Drug and Alcohol Dependence, 17 (1986) 279-295 Elsevier Scientific Publishers Ireland Ltd.

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REPORT OF THE COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE CONSENSUS COMMITTEE ON THE ABUSE LIABILITY OF 28 STIMULANTS AND HALLUCINOGENS

I. METHOD OF REVIEW

In conducting its rewiew, the Committee identified four principal medical and scientific considerations which are relevant to the World Health Organiz- ation’s (WHOs) responsibilities under the 1971 Convention. In the following section of this report (III), the Committee will summarize its findings regarding each of the substances being considered for control according to the’ following format:

1. Current medical use 2. Pharmacologic similarity to currently controlled drugs 3. Capacity to produce dependence 4. Evidence of abuse or likelihood of abuse

1. Current medical use The Committee relied upon reports prepared by interested and know-

ledgeable parties and standard reference sources to ascertain whether each compound considered has any current medical use. The Committee wishes to note however that, in the case of some compounds reported to be in medical use, it was difficult or impossible to confirm that such use is current or to determine the extent to which the compound was or is legally avail- able.

2. Pharmacologic similarity to currently con trolled drugs Under Article 2, paragraph 4(a) (ii) of the 1971 Convention, one of

the predicates for control is that a substance ‘has the capacity to produce similar abuse and similar ill effects as a substance [already controlled] .” Accordingly, the Committee reviewed what is now known about the phar- macological, neurochemical and behavioral profiles of the listed compounds and compared them in relevant dimensions with the profiles of stimulant and hallucinogenic drugs currently controlled under the 1971 Convention.

3. Capacity to produce dependence For most classes of psychoactive substances, the most important com-

ponent of the evaluation of the capacity of a substance to ‘produce similar abuse and similar ill effects’ to those of a currently controlled drug is an

0376-8716/86/$03.50 o Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

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assessment of its reinforcing properties. In addition, under Article 2, para- graph 4(a) (i) of the 1971 Convention, a substance is subject to control, without regard to its similarity to a previously controlled substance, if it ‘has the capacity to produce a state of dependence. . . .’ According to the Commentary on the Convention on Psychotropic Substances (p. 54), the ‘state of dependence’ to which the Convention refers ‘must always be a ‘psychological’ or ‘psychic’ dependence; it may, but need not also be a ‘physical’ dependence; it does not matter whether it is accompanied by tolerance.’

Accordingly, the Committee reviewed available studies, in animals and man, which assess whether the substance will be self-administered. In addi- tion, the Committee considered the available data regarding other measures of dependence potential, including drug discrimination studies and reports of subjective effects.

4. Evidence of abuse or potential for abuse A psychoactive substance which is pharmacologically similar to a cur-

rently controlled substance, or which has the capacity to produce depend- ence, is subject to control under Article II, paragraph 4(b) of the 1971 Con- vention only if the WHO finds ‘that there is sufficient evidence that the substance is being or is likely to be abused so as to constitute a public health or social problem. . . .’

In order to ascertain whether a listed substance ‘is being abused. . . . so as to constitute a public health and social problem,’ the Committee reviewed available epidemiological data. The data available to the Com- mittee included data from drug abuse reporting systems sponsored by the U.S. and West German governments; case reports of drug-related morbidity and mortality derived from the clinical literature; and data representing the findings of laboratory analyses of drug samples obtained from illicit channels of distribution.

The Committee reviewed these data for what contribution they could make to its assessment, but the Committtee wishes to note its concern about the reliability of such data and about the limitations of currently available methods for the epidemiologic study of drug. abuse. This concern is described in greater detail in section II.5 below.

In the absence of evidence that a substance is being abused on a scale, sufficient ‘to constitute a public health and social problem“ the prediction of likelihood of abuse is highly speculative and should be undertaken with considerable caution. In essence, it requires extrapolation from pharmaco- logical and laboratory data in order to postulate whether, if a drug were to become more widely available, it would be more widely used or abused, and whether more widespread use or abuse would be associated with signifi- cant adverse public health and social consequences.

Notwithstanding the speculative nature of this postulation, the Committee has indicated those instances in which the pharmacological and laboratory

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data seem to support such extrapolation. However, the Committee also believes it is important to emphasize that WHO must decide whether such speculation constitutes ‘sufficient evidence’ that a substance ‘is likely to be abused so as to constitute a public health and social problem’.

It should also be noted that, even if there is evidence ‘that the substance is being or is likely to be abused so as to constitute a public health and social problem’, the 1971 Convention requires a further judgment concern- ing whether the problem is of a kind to ‘warrant international control’. Although this judgment is not a medical or scientific one within the exper- tise of this Committee, it does seem instructive to observe that the case for ‘international’ control would seem to depend on a determination that the controls of the 1971 Convention are suitable to solve or alleviate an existing problem. In light of the costs of international regulation, it would seem appropriate to recommend these controls only if there is a serious prospect that a significant problem will develop in their absence.

Even if WHO determines that a substance meets the threshold criteria for control specified in Article II, paragraph 4, it must also determine ‘the extent or likelihood of abuse, the degree of seriousness of the public health and social problem, and the degree of usefulness of the substance in medical therapy’. These judgments of degree are necessary in order to take into account the costs and benefits of international control and to determine the most suitable levels of control. For the most part, the Com- mittee concentrated its attention on the predicates for international control specified in paragraph II (4). However, in several cases involving substances with current medical usefulness, the Committee has also commented on these questions of degree identified by the 1971 Convention.

II. SPECIAL CONSIDERATIONS REGARDING LIMITATIONS OF THE AVAILABLE EVIDENCE

For the majority of the 28 listed compounds, the evidence that would be sufficient for confident evaluation under the provisions of the 1971. Convention, as described above, was incomplete. In order to provide its best advice to WHO on these substances, the Committee deliberated and agreed upon certain considerations to guide its review within the limit- ations of the available information. The following is a description of these special considerations.

1. Concordance of evidence on pharmacology, dependence potential, and abuse

The Committee had the greatest confidence in its evaluations of those compounds for which there was available evidence regarding pharmacologic equivalence or similarity to a currently controlled substance, regarding preclinical and clinical dependence potential, and regarding actual abuse, and for which these sets of evidence were concordant. Thus, for example,

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if a given substance has been shown to resemble amphetamine in phar- macologic profile, to produce self-administration behavior in both animals and humans, and to appear in reports of actual abuse, the Committee had confidence in judging that it would be appropriate to consider such a sub- stance for international control.

2. Substances with no currently recognized medical usefulness The Committee felt that it was appropriate, and consistent with the

provisions of the 1971 Convention, to consider compounds for which there is no recognized medical use in a different light from those for which there is extensive medical use. In the former case, the Committee was often obliged to base its evaluation principally or exclusively on relatively limited evidence of pharmacologic similarity to substances currently under control and/or known to be subject to abuse. The Committee noted that there may be numerous chemical entities of this kind, for which information is similarly limited. The Committee has considerable reservations about the utility and economic efficiency of considering such entities for international control. On the other hand, these reservations should be balanced against possible benefit of such control. By requiring illicit distribution of use of such substances to be reported, international control might facilitate earlier epidemiologic detection of the emergence of substantial abuse of such compounds and thus speed efforts at intervention.

This consideration argues strongly for the analysis of pharmacologic equivalence of a large number of compounds, and especially those that can be readily synthesized as simple products of relatively familiar chemical reactions. In this connection, in view of its mandate to advise WHO on priorities among substances for review, the Programme Planning Working Group of WHO might wish to include in its membership a medicinal chemist who could offer advice on the relative ease with which various compounds might be synthesized.

3. Substances currently in medical use A somewhat different set of considerations applied in the case of those

compounds known to be in extensive current medical use. The Committee recognized that, even when substantial information is available from labora- tory studies of animal and human dependence potential, such information predicts only imprecisely to actual abuse in the general population. In the instance of some of the compounds that are in medical use, there was inadequate information on all measures of dependence potential and abuse liability. For substances known to be in extensive medical use, the Com- mittee believes that proof of the necessary predicate for international control should be based on a firm evidentiary foundation. That is, the evidence should not be regarded as ‘sufficient’ under the 1971 Convention in the absence of (i) strong laboratory evidence of dependence liability or (ii) a demonstrated pattern of actual abuse on a scale which is judged to be significant in light of the level of availability of the particular substance.

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It must also be noted, however, that confident assessments of depend- ence potential or actual abuse are impeded by the absence of systematic procedures for collecting such information. This problem can be remedied only by improving the adequacy of data-gathering resources. The new programs of the Committee on Problems of Drug Dependence (CPDD) for assessment of the abuse liability of stimulants should be of use for these purposes in the future.

In the case of at least one of the reviewed compounds in medical use, there was some information on actual abuse, but little information on dependence potential from animal or human studies. In the absence of such information on dependence potential, for a substance that does have extensive medical use, epidemiologic data on actual abuse should be inter- preted with particular caution and applied most conservatively.

As described immediately above, and as recognized in Article 2, para- graph 4 of the 1971 Convention, considerations regarding control of drugs differ depending on their medical usefulness. However, it is difficult or impossible to obtain reliable information on the nature and extent of medi- cal use of drugs in different countries. The Committee recognizes the diffi- culties inherent in any effort to gather such data; but, in view of the signifi- cance of such information to its deliberations, WHO may wish to consider appropriate means by which it might undertake or otherwise promote such an effort, at least with respect to psychotropic substances and at least with respect to those countries which are signatories to the 1971 Convention.

4. Difference in standards of evidence relevant to stimulants and hallucinogens

The Committee also recognized that the appropriateness of pharmaco- logical and behavioral measures of dependence potential differs markedly for stimulants and hallucinogens. Self-administration data in both animals and humans contribute significantly to the assessment of the abuse liability of amphetamine-like compounds, but may be far less relevant than other measures in the assessment of hallucinogens. Thus appropriate assessment of dependence potential depends to a significant degree on the specific pharmacologic and behavioral characteristics of the substance under con- sideration.

5. Limitations of current epidemiologic methods In preparation for its review, the Committee sought the opinions of

experts on the epidemiology of drug abuse. On the basis of their advice and its members’ collective expertise, the Committee was unanimous in its judgement that current methods for the epidemiologic study of sub- stance abuse are quite limited with respect to accuracy, reliability and consistency, as well as to geographic coverage.

One such limitation is that of the available resources for obtaining ade- quate samples of the populations surveyed. Adequate sampling is one of the conditions for the proposition that epidemiologic estimates are reason-

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ably accurate. In the absence of available resources for adequate sampling, then, estimates of the extent of abuse of or dependence on a given sub- stance in a given population cannot be accepted as reasonably accurate.

Another limitation of current epidemiologic methods is uncertain identi- fication of the substances implicated in reports of drug abuse or drug- related medical emergencies. Drug-abusing populations frequently use substances whose nature or constituents are not known to them, e.g. illicitly manufactured products that are represented as drugs on which abusers place great value. In the absence of toxicologic verification of the sub- stances implicated in reports of drug abuse, therefore, such reports cannot be regarded as reliable. The Committee therefore had reservations about the reliability of information available from the U.S. Drug Abuse Warning Network (DAWN) and other systems whose data frequently lack such analytic validation.

With respect specifically to assessment of drugs for international control, a particular limitation of current government-sponsored abuse reporting systems is that there is no obligation to report cases of abuse of substances that are not already under national or international control. This further complicates interpretation of the data available from such systems.

Finally, the Committee was reluctant to rely on any substantial degree on information regarding governmental seizures of small quantities of drugs or isolated reports of non-medical availability or use.

6. Substances postulated to be pro-drugs for currently controlled drugs Some of the substances reviewed by the Committee have been postulated

to be pro-drugs for substances currently controlled or otherwise known to be subject to abuse; in some instances, such a postulation rested solely on grounds of chemical structure which was advanced as the basis for an argument that the substance in question should be considered as equivalent to its hypothesized metabolite.

The designation of a substance as a pro-drug represents a simple hypo- thesis, as does any chemical modification, whose pharmacologic significance requires full demonstration by standard testing procedures. It cannot reason- ably be inferred that such a substance bears the same abuse liability as its hypothetical metabolite. Such an extrapolation would require, in the first place, appropriate studies to demonstrate that the metabolite occurs rapidly and in pharmacologically significant amounts; in addition, it would require as well, a demonstration that the alleged pro-drug has the same dependence potential as an appropriate mixture of metabolic products. In view of the complexity of substantiating such propositions, then, it would appear clearly more efficient to base an assessment of the abuse liability of an alleged pro-drug on appropriate studies of that substance itself.

III. REVIEW OF INDIVIDUAL COMPOUNDS

This section of the report describes the findings of the Committee with

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respect to assessment of the 28 compounds which WHO plans to consider for international control. As described in detail in the preceding section (I, Method of Review), the findings are presented in the following format:

1. Current medical use 2. Pharmacologic similarity to currently controlled drugs 3. Capacity to produce dependence 4. Evidence of abuse or likelihood of abuse

CATHINE

1. Cathine (d-norpseudoephedrine) is widely used, primarily as a nasal decongestant and an appetite suppressant. The Committee noted that this compound should not be confused with dl-norephedrine, which is customarily designated as phenylpropanolamine.

2. Cathine is similar to amphetamine and cathinone in behavioral effects, but neurochemical studies suggest that its mechanism of action may not be equivalent to those of amphetamine and cathinone.

3. The Committee was unable to find any data from animal or human studies relevant to dependence potential of this compound.

4. Cathine is in medical use in a number of countries. There have been a few case reports of abuse, but the incidence appears to be relatively low. Freshly-picked khat leaves have high concentrations of cat&none and are preferred by users to aged khat leaves, which contain predomi- nantly cathine. The low potency of cathine relative to that of cathinone, and the low prevalence of problems reported in countries where it is available, suggest that the substance presents little potential for public health and social problems.

, CATHINONE

1. Cathinone has no recognized medical usefulness. 2. Cathinone appears similar to amphetamine on the basis of its neuro-

chemical and behavioral profile. 3. Studies suggest that cathinone can produce self-administration behavior

in monkeys. The Committee is not aware of any studies relevant to the dependence potential of cathinone in humans.

4. There is no evidence that cathinone alone is currently being abused. Cathinone is the principal psychoactive alkaloid in khat leaves, which are widely used for recreational purposes in several African and Asian countries. The Committee has not reviewed any data on the abuse or abuse liability of khat. However, the Committee is aware of evidence that khat leaves are becoming available and are used recreationally in areas outside of those to which the plant is indigenous; it is therefore possible that cathinone could be extracted from khat leaves and could

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be subject to abuse similar to that of amphetamine, which would con- stitute a public health and social problem. The Committee has not considered whether international control of cathinone would in effect place khat under international control; nor has the Committee considered whether any public health or social prob- lem that may be associated with use of khat is sufficient to warrant international control of the plant itself, nor whether economic, social, legal, or administrative considerations might make such international control unsuitable.

CLOBENZOREX

1. Clobenzorex is in medical use as an anorectic or sympathomimetic. 2. The Committee was unable to find any information relevant to the

possible pharmacological similarity of clobenzorex to any currently controlled drug.

3. The Committee was unable to find any data from animal or human studies relevant to the dependence potential of this compound.

4. The Committee was unable to find sufficient information on actual abuse of this substance on which to judge whether it is being or is likely to be abused so as to constitute a public health or social problem.

DIMETHOXYAMPHETAMINE

1. There is no current recognized medical use of this compound. 2. Available evidence from studies of dogs, rodents and in vitro prepar-

ations suggests that dimethoxyamphetamine may be similar in phar- macological, behavioral and neurochemical profile to mescaline and LSD. Central stimulant effects of dimethoxyamphetamine increase with dose.

3. The dependence potential of this compound has not been thoroughly evaluated in animals, but there is some evidence from drug discrimination studies in rodents to indicate similarity to LSD. The Committee was unable to find adequate data from human studies relevant to the depend- ence potential of this compound.

4. There is evidence that this drug was abused in the United States before it was controlled, and there is some evidence of current illicit distribution in the United States. Pharmacological and laboratory data do not warrant firm conclusions regarding the likelihood of abuse if the drug were to become more widely available. ’

DIMETHOXYBROMOAMPHETAMINE

1. There is no current recognized medical use of this compound. 2. Available evidence suggests that the pharmacologic, neurochemical and

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behavioral profile of this compound in animals and humans is similar to that of mescaline and LSD.

3. Studies in dogs indicate that this compound is cross-tolerant with LSD; in discriminative stimulus studies in rodents the compound generalized to DOM.

4. There is evidence of illicit manufacture and trafficking in the U.S., and the Committee is aware of a few clinical reports of abuse. In view of this information, and the compound’s pharmacologic similarity to LSD, the Committee feels that, if dimethoxybromoamphetamine were to become widely available, it might be subject to abuse that would con- stitute a public health and social problem.

ETHYLAMPHETAMINE

1. Ethylamphetamine may be available as an anorectic; the extent of its medical use is unclear.

2. Ethylamphetamine is similar to amphetamine in pharmacologic profile. 3. The substance maintains self-administration in monkeys. The Committee

is not aware of any data relevant to its dependence potential in humans. 4. Although there is evidence that ethylamphetamine has been illicitly

manufactured in the U.S., there is insufficient evidence on which to base an assessment of the current level of abuse, if any. However, the pharmacological data suggest that, if the drug were widely available, it would have a liability for abuse similar to that of amphetamine.

FENBUTRAZATE

1. Fenbutrazate is in medical use, principally as an anorectic. 2. The Committee is not aware of any information relevant to the phar-

macologic similarity of this compound to any currently controlled drug, 3. The Committee was unable to find any data from animal or human

studies relevant to the dependence potential of this compound. 4. Although there have been isolated reports of abuse of this compound,

the available epidemiologic information is insufficient to warrant a con- clusion that fenbutrazate is subject to abuse of an order that would constitute a public health or social problem.

FENCAMFAMINE

1. Fencamfamine is in medical use as a central nervous system stimulant. 2. The compound shares many of the pharmacologic and behavioral actions

of amphetamine and cocaine. The Committee is not aware of adequate information relevant to its mechanism of action.

3. Fencamfamine produces self-administration behavior in dogs and monkeys

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similar to that produced by amphetamine and cocaine. The Committee is not aware of any data relevant to its dependence potential in humans.

4. Fencamfamine is not approved for medical use in the United States. However, there have been occasional reports of seizures of the substance by U.S. authorities. There is also information suggesting that fencam- famine has been detected in samples of cocaine seized in the United States. It is noteworthy that fencamfamine has been widely available for long periods in some countries with minimal reports of abuse.

FENETYLLINE

1. Fenetylline is in medical use as a psychostimulant, and possibly for treatment of attention deficit disorders.

2. Fenetylline has some acute psychomotor stimulant properties in common with amphetamine. There are some characteristics of amphetamine that are not associated with fenetylline, such as aggregate toxicity. The Committee is aware that data on fenetylline will soon become available from ongoing drug discrimination studies in a variety of species. Al- though there is evidence that fenetylline is metabolized in humans into amphetamine and theophylline, the extent to which these metabolites determine its pharmacologic actions, and its dependence potential, re- mains unclear.

3. One animal study indicates that fenetylline can produce self-administra- tion behavior. There have been studies of subjective effects of fenetyllline in humans. Although these studies suggest that the euphoriant properties of fenetylline are less than those of amphetamine, the limited nature of these studies (e.g. lack of dose effects and of investigation of different routes of administration) preclude conclusive interpretation of these data.

4. Data from several abuse reporting systems indicate that there has been illicit trafficking in fenetylline. Although such reports appear across all such sources available to the Committee, it is difficult to estimate the magnitude or persistence of abuse of fenetylline on the basis of these data. In addition, it is difficult to interpret these data in the ab- sence of clear information on the past and current distribution and medical use of the drug. In view of the fact that the evidence regarding pharmacologic properties and dependence potential is also inconclusive, it appears particularly important to obtain more information on the medical use and therapeutic value of fenetylline in order to arrive at a reasonable judgment of the overall significance of the liability of this substance to abuse and related public health and social problems.

FENPROPOREX

1. Fenproporex is in medical use as an anorectic.

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2. The Committee was unable to find any information relevant to the compound’s pharmacologic similarity to any currently controlled drug. It has been postulated that fenproporex may serve as a prodrug for amphetamine; the pharmacologic significance of this information, if accurate, remains untested.

3. The Committee was unable to find any data from animal or human studies relevant to the dependence potential of this compound.

4. The Committee was unable to find sufficient information on actual abuse of this substance on which to judge whether it is being or is likely to be abused so as to constitute a public health or social problem.

FURFENOREX

1. Furfenorex is available for medical use as an anorectic in a few countries. 2. The Committee is unaware of any information relevant to the pharmaco-

logic similarity of this compound to any currently controlled drug. 3. The Committee was unable to find any data from animal or human

studies relevant to the dependence potential of this compound. 4. The Committee was unable to find any information on actual abuse of

this substance.

LEVAMPHETAMINE

1. Levamphetamine has been used medically as an anorectic and central nervous system stimulant; the extent of its current medical use, if any, is unknown.

2. Levamphetamine appears to be qualitatively but not quantitatively similar in pharmacological profile to d-amphetamine; it is less potent than d-amphetamine on a milligram-for-milligram basis.

3. Studies in animals indicate that. levamphetamine has a dependence poten- tial similar to that of amphetamine. The Committee was unable to find any data from human studies relevant to the dependence potential of this compound.

4. There are no data available to the Committee indicating current or past abuse in humans. However, in view of its pharmacologic similarity to d-amphetamine, the Committee feels that, if this substance were to be readily available, it would be likely to be subject to abuse of an order that would constitute a public health and social problem.

LEVOMETHAMPHETAMINE

1. No information was available to the Committee on which to judge whether this drug is in medical use.

2. Data on the pharmacological profile of this compound are limited. How- ever, the available evidence indicates that it is most similar to amphet- amine.

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3. There is a report that levomethamphetamine produces self-administration behavior in rodents. The Committee was unable to find any data from human studies relevant to the dependence potential of this compound.

4. The Committee was unable to find any information on actual abuse of this substance.

METHYLENEDIOXYAMPHETAMINE (MDA)

1. MDA has no recognized medical usefulness. 2. Hallucinogenic activity has been documented for MDA. The pharmaco-

logical and neurochemical profiles of MDA (racemic) are substantially similar to those of both LSD and amphetamine: the (+ )-isomer is am- phetamine-like; the (-)-isomer is LSD-like.

3. MDA has been shown to serve as a reinforcer in animal paradigms that measure dependence potential. The Committee was unable to find ade- quate data from human studies relevant to the dependence potential of this compound.

4. Information regarding governmental seizures indicate that there has been illicit trafficking in MDA. Clinical reports indicate significant health problems associated with use of the substance. In systems designed to monitor substance abuse, MDA is occasionally mentioned. Recent studies in animals demonstrated long-lasting, possibly irreversible neuro- toxicity following administration of a single low dose. The Commmittee concludes that the evidence is sufficient to demonstrate significant public health and social problems associated with use of this substance.

MEFENOREX

1. Mefenorex is in medical use as an anorectic. 2. Available data are insufficient to judge whether mefenorex is similar in

pharmacologic profile to any currently controlled drug. 3. The CPDD has sponsored animal studies, which are currently underway,

to assess the dependence potential of this compound. The Committee is aware of no other data from animal or human studies on which to base an assessment of the dependence potential of mefenorex.

4. Insufficient data are available on which to judge whether the substance has been or is likely to be abused in humans. It is noteworthy that, despite widespread use of this drug as an anorectic in many countries, the reported incidence of abuse is minimal.

METHOXYAMPHETAMINE (PMA)

1. The Committee is not aware of any medical use of PMA. 2. The pharmacological profile of action of PMA is closely related to that

of amphetamine; it also shows some activities like those of LSD.

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3. Although the drug has discriminative stimulus properties similar to those of amphetamine in rodents, it is not self-administered in baboons. The Committee was unable to find any data from human studies relevant to the dependence potential of this compound.

4. Data on governmental seizures indicate isolated cases of illicit traffic in PMA. However, the several animal studies reported to date provide no clear indication of what form human abuse of this compound might take, if any, should the drug become more widely available.

MORAZONE

1. Morazone is reported to be in medical use and has analgesic, anti-inflam- matory, and antipyretic properties.

2. It medical use as an antipyretic and anti-inflammatory suggest that mora- zone is not similar to stimulants or hallucinogens in pharmacologic profile. It has been postulated that morazone may be a pro-drug for phenmetra- zine, which is currently controlled as a central stimulant under the Psychotropic Convention. No data were available for the Committee’s review relevant to morazone’s pharmacologic profile, or the significance of its possible function as a pro-drug for phenmetrazine.

3. The Committee was unable to find any data from animal or human studies relevant to the dependence potential of this compound.

4. Although there have been isolated reports of abuse of this compound, the available epidemiologic information is insufficient to warrant a con- clusion that morazone is subject to abuse of an order that would con- stitute a public health or social problem.

PARA-HYDROXYAMPHETAMINE

1. This compound is in medical use as an ophthalmic and pressor agent 2. It has been speculated that par-u-hydroxyamphetamine may be a meta-

bolite of both amphetamine and paru-methoxyamphetamine in some species. However, definitive studies of the pharmacologic profile of this compound have not been carried out.

3. The Committee was unable to find adequate data from animal or human studies relevant to the dependence potential of this compound.

4. The Committee was unable to find sufficient information on actual abuse of this substance on which to judge whether it is being or is likely to be abused so as to constitute a public health or social problem.

PEMOLINE

1. Pemoline appears to have therapeutic usefulness and is currently in medical use for treatment of attention deficit disorders.

2. Pemoline has some of the pharmacologic properties characteristic of

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amphetamine. However, it is far less potent than amphetamine in pro- ducing stimulant effects and is not similar to amphetamine with respect to neurochemical properties.

3. In animal studies, pemoline has not been shown to produce self-admini- stration behavior. The drug is currently under study to characterize its discriminative properties and to determine its subjective effects. Human studies have been reported, but the Committee knows of no evidence adequate to establish the dependence potential of the compound in humans.

4. Pemoline has been mentioned in information from drugs abuse and emergency reporting systems in the United States and western Europe, but at a level indicating a low frequency of problems. The Committee noted that pemoline is not readily soluble in water, so that intravenous abuse is unlikely. Although information was submitted to the Committee indicating that pemoline has been in medical use in many countries, available data do not indicate that use of the drug is or is likely to be associated with significant public health or social problems.

PROPYLHEXEDRINE

1. Propylhexedrine is in medical use in the oral form as an anorectic and as a central nervous system stimulant. It is also available without a pre- scription in an inhalant form for use as a nasal decongestant.

2. On the basis of the limited available information, propylhexedrine appears to have some stimulant actions in common with amphetamine, but is less potent. The Committee is aware of ongoing research designed to describe the compound’s discriminative stimulus properties.

3. The Committee was unable to find any data from animal or human studies relevant to the dependence potential of this compound.

4. Propylhexedrine has been mentioned at a low frequency in several abuse reporting systems. In addition, there are published reports describing severe acute toxic effects of abuse of the compound. The Committee notes that propylhexedrine, in its non-prescription form, was introduced as a replacement for amphetamine in a previous product of this kind because of the widespread abuse of this product. It may be assumed that abusers of the amphetamine product would have experimented with the similar propylhexedrine product. The available information suggests that this compound was not accepted by abusers as a substitute for amphetamine. In the context of the long-standing ready availability of this product, and of the extensive medical use of the oral forms of propylhexedrine, the available epidemiologic data suggest that this com- pound has minimal liability for abuse that would be likely to constitute a significant public health and social problem.

PYROVALERONE

1. Pyrovalerone is in medical use as a central nervous system stimulant.

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2. The Committee has no information on the pharmacologic profile of this compound.

3. The Committee was unable to find any data from animal or human studies relevant to the dependence potential of this compound.

4. The Committee was unable to find any information on actual abuse of this substance.

TRIMETHOXYAMPHETAMINE

1. The Committee is not aware of any medical use of this compound. 2. The pharmacological profile of trimethoxyamphetamine is predomi-

nantly similar to that of LSD, although there is some amphetamine- like action. It is cross-tolerant with LSD. The acute pharmacological effects in dogs and discriminative stimulus properties in rodents are similar to those of LSD.

3. The Committee was unable to find any data from animal or human studies of dependence potential of this compound.

4. Although there is evidence that the compound is illicitly produced and distributed in the United States, there is no evidence to date that abuse has been associated with significant adverse effects.

4-BROMO-2.5-DIMETHOXYPHENETHYLAMINE

1. The Committee is not aware of any medical use of this compound. 2. The Committee is not aware of any information relevant to the pharmaco-

logic similarity of this compound to any currently controlled drug. 3. The Committee was unable to find any data from animal or human

studies relevant to the dependence potential of this compound. 4. The Committee was unable to find any information on actual abuse

of this substance.

2,5-DIMETHOXY-4-ETHYLAMPHETAMINE (DOET)

1. The Committee is not aware of any medical use of this compound. 2. There is some behavioral and neurochemical evidence to suggest a phar-

macological profile similar to that of LSD, mescaline and psilocybin. 3. This compound is not self-administered by animals. However, in rats

trained to discriminate saline vs. drugs, DOET was generalized to LSD, mescaline and psilocybin (perhaps suggestive of an abuse potential similar to that of LSD). The Committee was unable to find any data from human studies relevant to the dependence potential of this compound.

4. The Committee is not aware of any evidence that this compound has been or is currently being abused. However, on the basis of some phar- macological similarity to LSD and other hallucinogenic substances, the Committee feels that, should the drug become widely available, it

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would have the potential for abuse which would be associated with public health and social problems.

.h’.lV-DIMETHYLAMPHETAMINE

1. Although there was a report that this compound was in medical use, at least in one country, the Committee was unable to confirm this. No other information was available regarding medical use of this compound.

2. The Committee is not aware of any information relevant to the phar- macologic similarity of this compound to any currently controlled drug.

3. The Committee was unable to find any data from animal or human studies relevant to the dependence potential of this compound.

4. Although there is evidence of sporadic illicit manufacture and trafficking in this compound in the United States, there have been no reports of its abuse or other adverse effects in humans.

h’-ETHYL-3.4-METHYLENEDIOXYAMPHETAMINE

1. The Committee is not aware of any medical use of this substance. 2. The Committee is not aware of any information relevant to the phar-

macologic similarity of this compound to any currently controlled drug. 3. The Committee was unable to find any data from animal or human

studies relevant to the dependence potential of this compound. 4. Although governmental seizure data indicate that this drug has been

illicitly synthesized (less than a hundred dosage units in a lo-year period), no other information is available to indicate that the substance has been or is being abused.

5-METHOXY-3,4-METHYLENEDIOXYAMPHETAMINE (MMDA)

1. The Committee is not aware of any medical use of this compound. 2. Studies suggest that MMDA has a pharmacologic profile that resembles

those of amphetamine and LSD, but a&o has other properties not asso- ciated with either of these substances.

3. The compound has amphetamine-like discriminative stimulus properties in rodents. The Committee was unable to find any other data from animal or human studies relevant to the dependence potential of this compound.

4. Although governmental seizure data indicate that this compound has been illicitly synthesized in the United States (less than 100 dosage units in a lo-year period), there have been no reports of abuse. However, on the basis of data suggesting that the compound has some pharmaco- logical properties of amphetamine and LSD, the Committee feels that, should the drug become more widely available, it could have the potential for abuse, although it is unclear what form this abuse might take.

295

3,4-METHYLENEDJOXYMETHAMPHETAMINE (MDMA)

1. The Committee is not aware of any medical use of this compound. 2. There is limited data with respect to the pharmacologic profile of MDMA.

However, in a discriminative stimulus paradigm in rodents MDMA was generalized to amphetamine.

3. With the exception of these discriminative stimulus data, the Committee was not aware of any data available from animal or human studies with respect to the dependence potential of this compound.

4. Governmental seizure data indicate that this drug has been illicitly syn- thesized, and there have been isolated reports of human abuse.

APPENDIX

COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE CONSENSUS COMMITTEE: PARTICIPANTS:

Dr. Theodore J. Cicero (Chairman)

Department of Psychiatry Washington University 4940 Audubon Avenue St. Louis, MO 63110, U.S.A.

Professor C.R. Schuster Department of Psychiatry University of Chicago 5841 South Maryland Chicago, IL 60637, U.S.A.

Professor Richard J. Bonnie School of Law University of Virginia Charlottesville, VA 22901, U.S.A.

Dr. Edward C. Senay Department of Psychiatry University of Chicago 5841 South Maryland Chicago, IL 60637, U.S.A.

Dr. Roland Griffiths Departments of Psychiatry

and Neuroscience Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.

Dr. James H. Woods (Ex. Officio)

Departments of Pharmacology and Psychology

University of Michigan Ann Arbor, MI 48109-0010, U.S.A.

Dr. Donald E. Jasinski National Institute of Drug Abuse Addiction Research Center P.O. Box 5180 Baltimore, MD 21224, U.S.A.

Mr. Edward Kaim (Rapporteur and Editorial Consultant)

185 Georgetown Road Weston, CT 06883, U.S.A.