Psychiatry & the psychedelic drugs. Past, present & future, James J.H. Rucker et al., 2018

Psychiatry & the psychedelic drugs. Past, present & future

James J.H. Rucker, Jonathan Iliff, David J. Nutt

Neuropharmacology, 2018, 142, 200e218


a b s t r a c t

The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called ‘psychoneurotic’ disorders sometimes benefited considerably from their tendency to ‘loosen’ otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

This article is part of the Special Issue entitled “Psychedelics: New Doors, Altered Perceptions

Keywords : Psychedelics, Psychiatric disorders, Clinical trials


1. Introduction . . . . . . . 201
2. Pre-prohibition clinical studies . . . . . . . 202
2.1. 1895e1940. Studies with mescaline . . . . . . 202
2.2. 1940e1970. Studies in psychotic disorders . . . . . 202
2.3. 1940e1970. Studies in neurotic disorders . . . . . . 203
2.4. 1940e1970. Studies with alcoholism . . . .  . . . . .204
3. Clinical trials prior to prohibition: discussion . . . . .  . . 204
4. Modern clinical studies . . . . . . . . . 205
5. Pathways to licensing : modern clinical trials & regulatory frameworks . . . . . 212
5.1. Safety . . . . . . . . . 212
5.2. Dependence and diversion . . . . . 212
5.3. Feasibility and validity of RCTs with psychedelics . . . . . . . . . 212
5.4. Commercial viability . . . . . . . 213
5.5. Schedule I . . . . . . . . . . 213

5.6. Patient groups . . . . . . . . . 213
5.7. Practical considerations in clinical trials with psychedelics . . . . . . . . 214
5.7.1. Recruitment . . . . . . . . . 214
5.7.2. Screening . . . . . . . . 214
5.7.3. Concomitant medications . . .  . . . . . . 214
5.7.4. Psychiatric & psychological support . . . . . . . . 214
5.7.5. Blinding . . . . . . . . 214
6. Conclusions . . . . . . . . . 215
Author agreement/declaration . . . . . . . . 215
Declaration of interests . . . . . . . . . . . 215
Funding . . . . . .. . . . . . . 215
References . . . . . . . . . 215


1. Introduction

The classical psychedelic drugs include mescaline, psilocybin, dimethyltryptamine (DMT) and D-lysergic acid diethylamide (LSD). Coined by psychiatrist Humphrey Osmond in a letter he wrote to Aldous Huxley in 1956, the word ‘psychedelic’ is derived from the ancient Greek words psyche (jycή, translated as “soul” or “mind”) and delein (dhlεin, translated as “to reveal” or “to manifest”). Therefore, psychedelic literally translates as ‘mind manifesting’ or ‘soul revealing’ (Osmond, 1957). Other terms such as ‘hallucinogen’ and ‘psychotomimetic’ are less favoured, perhaps because they place too much emphasis on individual elements of a multi-faceted subjective state.

Psychedelics were used long before the Western world was introduced to them in 1897, when Arthur Heffter isolated mescaline from the peyote cactus. The earliest direct evidence for use of psychotropic plants dates back 5700 years in the north eastern region of Mexico (Bruhn et al., 2002), where carbon-dated buttons of peyote cacti and red beans containing mescaline were found in caves used for human habitation. The Eleusian ceremonies of ancient Greece were likely based around some form of psychedelic compound (Wasson et al., 2008). Psilocybin containing ‘magic’ mushrooms, which grow all over the world, appear to have been used ubiquitously (Akers et al., 1992; Letcher, 2008). Mescaline is still used in Native American Church ceremonies (Stewart, 1987). In Brazil (McKenna et al., 1984) and the broader Amazonian basin (Schultes and Hofmann, 1979), ritual healing practices and spiritual ceremonies are practiced using ayahuasca, a drink which combines plant derived DMT and b-carboline monoamine oxidase inhibitors that allow it to be used orally.

The archetypal psychedelic in modernWestern society, LSD,was first synthesised in 1938 by Albert Hofmann as part of a systematic investigation of compounds derived from the ergot alkaloids at the Sandoz laboratories in Switzerland (Hofmann, 2013). The ergot alkaloids, which include lysergic acid and its derivatives, were known to be responsible for episodes of mass poisoning in medieval Europe from stocks of grain spoiled with the parasitic fungus Claviceps Purpurea. In smaller doses, a specific ergot alkaloid (ergometrine) was also known to be effective for treating bleeding in women after childbirth due to its vaso- and utero-constrictive properties. LSD was the 25th derivative of lysergic acid that Hofmann synthesised, explaining why it is sometimes referred to as ‘LSD-25’ (Hofmann, 2013). In animal testing, LSD was found to be physiologically unremarkable and the compound was shelved. Hofmann describes how he decided to resynthesize LSD in 1943 on the basis of a ‘peculiar presentiment … that this [compound] might possess properties beyond those established in the first pharmacological studies’ (Hofmann, 2013). On April 16th of that year Hofmann accidentally contaminated himself with a small amount and, noticing some unusual psychic effects, purposefully ingested 250 mcg 3 days later,
whereupon the full, and remarkably potent, effects of LSD on the psyche became apparent for the first time. Further investigation of LSD by Sandoz found that, despite its potency, it was a notably nontoxic compound physiologically. Recognising that its psychoactive properties were likely to be of interest both to psychiatrists and academics, it was marketed in 1947 under the trade name ‘Delysid’ and made freely available to those interested in researching its properties. Hofmann also isolated and synthesised the active component of psilocybe ‘magic’ mushrooms, psilocybin, in 1958 (Hofmann et al., 1959). This was marketed by Sandoz under the brand name ‘Indocybin’.

At a time when psychiatry lacked effective medical therapies, the discovery of LSD was of interest, with some key features noted. Firstly, acute intoxication appeared to mimic some of the symptoms of acute psychosis, particularly ego-dissolution, thought disorder and visual misperceptions (although not, notably, auditory hallucinations). Secondly, there appeared to be an increased awareness of (and emotional connection to) repressed memories and other elements of the subconscious, which was thought to be potentially useful in those failing to make progress in psychotherapy. Physiological
toxicity was not observed, even after very large overdose.

However, initial testing of psychedelics in patients with schizophrenia showed that they were not helpful, exacerbating psychotic symptoms and failing to lead to clinical improvement. Trials in depressive, anxious, obsessive and addictive disorders were more encouraging, with the psychedelics noted to have therapeutic potential within psychologically supportive contexts (Eisner and Cohen, 1958) and a low risk of toxicity (Cohen, 1960). By the end of the 1960s, hundreds of papers described the use of mescaline, psilocybin and (most frequently) LSD in a wide variety of clinical populations with non-psychotic mental health problems (Grinspoon and Bakalar, 1981).

However, as the psychedelics diffused into wider society and recreational use increased, some individuals reported a variety of ongoing symptoms including visual distortions, flashbacks and
other symptoms that occurred long after the drugs had left the body. This came to be classified as ‘Hallucinogen Persisting Perceptual Disorder’ (Halpern and Pope, 2003). Unethical and covert use of psychedelics along with a general hardening of sociopolitical attitudes towards drug use contributed to the decision to place psychedelics in Schedule I of the 1967 UN Convention on Drugs. Medical use ceased and research dwindled until the turn of the millennium, since when there has been a steady renaissance of clinical and academic interest in the psychedelic drugs, reflected by a socio-political narrative that has increasingly questioned the relative benefits and harms of the so-called ‘war on drugs’ (Godlee
and Hurley, 2016; Hari, 2015).

This paper presents a synopsis of selected clinical studies with psychedelics performed before 1970 and all major clinical studies since the turn of the millennium.We discuss the controversies and practical considerations in designing modern clinical trials with psychedelics and review the formidable legal and regulatory hurdles that must be overcome if psychedelics are to become licensed medicines in psychiatry again.

2. Pre-prohibition clinical studies

2.1. 1895e1940. Studies with mescaline

The first medical report of use of a classical psychedelic in Western medicine was made by Prentiss and Morgan in the United States in 1895, who reported the ceremonial use of buttons of the peyote cactus by indigenous people in Central America (Prentiss and Morgan, 1895). Mitchell, reporting in the British Medical Journal in 1896, reports self-experimentation with peyote, describing closed-eye visual experiences and commenting that ‘for the psychologist this agent should have value’ (Mitchell, 1896). This was a view repeated by Havelock Ellis in 1897, describing the experience as ‘…mainly a saturnalia of the specific senses, and chiefly an orgy of vision … it is of no little interest to the physiologist and psychologist’ (Ellis, 1897).