdrawal dyskinesia8 It is likely that niacin and niacinamideare of some value in many cases ofdrug-induced extrapyramidal syndrome.9 More extensive and better controlled

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studies are needed to evaluate all ofthese observations and impressions

One of us (AH) observed similarresponses It is now (AH) policy to usemanganese in combination with zinc forany patient where there is any evidenceof dyskinesia developing or present.

It is likely Kunin's work will beconfirmed when it is done by competentorthomolecular psychiatrists His worksuggests that tranquilizer preparationsshould contain enough manganese toprevent the production of manganesedeficiencies

to

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SECTION VIII—Letters

April 14, 1971

Dr M A LiptonDepartment of PsychiatryUniversity of North CarolinaCHAPEL HILL, North Carolina

Dear Dr Lipton:

I recently noticed with some surprisethat you were Chairman of an APAcommittee given the mission of lookinginto the megavitamin B3 claims Youhave clearly established yourself as a vig-orous and unrelenting opponent of theuse of this approach as is witnessed byyour address to the symposium inCalifornia, by your press conference withAPA Newsletter, and in your letters toMr. J De Silva which you circulatedwidely

In view of your known and evident biasagainst the use of vitamins I now ask youto disqualify yourself as Chairman Forany report coming from your committeewith you as Chairman would properly beas suspect as a favorable report comingfrom a committee whose Chairman is arabid enthusiast

If you decline to accede to my requestI will make this an official request to thePresident of APA, Dr R Garber In orderto acquaint him with my intention, I amsending him a copy of this letter.

To give him a complete record of yourviews, I also ask you to send him a copyof your letter to Mr. J De Silva in which Iwas slandered and a copy of my letter toyou which you did not acknowledge Ifyou feel reluctant to do so, I will bepleased to send him copies

Yours truly,A Hoffer, M D , Ph D

AH:afmcc: Dr R Garbercc: Dr. H. Osmond

112

June 8, 1971

Dr R S. Garber, PresidentAmerican Psychiatric AssociationCarrier ClinicBELLE MEAD, New Jersey 08502

Dear Bob:

Sometime ago I wrote a letter to Dr.Morris Lipton, the Chairman of a specialcommittee to investigate the mega-vitamin claims, and I sent a copy to youroffice. So far I have not received anyreply from Dr Lipton who seems to be aman who refuses to answer his mail.

I now write to you directly to protesthis appointment as Chairman of acommittee to investigate the mega-vitamin claims since he has alreadyexpressed himself publicly over the pastyear as being very much against theposition of those of us who are usingthese treatments I do not see how anyCommission with such a Chairman at itshead can possibly come up with aneutral and objective assessment.

For this reason, I therefore request youas President of the American PsychiatricAssociation to take action in connectionwith my request.

You realize, of course, that if you donot do so any report that comes out fromthis Committee will obviously be verybiased and I, of course, will make itwidely known that this is the case

Sincerely,A Hoffer, M D , Ph D

AH:afm

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A Hoffer, M D , Ph D1201 CN Towers, First Avenue SouthSaskatoon, SaskatchewanCanada

Several weeks ago I received yourletter from Dr. Garber In your letter ofJune 8, you expressed some concernregarding the APA Task Force on VitaminTherapy and the Chairman, who is DrMorris Lipton The Task Force membersare Dr. Morris A Lipton, Chairman; andDrs Thomas Ban, Francis Kane, JeromeLevine, Loren Mosher, and RichardWittenborn (consultant) The Task Forceis responsible to the Council on Researchand Development. The Council ispresently composed of Dr. SidneyMalitz, Chairman; Drs. Monroe, Blueck,Hamburg, Schwab, and Shervington. Anyreports that the Task Force prepares arefirst submitted to the Council for review.If the Council approves, the report isconsidered by the Reference Committeeand finally by the Board of Trustees Ibelieve it is obvious that a very excellentreview mechanism exists and that theTask Force, as well as the Council, iscomposed of highly qualified psychiat-rists who are thoroughly familiar with thescientific method and are capable ofevaluating published literature.

I hope this information is of value toyou

Sincerely yours,Ewald W Busse, M DPresident

EWB:bskcc: Drs Garber and Barton

113

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SECTION IX—References

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Von HILSHEIMER. G KLOTZ.S D McFALL G., LERNER,H. Van WEST, A.. and QUIRK, D'. The Use of MegaVitamin Therapy Regulating Severe Behavior DisordersDrug Abuses and Frank. Psychoses Schizophrenia 3. 67.73. 1971

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._

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HOFFER, A : A program for treating schizophrenic and otherconditions using megavitamin therapy Available from AHoller 1967 Revised 1974

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HOFFER A.: Five California Schizophrenics J Schizo-ohrenia 1 209-220 1967a

HOFFER, A.. Biochemistry of Nicotinic Acid and Nicotineamide Psychosomatics 8. 95 . 100. 1967b

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KRIPPNER, S . and FISCHER, S.: A Study of NeurologicalOrganization Procedures and Megavitamin Treatment forChildren with Brain Dysfunction J Orlhomolecular Psy-chiatry 1. 121-132. 1972

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MICKELSON. C H.: Megavitamin Spinoff Canada's MentalHealth 23 11-13. 1975

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NEWBOLD, H. L : How One Psychiatrist Began Using NiacinSchizophrenia 2. 150-160 1970

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PFEIFFER, C. C.. ILIEV, U.. and GOLDSTEIN, I.: BloodHistamine, Basophil Counts. and Trace Elements in theSchizophrenias Orthomolecular Psychiatry. Ed.: Hawkins.D.. and Pawling. L W H Freeman and Co San Francisco.Calif . 1973

PFEIFFER, C. C , SOHLER, A.. JENNEY, M S., and ILIEV,V.: Treatment of Pyroluric Schizophrenia IMalvanal withLarge Doses of Pyridoxine and a Dietary Supplement ofZinc J Applied Nutrition 26. 21 .28. 1974

PFEIFFER, C. C., WARD. J , EL-MELIGI, M , and COTT, AA.: The Schizophrenias. yours and mine Pyramid Books.New York. N Y 1970

PHILPOTT. W H : Personal communication 1967

PHILPOTT. W H : Private Communication 1973

PLOTCHIK, R , PLATMAN. S. R . and FIEVE. R. R.: ThreeAlternatives to the Double Blind Arch Gen Psychiatry 20.428-432. 1969

REES, E. L.: Clinical Observations on the Treatment ofSchizophrenic and Hyperactive Children with MegavitaminsJ Orthomolecular Psychiatry 2. 93-103. 1973

RESTAK. R M : New York Times. Sunday. July 20. 1975

RIMLAND, B.: Recent Research in Infantile Autism 1Operational Psychiatry 3. 35-39. 1972

RIMLAND. B, DREYFUS. P., and CALLAWAY, E: ADouble-blind Cross Over Evaluation of Higher Doses ofVitamin Be on Autistic Children Sac. Biel Psychiatry. 31stAnnual Meeting. San Francisco. 1976

ROBIE, T R.: Cyproheptadine; an Excellent Antidote forNiacin-induced Hypothermia 1 Schizophrenia 1. 133 . 139.1967

SEHDEN, H S., and OLSON, J. L : Nicotinic Acid Therapyin Chronic Schizophrenia Comp Psychiatry 15. 611-617-1974

SIEGLER, M., and OSMOND, H : Models of Madness.Models of Medicine Macmillan Pub Co Inc New York.N Y .1974

SILVERMAN. L. B.: Orthomotecular Treatment in Distur-bances Involving Brain Function 1 Orthomotecular Psychia-try 4. 7184. 1975

STEWART, C. N., and MAHOOD, M C.: A Multiple GroupComparison of Scores on the HOD Can Psychiat AssocJ 8. 133-137. 1963

VAJAY. A.: Treatment of drug addicts in private practiceMedical Times 101. 5462. 1973

WALKER, J L : Neurological and behavioral toxicity of kry-ptopyrrole in the rat. Pharmacology. Biochemistry andBehavior 3 243250 1975

WARD. J L t Relationship of Kryptopyrrole, Zinc andPyridoxine in Schizophrenics 1 Orthomolecular Psychiatry4. 27-31. 1975

WARD. J L.: Treatment of Neurotics and Schizophrenicsusing Clinical and HOD Criteria J Schiz 1. 140-149.1967

WILLIAMS, M W : A First Evaluation Schizophrenia 3.114. 115. 1971

WILLIAMS, M. W : Clinical Impressions on Early arid ChronicSchizophrenia and Diagnostic Procedures OrthomolecularPsychiatry t. 5659. 1972

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WIT TEN BO RN. J. R.: The Selective Efficacy of Niacin in theTreatment of Schizophrenia N I M H ConferenceWashington. 1973

WITTENBORN, J R.'. A Search for Responders to NiacinSupplementation Arch Gen Psychiatry 31. 547552. 1974

WITTENBORN. 1 R., WEBER, E S. P.. and BROWN, M.:Niacin in the Long-Term Treatment of Schizophrenia ArchGen Psychiatry 28. 308315. 1973

WYATT, R J Comment Amer J Psychiatry 131 1258-1262 1974

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SECTION X— Reading List inOrthomolecular Psychiatry

New advances in medicine are fol-lowed by a gathering of the informationin scientific journals and books The newjournals arise because standard medicaljournals refuse to accept papers whichappear critical of the standard approach.The new books arise in response to publicdemand The presence of the newliterature stimulates interest amongphysicians and other professionalworkers who in turn contribute to it Thisis happening in the field of ortho-molecular psychiatry. There is a largebody of literature available. Most of it islisted here for the convenience ofeveryone, lay person and professionalEvery book contributes directly or in-directly to the theory or practice oforthomolecular psychiatry

ADAMS, R , and MURRAY. F : Body. Mind and the BVitamins Larchmont Books. New York. N Y 1972

ADAMS, R , and MURRAY. Fr, Megavitamin TherapyLarchmont Books. New York. N Y . 1973

ALTSCHUL, R.: Niacin in vascular disorders and hyper-tipemia C C Thomas. Springfield. III 1964

CHERASKIN, E., RINGSDORF, W. M., and CLARK, J. W rDiet and Disease Rodale Books. Emmaus. Penn . 1968

CHERASKIN. E. RINGSDORF. W. M , and BRECHER, A :Psychodietetics Stein and Day. New York N Y 1974

CLEAVE, T. L.: The Saccharine Disease Keats PublishingInc . New Canaan. Conn . 1975

CLEAVE. T. L., CAMPBELL, G. D , and PAINTER, N.S.'.Diabetes, coronary thrombosis and the saccharine diseaseJohn Wright and Sons Ltd Bristol. England. 1969

COTT. A : Fasting: the ultimate diet Bantam Books. NewYork. N Y . 1975

ELMELIGI, A. M., and OSMOND, H : EWt. manual for theclinical use of the experiential world inventory Mens SenaPublishing Co . New York. N Y 1970

FOY, J G : Gone is Shadow's Child Watching Book Sales.Watching N .J 07061. 1970

FREDERICKS. C.: Psychonutrition Grosser and Dunlap. NewYork N Y . 1976

HALL, R H : Food for Nought - the Decline in NutritionHarper and Row. New York. N Y 1974

HAWKINS, D R., and PAULING. L : Orthomolecular Psy-chiatry W H Freeman and Co . San Francisco, Calif 1973

HILSHEIMER, G. Von: How to live with your special childAcropolis Books. Washington. D C . 1970

HOFFER. A , and OSMOND, H The Chemical Basis ofClinical Psychiatry C C Thomas. Springfield. III . 1960

HOFFER. A Niacin Therapy in Psychiatry C C Thomas.Springfield. III . 1962

HOFFER, A : A program for treating schizophrenic and otherconditions using megavitamin therapy Available from AHoffer. 1967 Revised. 1974

HOFFER, A., and OSMOND. H.: The HallucinogensAcademic Press New York. N Y . 1967

HOFFER, A„ and OSMOND, H.: New Hope for AlcoholicsUniversity Books. Secaucus. N J 1968

HOFFER. A., KELM. H., and OSMOND, H : The Holler .

Osmond Diagnostic Test R A Krieger Pub Co.. Hunting .

ton, N.Y., 1975. HOD test kit available from BehaviorScience Press. Box AG. University. Alabama 35486

HOGBEN, L.: Statistical theory: the relationship of probabil-ity, credibility, and error George Allen and Unwin LtdLondon. England. 1957

KAUFMANN, W : Common Form of Niacinamide DeficiencyDisease. aniacinamidosis Yale University Press. NewHaven. Conn . 1943

KAUFMANN, W.: The Common form of Joint Dysfunction:its incidence and treatment E L Ftildreth and Co . Brattle-boro. Vermont, 1949

LILLISTON, L.: Megavitamins - a new key to healthFawcett Publications. Inc . Greenwich. Conn 1975

NEWBOLD. H L The psychiatric programming of peoplePergamon Press Inc Elmsford. N Y . 1972

NEWBOLD, H L.: Meganutrienls for Your Nerves Peter HWyden. New York. N Y . 1975

PASSWATER. R : Supernutrition Dial Press. New York.N Y . 1975

PAULING L.: Vitamin C and the Common Cold W H Free .

man and Co San Francisco. Calif . 1970

PFEIFFER, C C.: Mental and Elemental Nutrients KeatsPublishing Co New Canaan Conn 1975

PFEIFFER. C. C , WARD, J EL-MELIGI, M., and COTT, A :The Schizophrenias: yours and mine Pyramid Books. NewYork N Y . 1970

ROSENBERG, G H., and FELDZAMEN, A N.: The Doctor'sBook of Vitamin Therapy Putnam's Sons. New York. N Y1974

ROSS, H : Fighting Depression Keats Publishing Inc . NewCanaan Conn 1975

SCHROEDER. H. A.: The Trace Elements and Man Devin-Adair Co Old Greenwich. Conn . 1973

SCHROEDER, H A : The Poisons Around Us IndianaUniversity Press. Bloomington. Ind . 1974

SHUTE, W. E : Vitamin E Book Keats Publishing. Inc .New Canaan. Conn .1975

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SIEGLER. M., and OSMOND, H : Models of Madness.Models of Medicine Macmillan Pub Co Inc . New York.N Y 1974

STEFAN, G : In Search of Sanity University Books. NewHyde Park. N Y 1966

STONE, I.' The Healing Factor, Vitamin C against DiseaseGrosser and Dunlap. New York. N Y 1972

VONNEGUT, M : The Eden Express Praeger N 1 . 1975

WATSON, G : Nutrition and Your Mind Harper and Row,New York N Y . 1972

WILLIAMS. R J : Biochemical individuality .John Wiley andSons. Inc . New York. N Y . 1956

WILLIAMS. R. J : You are extraordinary Random HouseInc New York. N Y 1967

WILLIAMS. R. J Nutrition against Disease Pitman PubCorp . New York N Y . 1971

WILLIAMS, R J.: Physician's Handbook of NutritionalScience C C Thomas. Springfield. III . 1975

YUDKIN, .1 : Sweet and Dangerous Peter H Wyden. IncNew York N Y . 1972

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SUMMARY

We have examined critically andcarefully the APA Task Force Report onmegavitamins and orthomolecular psy-chiatry We concluded that the reportwas biased, unfair, and contained a largenumber of major and minor errors Astudy of the composition of the com-mittee and the way it behaved explainedwhy it carried out its mandate the way itdid

The chairman clearly voiced his biasand antagonism in a public presentationgiven several years before It is likely hewas influential in selecting other mem-bers of his committee This included oneof his junior professors who wouldunlikely see things differently from hischairman, two from NIMH then wellknown for its antagonism toward ourwork, and one man just preparing himselfto launch a series of critical assaultsbased upon experiments we considerinadequate He made no attempt torepeat in any scientific way any of ourearly controlled experiments

Not only was the committee clearlybiased, it conducted its affairs in such away as to avoid that degree of objectivityessential for any proper investigationsThe committee not only should havebeen fair, it should have appeared tohave been fair Objectivity could havebeen insured by having orthomolecularrepresentatives on the board and byinviting orthomolecular psychiatrists topresent their data This was not done, nordid the committee conduct any clinicalresearch

The report is characterized by thefollowing:(a) Pronounced bias against ortho-molecular psychiatry

1 By a selective examination of thepublished reports In any corroboratingpaper the positive conclusions wereplayed down and minimized and possibleside effects and toxicity were exagger-ated In every negative paper the positiveor beneficial effects in these reports wereminimized, played down, or ignoredwhile negative findings, no matter how

insignificant, were exaggerated2 By the use of adjectives designed to

support the preconceived bias of thecommittee

3 By distorting our conclusions:(a) by ripping phrases out of

sentences which changed themeaning, and

(b) by misreading simple tables andstatistical data

Support for these charges is providedby a careful examination of all thepublished' reports with the way thecommittee abstracted them Our reportsare listed and briefly summarized in theappendix This is followed by a briefabstract of all the corroborative reports,most of them missed by the committeeWe would have given equal emphasis toany negative report where a seriousattempt was made to repeat any of ourwork We have not been able to find one.

Finally we have reprinted Dr LPauling's critique of the APA Task ForceReport and his rebuttal of the threeletters attacking his position

Since the committee accepted onlyevidence from double blinds (even ifthey were not) completed by others, wehave presented a discussion of thetheoretical and practical aspects of thedouble blind methodology We were thefirst psychiatrists to use the double blindand among the first to realize its seriouslimitations as a method for testingefficacy of treatment

Double-blind methodology is underattack by cancer research scientists.Recently Dr C Freireich, Director ofDevelopmental Therapeutics at M DAnderson Hospital and Tumor Center inHouston concluded that the limitationsof such trials are so serious that there arefew, if any, indications for using theclassical clinical trial strategy for evaluat-ing and discovering new treatments forcancer Other types of controlled studiesin clinical research are superior, heconcluded National study groups fosterconsensus-type research which stifles thecreative individual with the capacity forinnovative work It is obvious thatscientists are beginning to question

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seriously double-blind experimentsWe finally concluded that the actions

of the American Psychiatric Associationand its subcommittee are explainableonly if one took into account the spirit ofWatergate then rampant in Washington,among some of the government agenciesand the American Psychiatric Associa-tion, headquartered in Washington

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SECTION XI—REAL Attempts toCorroborate with Failure to Confirm

Original Studies

We have been unable to find a singlepublished study The negative studiesreferred to by the APA Task Force madeno attempt to replicate any of theoriginal double-blind studies They madeno attempt to use comparable patients,to use the same treatment protocol, or touse the same criteria of improvement inhospital or after discharge Lehmann(1976) admits this, but then complainsthat the treatment has changed Noteven our first two double-blind experi-ments were replicated His argumentwould be much more persuasive if he, oranyone else, had duplicated our firstcontrolled experiments

Suppose our first double blinds wereduplicated with careful attention to ourpublished procedures, but the results

were negative If then we had argued thatwe had now changed (improved) thetreatment procedure so that the attemptto corroborate was invalid, then wecould have been accused of slipping outof the debate But this has neverhappened Lehmann's argument reallycannot be taken very seriously until ouroriginal experiments are repeated Wecannot analyze why no attempts toduplicate have been made It is as Joycehas written -

"To explore the reasons why some peoplechoose a design for their experiments that isalmost bound to lead to negative results is alittle outside our brief "

There is no bibliography of negativereports with respect to orthomolecularpsychiatry

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ADDENDUM

A Memo Received from H, Osmond AfterCompletion of This Report

Psychiatric News, July 2, 1976, carrieda report of an open meeting held by anAPA Task Force on ElectroconvulsiveTherapy. It was called to hear the viewsof APA members in order to guide theTask Force in drafting a report to APADozens of members spoke in a total of sixhours of hearings The Task Force alsoinvited comments from APA memberswho did not appear at the meeting

It appears from this that the APA canpossess no general instructions for theconduct of its Task Forces Nothingcould be less alike than the behavior ofthose running the ECT Task Force andthose examining megavitamins Just whythis should be is anyone's guess, but it isa striking bit of evidence that the Mega-vitamin Task Force was conducteddifferently from at least one other TaskForce The procedure, that of an openhearing at which those who support andthose who oppose the particular treat-ment give their views and can bequestioned, seems a considerableimprovement upon the practices of thatother Task Force As it turned out theopponents of ECT either did not turn up,or there are far fewer of them than wehave been led to believe

It is interesting that the discussantsdealt with two problems which pre-occupied the Task Force:

(1) No one knows why ECT works(2) The data base for ECT, after nearly

40 years, is not all that it might beThis is one of the well-known dif-

ferences between Clinidok and thecombination of Superdok and MegadokIt is also of interest that the question ofthe efficacy of psychotherapy comes uponce again It seems that the evidence infavor of megavitamins is a great dealmore than for psychotherapy and appar-ently ECT if this account is correctOddly enough Lothar Kalinowsky, whowas present for most of the session,which lasted six hours, did not partici-

pate I presume that the Task Force willor have already interviewed him so thathere he was exercising a watching brief

After this six-hour free-for-all the TaskForce is still open to comments from APAmembers It gives them an open invita-tion to address their further suggestionsand views to the chairman, Dr Frankel

Had the Megavitamin Task Forceconducted its business in such an openand straightforward manner, it wouldhave been far more difficult for us tocriticize its conclusions

In a public session of this kind it woulddoubtless come to light fairly quickly ifthe chairperson was known to beflagrantly biased against ECT, or for thatmatter a keen proponent One mayassume that this may have excluded DrKalinowsky from being a Task ForceMember There is no reason why heshould have been excluded, provided ananti-ECT representative was included

It looks as if the composition of theTask Force and the method which it hasadopted is totally different from thatemployed by the Megavitamin TaskForce under Dr Morris Lipton These areseveral explanations for this:

(1) The APA may have learned from itsearlier error, which seems unlikely sinceit does not admit to error

(2) The Megavitamin Task Force didnot follow Standard Operating Procedureand was not corrected, even though theAPA pledged itself to give propersupervision

(3) Too many APA members have aninterest in ECT to permit any hankypanky

(4) By sheer good luck they picked afair unbiased chairperson

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