Running head: PSYCHEDELIC DRUGS 1

Therapeutic Potential of Psychedelic Drugs

Justin Briglio

University of Maine

PSYCHEDELIC DRUGS 2

Table of Contents

Introduction......................................................................................................................................3

History of Psychedelic Research.....................................................................................................6

Recent Research...............................................................................................................................8

Neurobiology of Psychedelics.........................................................................................................9

Therapeutic Potential of Psilocybin...............................................................................................12

Therapeutic Potential of LSD........................................................................................................15

Therapeutic Potential of Ayahuasca..............................................................................................19

Therapeutic Potential of Ibogaine..................................................................................................22

Conclusion.....................................................................................................................................26

References......................................................................................................................................28

PSYCHEDELIC DRUGS 3

Therapeutic Potential of Psychedelic Drugs

A psychedelic compound is a psychoactive drug whose main action is to alter perception

and cognition. Psychedelics are distinctive from other psychoactive drugs in that they alter the

mind, whereas opiates or stimulants alter the mood (Meyer & Quenzer, 2013). Psychedelics

affect nature of consciousness itself and access otherwise unknown states of consciousness, as

opposed to affecting the degree or extent of one's consciousness and inducing proverbial moods

such as happiness, excitement, anxiety or apathy (Strassman, 2001). While compounds such as

cocaine, morphine, heroin, or methamphetamines are typically capable of producing addiction

and physiological dependence, most psychedelics are not likely to produce either (Meyer &

Quenzer, 2013).

The psychedelic class covers a large family and wide spectrum of psychoactive compounds

which induce a spectrum of psychedelic effects ranging from trance-like meditative states, to

hallucinations, dissociation, and temporary loss or distortion of self-awareness. The psychedelic

category comprises of multiple specific drug classes. This paper will be focusing on

hallucinogens such as lysergic acid diethylamide (LSD), and psilocybin and entheogens such as

ayahuasca and ibogaine. Hallucinogens produce intense changes and distortions in sensory

perception, awareness, and thought process. LSD and psilocybin are classic hallucinogens.

Hallucinogens are in general serotonergic and in some cases, dopaminergic. Entheogenic

compounds are classified based more on framework of use rather than pharmacology.

Entheogens are generally used for spiritual, religious, shamanic or self-exploration purposes,

because of their transcendent and meditative properties. Many entheogens are obtained and used

in their raw or natural plant or extract state (Grinspoon , 1983).

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Numerous species of mushrooms manufacture alkaloids with hallucinogenic properties.

These fungi, which are sometimes called "magic mushrooms" or "shrooms," include members of

the genera Conocybe, Copelandia, Panaeolus, Psilocybe, and Stropharia, which are found in

many places around the world. Depending on the certain species, users typically take 1 to 5

grams of dried mushrooms to achieve the preferred effects. The dried material may be eaten raw,

boiled in water to make tea, or cooked with other foods to cover its bitterness in taste. The major

ingredients of these mushrooms are psilocybin and the compound psilocin. After ingestion, the

psilocybin is enzymatically converted to psilocin, which is the actual psychoactive agent (Meyer

& Quenzer, 2013).

Unlike psilocybin, LSD is a synthetic compound, although its structure is based on a

family of fungal alkaloids. LSD is well known for its psychological effects, which can include

altered thinking processes, closed- and open-eye visuals, synesthesia, an altered sense of

time and spiritual experiences, as well as for its key role in 1960s counterculture.  LSD is non-

addictive, is not known to cause brain damage, and has extremely low toxicity relative to dose

(Lüscher & Ungless, 2006). However, acute adverse psychiatric reactions such as anxiety,

paranoia, and delusions are possible (Passie et al, 2008). LSD's psychological effects differ

greatly from individual to individual, depending on factors such as previous experiences, state of

mind and environment, as well as dose strength. They also vary from one trip to another, and

even as time passes during a single trip. An LSD trip can have long-term psychoemotional

effects; some users cite the LSD experience as causing significant changes in their personality

and life perspective (Harris, 2014). Some psychological effects may include an experience of

radiant colors, objects and surfaces appearing to ripple, colored patterns behind the closed

eyelids (eidetic imagery), an altered sense of time, crawling geometric patterns overlaying walls

PSYCHEDELIC DRUGS 5

and other objects, morphing objects, a sense that one's thoughts are spiraling into themselves,

loss of a sense of identity or the ego and other powerful psycho-physical reactions (Masters &

Houston, 2000). Many individual users experience a dissolution between themselves and the

outside world (Linton & Langs, 1962).

Ayahuasca is a psychedelic brew made out of Banisteriopsis caapi vine alone or in

combination with various plants. It is either mixed with the leaves of dimethyltryptamine (DMT)

containing species of shrubs from the genus Psychotria or with the leaves of the Justicia

pectoralis plant which does not contain DMT. The brew was first described academically in the

early 1950s by Harvard ethnobotanist Richard Evans Schultes, who established it employed

divinatory and healing purposes by the native peoples of Amazonian Peru (McKenna, 1999).

Individuals who have consumed ayahuasca report having spiritual revelations regarding their

purpose on Earth, the true nature of the universe as well as deep insight into how to be the best

person they possibly can (Gorman, 2010). In addition, it is often reported that individuals feel

they gain access to higher spiritual dimensions and make contact with a variety of spiritual or

extra-dimensional beings who can act as guides or healers (Metzner, 1999). The most reported

side-effect of ayahuasca is nausea, followed by intense repetitive vomiting. For some, the

vomiting comes early, while for others it occurs during the hallucinations.  Deaths due to

participation in the consumption of ayahuasca have been reported. However, the deaths may be

due to preexisting heart conditions, as ayahuasca may increase pulse rates and blood pressure, or

interaction with other medicines taken, such as antidepressants (Hearn, 2013). For various

reasons some shamans and experienced users of ayahuasca advise against consuming ayahuasca

when not in the presence of one or several well trained shamans (Campos & Roman, 2011).

PSYCHEDELIC DRUGS 6

Ibogaine is a natural psychoactive substance found in plants in the Apocynaceae family

such as Tabernanthe iboga, Voacanga africana and Tabernaemontana undulata.

A psychedelic with dissociative properties, the substance is banned in some countries; in other

countries it is used by proponents of psychedelic therapy to treat addiction to methadone,

heroin, alcohol, cocaine, methamphetamine, anabolic steroids, and other drugs. Ibogaine is also

used to treat depression and post traumatic stress disorder. Derivatives of ibogaine that lack the

substance's psychedelic properties are under development (Hamilton, 2010). The experience of

ibogaine is broken down in two phases; the visionary phase comes first, then the introspection

phase. The visionary phase has been depicted as oneirogenic and lasts for 4 to 6 hours. The

second phase, the introspection phase, is responsible for the psychotherapeutic effects of

ibogaine. Ibogaine can allow people to conquer their fears and negative emotions. Ibogaine has

been referred to as an oneirogen, which refers to the dreamlike nature of its psychedelic effects.

Ibogaine catalyzes an altered state of consciousness reminiscent of dreaming while fully

conscious and aware so that memories, life experiences, and issues of trauma can be processed

(Obembe, 2012).

History of Psychedelic Research

It wasn’t until the 20th century that western scientists began to take an interest

in psychedelic drug effects. Swiss chemist, Albert Hoffman first synthesized LSD-25 while

studying derivatives of the fungus ergot for use as potential medicine. He accidentally absorbed

some LSD during a laboratory session where he started experiencing intense perceptual and

emotional effects (Hoffman, 1980).

By the late 1940's psychiatrists were starting to experiment with LSD as a tool, and in 1951

it was the topic of a presentation at the annual conference of the American Psychological

PSYCHEDELIC DRUGS 7

Association. Early work explored the possibility that psychedelics might be used as

psychotomimetics, to mimic the mental states of patients with schizophrenia (Osmond, 1957),

and many other health professionals were encouraged to partake in self-discovery or shared

psychedelic experiences with their patients. Other research looked into utilizing psychedelic

drugs as adjuncts to psychotherapy. The therapy took the form of two broad types: first,

psycholytic or mind loosening psychotherapy which included taking low doses of LSD as part of

ongoing psychoanalytical therapy. The drug assisted with the exploration of repressed material.

The second type, psychedelic psychotherapy or mind manifesting, included preparation sessions

without LSD, then one single large dose session that promoted an intense reaction, followed by

further non-drug sessions to explore the meaning and material that emerged (Grinspoon &

Bakalar, 1997)

By 1965 over 2000 papers had been published describing positive results for over 40,000

patients who took psychedelic drugs with few side-effects and a high level of safety (Masters &

Houston, 1970). The techniques were applied to the treatment of anxiety disorders, depression,

obsessive compulsive disorders, bereavement reactions and sexual dysfunction (Newland, 1962;

Grof, 2001). In the treatment of addiction, repeated controlled experiments established a steady

recovery and 6 month abstinence from drinking 50-90% of participants after brief psychedelic

therapy (Abramson, 1967; Hoffer, 1970). Another area where therapy was used successfully was

in alleviating pain and anxiety in individuals with terminal cancer (Kast, 1964).

Despite the quantity of publications from this period, most of the published material refers

to anecdotal case reports that are of little value by contemporary research standards since they

lack adequate follow-up and control participants (Groh, 1994). Even though results emerged as

promising, by the 1970s, under pressure and scrutiny from the US justice department, nearly all

PSYCHEDELIC DRUGS 8

research had ended. LSD had leaked from the scientific community to a broader audience. By

1966, LSD misuse had become an issue and possession was ordered illegal. This impelled the

scientific community to distance themselves from interest in such substances. Governments

constricted research licenses, and increasing reports of harmful reactions to psychedelics taken

recreationally as opposed to those used in controlled and scientific circumstances appeared in

literature (Strassman, 2001). Consequently, research use halted while illicit use remained, fed by

a growing criminal distribution and financial system. Until very recently, research on

psychedelic drugs has been rigorously constricted, which explains the current lack of knowledge

amongst psychiatrists.

Recent Research

Since the 1970s, 3,4-methylenedioxy-methamphetamine (MDMA) psychotherapy has seen

an emergence underground use by analysts. MDMA, strictly speaking an empathogen rather than

a psychedelic drug, is less intense and shorter-acting than LSD. MDMA seems to tender a

similar therapeutic potential for lowering a patient's defenses and aiding the psychotherapeutic

process (Holland, 2001).

A lifting of the ban on psychedelic research by the government in Switzerland between

1988 and 1993 permitted a brief continuation of psychedelic psychotherapy using LSD and

MDMA for patients with personality, adjustment, and affective disorders. There are currently

projects under development in Israel, Spain and the United States looking at MDMA-assisted

psychotherapy in the treatment of post-traumatic stress disorder (PTSD) and as a treatment for

anxiety and depression related to cancer. Between 1990 and 1995 extensive studies of N,N-

Dimethyltryptamine (DMT), a strong but short-acting agent, were administered with human

participants in the United States (Strassman, 2001). Other research includes a double-blind

PSYCHEDELIC DRUGS 9

placebo control study in Russia using ketamine in the treatment of heroin addiction which has

established improved rates of abstinence, maintained a 2 year follow-up (Krupitsky et al, 2002).

In addition, studies looking at psilocybin in the treatment of OCD and for reducing anxiety and

pain in cancer patients. All of this research is precisely summarized on the Multidisciplinary

Association for Psychedelic Studies (MAPS) website.

Ongoing problems with the current research on psychedelic therapy remains. Even though

drug abuse remains a growing occurrence in today's society the public and governments are

apprehensive of psychedelic research. The reputation and image of psychedelics, was severely

tarnished by the 1960s drug culture, and today it is further damaged by the rave scene. Coming

across unbiased information on psychedelic research is habitually difficult. Nonetheless, many of

the early pioneers of psychedelic research continue to endorse it for the field of mental health.

Dr. Humphrey Osmond, the British psychiatrist, who coined the term "psychedelic" in the 1950s

with Aldous Huxley, keenly supported psychedelic research until his death (Hopkins Tanne,

2004).

Researchers of the past and present believe these drugs are important tools for further

academic study (Sessa, 2004). Their documented psychological effects fit suitably into an

approach looking for neurobiological links between mental and physical states. From a clinical

point of view, the practice of traditional psychedelic psychotherapy has a great deal in common

with the current practice of cognitive-behavioral therapy (Sessa, 2004).

Neurobiology of Psychedelics

The 5HT system is composed of ascending cortical pathways and descending spinal

pathways which project from a central component in the brainstem. Serotonergic transmissions

PSYCHEDELIC DRUGS 10

run from the raphe nuclei to areas of the cortex and the dorsal spinal cord where they modulate a

variety of neurotransmissions via 5HT receptors (Meyer & Quenzer, 2013).

5HT is known for its supposed role in modulating the extent and intensity of moods. The

5HT receptor system is thought to exert an influence biological states of anxiety, contentment,

self-perception and ego, cognition, imagination, aggression, social disposition, sleep cycle, spinal

pain modulation, eating habits and appetite, secretion of the hormone oxytocin (5HT1A), and

regulation of smooth muscle movements in the heart and digestive tract (Meyer & Quenzer,

2013).

The 5HT receptor consists of numerous subtypes which execute a spectrum of biological

functions. One subtype in particular has been implicated in the subjective & behavioral effects of

psychedelic compounds, this would be the 5HT2A receptor (Meyer & Quenzer, 2013). It has

been observed that LSD, psilocybin, DMT, and similar compounds similarly act at the 5HT-2A

receptor, with agonist or partial-mixed agonist properties. Blocking the action of 5HT-2A

receptors is shown to inhibit the effects of such compounds in test subjects. The 5HT-2A

receptor is a G-protein coupled receptor. It is but one subtype of serotonergic receptor and

exhibits predominantly excitatory, though some inhibitory, effects. The mapping of the 5HT2A

receptor in the brain serves to further explain the effects produced by classic psychedelics.

(Vollenweider & Kometer, 2010). Classical hallucinogens (LSD, psilocybin) display high

affinity for 5-HT2 receptors, they also interact to some degree with 5-HT1, 5-HT4, 5-HT5, 5-

HT6 and 5-HT7 receptors. In contrast, to the tryptamines (psilocybin), the ergolines (LSD) also

show high intrinsic activity at dopamine D2 receptors and at α-adrenergic receptors (Marona-

Lewicka, Thisted & Nichols, 2005). Several studies have demonstrated that activation of 5-

HT2A receptors by classical hallucinogens or by serotonin leads to a robust, glutamate-

PSYCHEDELIC DRUGS 11

dependent increase in the activity of pyramidal neurons, preferentially those in layer V of the

prefrontal cortex (PFC) (Aghajanian, & Marek, 1999).

5-HT2A receptor activation not only seems to underlie the occurrence of the acute

psychedelic effects of hallucinogens but may also lead to neuroplastic adaptations in an extended

prefrontal–limbic network. For example, in rats a single dose of the hallucinogen 2,5-dimethoxy-

4-iodoamphetamine (DOI) transiently increased the dendritic spine size in cortical neurons

(Jones et al., 2009) and repeated doses of LSD down regulated cortical 5-HT2A but not 5-HT1A

receptors; effects that were the most pronounced in the frontomedial cortex and anterior

cingulate cortex (ACC) (Buckholtz et al., 1990).

It is likely that such adaptations and particularly a downregulation of prefrontal 5-HT2A

receptors might inspire some of the therapeutic effects of hallucinogens in the

treatment of depression, anxiety and chronic pain. In favor of this theory, 5-HT2A receptor

density was found to be increased in the PFC in a post-mortem sample (Shelton et al., 2008) and

in vivo (Bhagwagar et al., 2006) in patients with major depression, and to be reduced after

chronic treatment with a variety of antidepressants the reduction coinciding with the onset of

clinical value (Yamauchi et al., 2006). Additionally, chronic, antisense-mediated downregulation

of 5-HT2A receptors in rats (Cohen, 2005) and in 5-HT2A knockout mice (Weisstaub, 2006)

reduced anxiety-like behavior, and selective restoration of 5-HT2A receptors in the PFC

normalized anxiety-like behavior in these 5-HT2A knockout mice. These findings suggest that

prefrontal 5-HT2A receptors might modulate the activity of subcortical structures, such as the

amygdala (Weisstaub, 2006). Anxiety and depression are interrelated with stress (Anisman,

Merali & Stead, 2008), which also affects the serotonin system (Lukkes et al., 2009). Stress

elevates corticotropin-releasing factor (CRF) (Reul, 2002), and administration of CRF into the

PSYCHEDELIC DRUGS 12

mPFC of mice enhanced anxiety-like density correlated with responses to tonic pain but not with

responses to short phasic pain stimuli. This suggests a role of the 5-HT2A receptors in the

cognitive evaluation of pain experiences (Kupers, 2009), and points to additional therapeutic

potential for hallucinogens in individuals with chronic pain.

Therapeutic Potential of Psilocybin

Advocates for advanced research in the field of ethnobotany have been asking for

medical investigation of the use of synthetic and mushroom-derived psilocybin for the

development of improved treatments of various neurological disorders (Sun-Edelstein &

Mauskop, 2011). A study conducted by (Johnson, Garcia-Romeu & Cosimano, 2014) included a

15 week course of smoking cessation treatment, with psilocybin administration taking place in

weeks 5, 7 and 13. This study was approved by the John Hopkins University School of Medicine

Institutional Review Board, and participants provided informed consent. This was the first study

to present preliminary data on the safety and feasibility of psilocybin as an adjunct to smoking

cessation treatment. The present results are consistent with previous studies examining 5-HT2AR

agonists in the treatment of drug dependence suggesting both safety and feasibility. The results

suggest potential regarding the safety of psilocybin as an adjunct to smoking cessation treatment.

Adverse effects associated with psilocybin consisted of modest acute increases in blood pressure,

heart rate, dysphoric subjective effects (e.g. anxiety, fear; <7 hours), and headaches (<24 hours).

Consistent with previous research administering psilocybin in controlled settings, these effects

were readily managed. Results of the present pilot study also back the feasibility of the approach,

as 80% of participants were abstinent at 6-month follow-up. Results should be interpreted with

caution given the small number and open-label design. Therefore, no definitive conclusions can

be drawn about the causal role of psilocybin as such. However, abstinence rates were

PSYCHEDELIC DRUGS 13

substantially higher than typical. This study is the first to examine a 5-HT2AR agonist in the

treatment of tobacco addiction, and demonstrates a viable framework for psilocybin-based

addiction treatment interventions. Given the global scale of smoking-related mortality, and the

modest success rates of approved smoking cessation treatments the novel approach presented in

this study warrants further investigation with a randomized controlled trial.

A study by (Kraehenmann, 2014) assessed the effects of acute administration of the

hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in

25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance

imaging. Mood changes were assessed using the Positive and Negative Affect Schedule and the

state portion of the State-Trait Anxiety Inventory. A double-blind, randomized, cross-over design

was used with volunteers counterbalanced to receive psilocybin and placebo in two separate

sessions at least 14 days apart. Results showed amygdala reactivity to negative and neutral

stimuli was lower after psilocybin administration than after placebo administration. The

psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was

related to the psilocybin-induced increase in positive mood state. These results demonstrate that

acute treatment with psilocybin decreased amygdala reactivity during emotion processing and

that this was associated with an increase of positive mood in healthy volunteers. These findings

may be relevant to the normalization of amygdala hyperactivity and negative mood states in

patients with major depression. In this study, it was found that psilocybin attenuated task

induced activation in the amydala in response to negative and neutral pictures but had no effect

on activation of the primary motor cortex. This psilocybin-induced effect was significantly

stronger in the right amygdala than in the left amygdala. Furthermore, psilocybin increased

subjective reports of positive mood but did not increase anxiety. Importantly, the effect of

PSYCHEDELIC DRUGS 14

psilocybin on amygdala reactivity was most strongly associated with positive mood change.

Reduction of amygdala reactivity by psilocybin is consistent with our a priori hypothesis and

provides a mechanistic framework to understand psilocybin-induced effects on emotion

processing. The current findings support the notion that psilocybin has the potential to normalize

limbic hyperactivity in persons with depressed mood state.

A study done by (Moreno et al., 2006) with nine subjects that had DSM-IV-defined OCD

and no other existing major psychiatric disorder participated in up to 4 single-dose exposures to

psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100

mg/kg), medium (200 mg/kg), and high (300 mg/kg) doses were given in that order, and a very

low dose (25 mg/kg) was inserted randomly and in double-blind fashion at any time after the first

dose. Testing days were separated by at least 1 week. Each session was done over an 8-hour

period in a controlled environment in an outpatient clinic; subjects were then transferred to a

psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive

Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom

severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating

Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after

ingestion. The study was conducted from November 2001 to November 2004. The nine subjects

were administered a total of 29 psilocybin doses. One subject experienced transient hypertension

without relation to anxiety or somatic symptoms, but no other significant adverse effects were

observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects

during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-

measures analysis of variance for all YBOCS values showed a significant main effect of time on

Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3;

PSYCHEDELIC DRUGS 15

p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement in

general lasted past the 24-hour period. The study showed that in a controlled clinical

environment, psilocybin was safely used in subjects with OCD and was associated with acute

reductions in core OCD symptoms in many subjects.

Therapeutic Potential of LSD

LSD has been used in psychiatry for its perceived therapeutic value, in the treatment of

alcoholism, pain and cluster headache relief, for spiritual purposes, and to enhance creativity. A

study by (Krebs & Johansen, 2012) regarding a meta-analysis of randomized controlled trials

regarding treatment for alcoholism had two reviewers independently extracted the data, pooling

the effects using odds ratios (ORs) by a generic inverse variance, random effects model. They

identified six eligible trials, including 536 participants. There was evidence for a beneficial effect

of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36–2.84; p = 0.0003). Between-trial

heterogeneity for the treatment effects was negligible (I² = 0%). Secondary outcomes, risk of

bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism

treatment programs, is associated with a decrease in alcohol misuse. They included randomized

controlled trials of LSD for alcoholism, in which control condition involved any type of treat-

ment, including doses of up to 50 mcg LSD as an active control. If a trial included multiple

randomized treatment arms, all participants in the eligible LSD arms and all participants in the

eligible control arms were pooled for analysis. They excluded participants with schizophrenia or

psychosis from analysis, as psychosis is recognized as a contraindication for treatment with LSD

(Johnson et al., 2008; Passie et al., 2008). Results showed In a pooled analysis of six randomized

controlled clinical trials, a single dose of LSD had a significant beneficial effect on alcohol

misuse at the first reported follow-up assessment, which ranged from 1 to 12 months after

PSYCHEDELIC DRUGS 16

discharge from each treatment program. This treatment effect from LSD on alcohol misuse was

also seen at 2 to 3 months and at 6 months, but was not statistically significant at 12 months post-

treatment. Among the three trials that reported total abstinence from alcohol use, there was also a

significant beneficial effect of LSD at the first reported follow-up, which ranged from 1 to 3

months after discharge from each treatment program. The findings from randomized controlled

trials of a sustained treatment effect of a single dose of LSD on alcohol misuse, which may fade

within 12 months, are consistent with many reports of clinical experience and with data from

most non-randomized controlled and open-label studies of LSD for alcoholism. Given the

evidence for a beneficial effect of LSD on alcoholism, it is puzzling why this treatment approach

has been largely overlooked. Based on reviewing the literature, they have four suggestions for

why this happened. First, the randomized controlled trials were underpowered and most did not

reach statistical significance when considered individually. Second, trial authors expected

unrealistic results and tended to discount moderate or short-term effects. Third, early non-

randomized clinical trials were poorly described and had methodological problems, creating the

mistaken impression that well-designed studies did not exist. Finally, the complicated social and

political history of LSD led to increasing difficulties in obtaining regulatory approval for clinical

trials.

A study (McCabe et al, 1972), with subjects that were patients of Spring Grove State

Hospital who received a psychoneurotic diagnosis for the treatment of neurotic disorders with

LSD. Eliminated from consideration for the study were any patients who were suffering from

organic illness, defective intelligence, and those under 18 or over 55 years of age. Clinically, the

patients were depressed, anxious, and typically received "depressive reaction" diagnosis. In order

of frequency of occurrence, the presenting problem behaviors upon admission to the hospital

PSYCHEDELIC DRUGS 17

were: 1) suicide attempt; 2) sleeplessness; 3) crying; 4) anorexia; and 5) psychomotor

hyperactivity. The average age of the total sample was approximately 33 years (32.9). The mean

amount of formal education was 11 years. Of the 85 patients compromising the study population,

65% were female. Approximately half (51%) of the subjects were married, and most were white

(95%), Protestant (50%) and employed in clerical or sales work (34%). The subjects were

administered the following tests: 1) the Minnesota Multiphasic Personality Inventory (MMPI), 2)

the Eysenck Personality Inventory (EPI), and 3) the Personal Orientation Inventory (POI). The

MMPI was selected as the major measure of evaluation because it is an objective measure that is

well constructed, empirically derived, and extensively validated. The EPI measures two

pervasive, independent dimensions of personality, Extraversion-Introversion and Neuroticism-

Stability which, according to Eysenck's factor-analysis studies, account for most of the variance

in the personality domain. The POI, based on Maslow's concept of the "self- actualized" person,

provides a comprehensive measurement of values and behavior seen to be of importance in the

development of self-actualization. In the past, diagnostic instruments (e.g., the MMPI) have

provided a negative approach to evaluating the therapeutic process. When used as a pre- and

post-therapy measure, the POI provides a much needed measure of the change in level of

positive mental health. After psychometric assessment, patients were randomly assigned to one

of the three groups: a conventional treatment group (N, 27), a low-dose (50 mcgs), LSD control

gorup (N, 30), or a high-dose (350 msgs), and LSD experimental group (N, 28). The random

assignment of subjects to groups was accomplished by the supervising physician. Results

showed the present investigation suggested that psychedelic psychotherapy can effect personality

change in subjects willing to undergo, and specially prepared form such procedure. . The

especial rapidity with which this occurs seems primarily attributable to the pharmacologically-

PSYCHEDELIC DRUGS 18

induced receptivity occasioned by the LSD administration and must be considered promising in

light of greater duration of time and environmental manipulation upon which the more common

methods of behavior modification rely. The functional significance of these changes and their

relative permanence, as well as their modes of action, are issues which lie beyond the scope of

the present study. Other studies (Kurland et al. and Savage & McCabe, 1972) have indicated that

psychedelic therapy-induced change is relatively enduring and meaningful as indicated by one-

year follow-up assessments of community adjustment. It should be understood that psychedelic

therapy utilizing high-dose LSD administration hardly has far-reaching public health

implications, mainly because it is a highly specialized technique requiring intensive training, thus

precluding its use on a mass basis.

A study conducted by (Pahnke et al, 1970), utilizing LSD with cancer patients found that

LSD helped patients face death. The results of this study focused on two parameters: 1) the

amount of pain medications required pre- and post- LSD and 2) average global evaluations of the

change in the patient's condition. In regard to the first, a narcotic scale of equivalent dosages was

developed so that the unit equivalents of the various pain medications used before LSD was

always compared to the same length of time after LSD for any one patient. These periods ranged

from 2 to 7 days between different patients because some patients were discharged within two

days after LSD. Such estimations of narcotic usage must remain rough indications only because

of other variables which we uncontrolled at this point. Nonetheless, a decreased need for

narcotics can be seen in some of the patients. However, analgesia alone would not justify the

large expenditure of effort required for LSD treatment. In regard to the second parameter, the

change in the patient's condition included an estimate of closeness and openness in interpersonal

relationships with family and others, ease in medical management, mood, state of relaxation and

PSYCHEDELIC DRUGS 19

comfort, and sense of well-being. These changes were evaluated from the viewpoint of the

attending physicians, the nurses, the LSD therapist, and the patient's family. Subsequent to our

initial pilot study with the six patients described here, they have continued their research. So far,

they have treated 22 more cancer patients. Results consistently have shown very dramatic

positive changes in global adjustment in about 1/3 of the cases, significant beneficial changes in

another 1/3, and no change in 1/3. Again, the sicker and more terminal patients seemed to show

the least benefit, thus strengthening their early, still tentative, impression that the earlier a case is

treated in the course of the disease the better. None of the patients, even the most ill, appeared to

have been harmed by the procedure. There are many questions concerning the psychological

influence of the positive psychedelic peak experience and its impact on anxiety, apprehension,

and depression. Although the psychological mechanisms underlying such changes need much

more study, one factor which appears to make this experience so meaningful to the patient is the

profound sense of fulfillment which resolves the intense feeling of unfinished business and its

accompanying frustrations. There is the appearance of a positive mood state characterized by

joy, peace and love. There is less worry about the future (sometimes even about death itself) and

at the same time an increased willingness and ability to live each moment fully for the here and

now. Another possible result is an increased openness and honesty which can have an vital

impact on interpersonal relationships at this critical time.

Therapeutic Potential of Ayahuasca

 The brew ayahuasca is used in the treatment and management of various diseases and

ailments, especially its role in psychological well-being and for treating depression, PTSD, and

substance dependence. Qualitative results from a study done by (Loizaga-Velder & Verres,

2014) on the ritual of ayahuasca and use in the treatment of substance dependence found that

PSYCHEDELIC DRUGS 20

over half of the ritual participants (9/14) reported that they felt a reduction of cravings after their

participation in ayahuasca rituals. Also, interviewed therapists steadily pointed out that they

observed such effects in their patients, lasting for periods ranging from several days to up to

several years. Three out of the fourteen patients and four out of the fifteen therapists reported

reduction of withdrawal symptoms. One of the interviewed scholars suggested that heavy

vomiting under the ayahuasca-induced, non-ordinary state of consciousness could trigger

endorphin release, which could play a part to this effect. Ayahuasca-induced spiritual

experiences were given high therapeutic value by both the patients and the therapists. Several

patients reported that ayahuasca-induced transcendental experiences transformed their

consciousness in a way that permitted them to overcome their craving for drugs without effort.

All therapists stressed that ayahuasca is a very potent plant medicine which needs to be

conducted with care and professionalism in order to avoid or lessen side-effects; conversely, they

also considered ayahuasca to be relatively safe when used in well-structured therapeutic

contexts. Most therapists acknowledged that they had never observed ongoing undesired side

effects in their patients. Three complications were reported, two incidents were transient

psychotic episodes that dissipated after a few days, and one of these cases resolved with help of a

traditional healer; while the other resolved with psychiatric medication. The third incident was a

suicide on the day after the ayahuasca ceremony. The interviewed therapist credited the suicide

to the fact that ayahuasca was taken in an outpatient setting and the patient had received

inadequate support for integration before leaving. The therapists did not consider ayahuasca as

being subjected to abuse or dependence. The findings of this study allow the conclusion that the

use of ayahuasca in appropriate contexts can help therapeutic processes in the treatment of

substance dependence by assisting with interconnected body-orientated, psychological, and

PSYCHEDELIC DRUGS 21

spiritual experiences. One significant finding is that ayahuasca experiences can be a factor with

diminished drug cravings. This has important therapeutic implications, as craving and relapse are

strongly correlated. In addition to the psychological aspects, which were the principal focus of

the present study, pharmacological aspects of ayahuasca-assisted addiction treatment merit

further research. Ayahuasca should not be used as a primarily pharmacological intervention.

Rather, it should be conceptualized as a medium with a therapeutic value that can progress when

the substance, setting, and integration are properly administered.

A comprehensive review by Schenberg concerning nine case reports on the subject of the

use of ayahuasca in the treatment of brain, prostate, uterine, ovarian, breast, stomach and colon

cancers were found. Many of these were considered improvements, one case was considered

worse, and another case was rated as difficult to evaluate. A theoretical model is presented which

explains these effects at the molecular, cellular, and psychosocial levels. Attention in particular is

given to ayahuasca's pharmacological effects through the activity of N,N-dimethyltrypatamine

(DMT) at intracellular sigma-1 receptors. The sigma-1 receptor (Sig1R) is a ubiquitous

membrane protein that has been involved in many cellular processes. While the precise function

of Sig1R has long remained mysterious, recent studies have shed light on its role and the

molecular mechanisms triggered. Sig1R is in fact a stress-activated chaperone mainly associated

with the ER-mitochondria interface that can regulate cell survival through the control of calcium

homeostasis. Sig1R functionally regulates ion channels belonging to various molecular families

and it has thus been involved in neuronal plasticity and central nervous system diseases including

stroke, cocaine addiction, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis (ALS),

retinal degeneration, and cancer (Crottès et al., 2013). The effects of other components of

ayahuasca, such as harmine, tetrahydroharmine, and harmaline, are also considered. The

PSYCHEDELIC DRUGS 22

proposed model, which is based on the molecular and cellular biology of ayahuasca's know

active components and the available clinical reports, suggests that these accounts may have

consistent biological groundwork. Further study of ayahuasca's possible antitumor effect is vital

because cancer patients continue to see out this traditional medicine. As a result, based on the

social and anthropological observation of the use of this brew, suggestions are provided for

further study into the safety and effectiveness of ayahuasca as a possible medicinal aid in the

treatment of cancer.

Therapeutic Potential of Ibogaine

The most known therapeutic effect of ibogaine is the reduction or elimination

of addiction to opioids. Research also suggests that ibogaine may be useful in treating

dependence on other substances such as alcohol, methamphetamine, and nicotine and may affect

compulsive behavioral patterns not involving substance abuse or chemical dependence (Alper et

al., 1999).

A retrospective study by Schenberg, evaluated data from a residential, private clinic in

Curitiba, Parana, Brazil, which treats patients with substance use disorders using cognitive

behavioral therapy (CBT). Data was gathered from 75 drug-dependent patients (67 male, 8

female) who underwent a total of 134 ibogaine HCl sessions. All women reported that they were

abstinent at the time of contact, and only two reported having had a relapse after the initial

ibogaine session. Both of these women then took ibogaine a second time and have reportedly not

relapsed since. Forty-eight men (72%) stated that they were abstinent, but 10 of those were

currently undergoing other treatment interventions. Except for those 10, 38 (57%) men achieved

abstinence with no other treatments. After the first ibogaine session, 22 of the male patients

(29%) recovered without relapses, whereas 53 (71%) relapsed. After the second session, 15

PSYCHEDELIC DRUGS 23

patients (45%) maintained sobriety, and 18 reported relapse (55%). After the third session, eight

(57%) remained abstinent, and six (43%) relapsed. After the fourth session, one patient did not

relapse (20%), and four relapsed (80%). After the fifth session, one patient maintained

abstinence (50%), and one patient relapsed, and continued to take ibogaine four more times.

There was a significant association between gender and relapse after the first ibogaine session,

with men relapsing more frequently than women (Chi2 = 9.009; p = 0.007). The most important

result from the present data is that no fatalities occurred as a result of ibogaine administration in

the controlled dosing (between 7.5 and 20 mg/kg). The absence of fatalities in the present results

suggests a relative safety of the use of ibogaine hydrochloride in a controlled hospital setting.

Considering the occurrence of relapses after ibogaine administrations, the present results are very

encouraging. Although there were only eight women in the sample, all were found abstinent at

the time of contact. Among men, 51% were also abstinent at the time of contact, and an

additional 10 participants were also abstinent, but were participating in other drug dependence

treatment interventions. Future studies also seek to establish the advantages and disadvantages of

using ibogaine instead of other related psychedelic compounds, such as LSD, which has

therapeutic potential in the treatment of alcoholism (Krebs and Johansen, 2012). While ibogaine

may be more effective at treating a wider range of chemical dependencies (e.g. opioids, alcohol,

cocaine, crack) than other psychedelic substances, it may present higher risks for medical

complications. For example, LSD has very low toxicity and none of the effects on heart rhythm

(Hintzen and Passie, 2010) that ibogaine does. Despite the limitations of the present report, the

present data are the first formal clinical report to our knowledge that suggests that ibogaine has a

strong therapeutic potential in the treatment of dependence to stimulants and other non-opiate

PSYCHEDELIC DRUGS 24

drugs and that the medical complications previously reported can be avoided by administering

the compound in the presence of a physician in a safe and legal medical setting.

A study by Hittner & Quello (2014) on combating substance abuse with ibogaine looked

at six-heroin-dependent individuals (four males, two females, mean age = 28) who were

originally presented in Sheppard's (1994) study. As mentioned in Sheppard (1994), participants

first received a counseling session and a trial dose of 100 to 200 mgs of ibogaine. Approximately

one to two hours after the trial dose, participants self-administered a single oral dose of ibogaine

that ranged between 700 and 1800 mgs. The organically derived ibogaine hydrochloride was

determined to be over 98% pure. The original data presented in Sheppard were reanalyzed using

correlation and regression analyses to examine how number of post ibogaine weeks drug free

related to dose-to-weight ratio. The results of a bivariate Pearson correlation between number of

weeks drug free following ibogaine administration and dose-to-weight ratio (DWR) was r = . 80,

p = .05. The corresponding association between weeks drug free and dose was considerably

smaller at r = .54, p = .26. In order to control for the potential confounding effects of previous

duration of heroin use, a partial correlation analysis was performed. Results revealed that despite

partialing out weeks of heroin use prior to ibogaine treatment, DWR was still correlated at r

= .80 with the number of weeks drug free following ibogaine administration. Furthermore,

inspection suggests that a threshold barrier is associated with DWR. Regarding the data provided

in the figures displayed in the article, an S-shaped pattern appears to characterize the data

whereby the two subjects with low DWRs (11.7 mgs/kg and 15. 7 mgs/kg, respectively) showed

no benefit from the single-dose administration of ibogaine (0 weeks drug free), and the four

subjects with DWRs above 16 mgs/kg experienced notable benefits from the ibogaine treatment

(between 10 and 17 weeks drug free). In light of the apparent S-shaped pattern and implied

PSYCHEDELIC DRUGS 25

threshold barrier, a sigmoidal dose-response curve was used to fit the data. Relative to the

quadratic regression results (R2 = .68), the sigmoidal dose-response regression resulted in a

substantial improvement in model fit (R2 = .88). The present reanalysis of Sheppard's (1994)

data not only established the efficacy of conducting successive model fitting analyses, but the

results also indicated the presence of a DWR threshold barrier of approximately 16mgs/kg.

Clients with DWRs above this value experienced favorable treatment outcomes, and clients with

DWRs below 16 mgs/kg experienced little, if any, benefit. An interesting observation concerns

the range of DWR values for the clients reported in Sheppard's (1994) study. In particular, the

DWRs, which ranged from 11 .70 to 25.00 mgs/kg (Mean = 20.40, SD = 5.62), differ

considerably from the DWR values reported by Lotsof (1985) in his application to patent

ibogaine as a treatment for narcotic addiction. Specifically, Lotsof (1985) stated that a single

treatment with ibogaine in doses ranging from six to 19 mgs/kg effectively interrupted heroin use

for about six months. The considerable discrepancy between these two ranges of DWR values is

interesting and future research should investigate the clinical implications of such differences in

ibogaine dosage levels. Although this article recognizes that Sheppard's (1994) sample of six

heroin addicts is far too small to draw generalizable conclusions, the model fit that they attained

for the sigmoidal dose-response regression (R2 = .88, Adj R2 = .84) is quite impressive and

suggests the presence of a dose-to-weight ratio threshold barrier of approximately 16mgs/kg.

Given the strength of the model fit, they recommend that other ibogaine researchers conduct

similar successive model fitting analyses in an effort to further understand the nature of the

association between DWR and the ability to maintain drug abstinence following ibogaine

treatment.

PSYCHEDELIC DRUGS 26

Conclusion

Sessa (2014) states there remains such considerable ignorance about the potential of these

substances from within psychiatry itself. As with Galileo’s telescope and Darwin’s suggestion of

our ascendancy from apes, radical scientific challenges tend to take the form of an attack on the

anthropocentric model of the world. In the light of this, he articulates that research that explores

alternative states of consciousness and then offers a viable neurobiological substrate for the very

human experience of religious encounter is bound to meet with objection from a generation of

psychiatrists who have been conditioned to consider such work as ‘mysticism’. Conceivably a

more dispassionate criticism based upon scientific reasoning and not influenced by social or

political pressures is called for to investigate whether these substances can have a useful role in

psychiatry today.

Until it is clearly understood that the results of the administration of psychedelics are

critically influenced by the factors of set and setting, there is no hope for rational decisions in

regard to psychedelic drug policies. Psychedelics can be used in such a way that the benefits far

outweigh the risks as controlled studies have shown in the past. Whether or not psychedelics will

return into psychiatry and will again become part of therapeutic techniques is a convoluted

problem and its solution will probably be determined not only by the results of scientific

research, but also by a variety of political and legal factors. 

It is encouraging that in a few cases, researchers in the United States, Switzerland, and

other countries have in recent years been able to obtain official permission to start programs of

psychedelic therapy involving LSD, psilocybin, DMT, MMDA, and ketamine. There is hope that

this is the beginning of a rebirth of interest in psychedelic research that will eventually return

these substances and compounds into the hands of responsible therapists and therapy sessions. In

PSYCHEDELIC DRUGS 27

conclusion, more research and studies that are accurately presented and controlled for need to be

conducted to ensure that the therapeutic potentials of psychedelics can be applied to mainstream

treatment in the near future.

PSYCHEDELIC DRUGS 28

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