Psychiatry & the psychedelic drugs. Past, present & future

This review article (2018) looks at the pre- and post-prohibition clinical studies on psychedelics and offers strategic advice on the legal and regulatory hurdles.

Abstract 

“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.”

Authors: James J. H. Rucker, Jonathan Iliff & David J. Nutt

Summary

Experimentation and clinical trials using psychedelics pre and post prohibition suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, some people with so-called ‘psychoneurotic’ disorders may benefit considerably from their tendency to ‘loosen’ otherwise fixed, maladaptive patterns of cognition and behaviour.

This article is part of a special issue on psychedelics.

1. Introduction

Psychedelics were used long before the Western world was introduced to them in 1897. Carbon-dated buttons of peyote cacti and red beans containing mescaline were found in caves used for human habitation in the north eastern region of Mexico.

LSD was first synthesized in 1938 by Albert Hofmann as part of a systematic investigation of compounds derived from the ergot alkaloids at the Sandoz laboratories in Switzerland. It was subsequently shelved, but Hofmann resynthesized LSD in 1943 and accidentally ingested 250 mcg 3 days later. Sandoz found that LSD was a non-toxic compound, and marketed it under the trade name Delysid. Hofmann isolated the active component of psilocybe ‘magic’ mushrooms, and marketed it under the brand name Indocybin.

At a time when psychiatry lacked effective medical therapies, the discovery of LSD was of interest. It was thought to have therapeutic potential in patients with non-psychotic mental health problems, and had a low risk of toxicity.

As the psychedelics diffused into wider society and recreational use increased, some individuals reported ongoing symptoms. This was classified as Hallucinogen Persisting Perceptual Disorder and contributed to the decision to place psychedelics in Schedule I of the 1967 UN Convention on Drugs.

This paper reviews clinical studies with psychedelics performed before 1970 and since the turn of the millennium. It discusses controversies and practical considerations.

2.1. 1895e1940. Studies with mescaline

In 1895, Prentiss and Morgan reported the ceremonial use of peyote in Central America. In 1896, Mitchell reported self-experimentation with peyote and commented that “for the psychologist this agent should have value”.

Arthur Heffter isolated the active component of peyote (mescaline) in 1897, but Alwyn Knauer administered mescaline by subcutaneous injection to himself and other volunteering physicians in 1913. Knauer and Maloney noticed that the mental state induced by mescaline bore some similarity to the psychotic state.

Erich Guttman, working at The Maudsley Hospital in London, gave mescaline to a variety of patients, including medical students, undergraduates, normals, psychopaths, manic-depressives, schizophrenics, depressives, morphinists and those suffering from derealisation and depersonalisation phenomena.

2.2. 1940e1970. Studies in psychotic disorders

Because of the predominance of psychoanalytic theory at the time, mescaline was never marketed, and its use by psychiatrists was sporadic and infrequent. However, after Hofmann synthesised LSD in 1943, it was provided free of charge to psychiatrists, and growth of interest in LSD was rapid.

In a further group of 59 individuals with schizophrenia, Paul Hoch and colleagues administered LSD and mescaline. They observed worsening in those with undeteriorated and deteriorated forms of schizophrenia, but improvement in some with ‘pseudoneurotic’ forms of schizophrenia.

Herman Denber and Sydney Merlis gave mescaline intravenously to 25 patients with schizophrenia and found that 1 patient achieved complete remission, 3 showed temporary remission, and in the remainder psychotic symptoms were either reactivated or worsened.

Clinical studies of the use of LSD and mescaline in psychosis rapidly diminished after it became clear that the drugs exacerbated the symptoms of most and did not lead to clinical improvement. However, the differences between the psychoses characterised by schizophrenia and the state characterised by LSD were still of interest.

2.3. 1940e1970. Studies in neurotic disorders

Ronald Sandison used LSD in the context of psychotherapy to treat 36 patients with predominantly ‘psychoneurotic’ disorders. 27 out of 30 patients benefited from the intervention, although this was a subjective judgement made by the treating clinician.

In 1957, Sandison reported follow up on 93 patients with severe neuroses. Of these, 21 were ‘recovered’, 20 were ‘greatly improved’, 20 were ‘moderately improved’ and 32 were ‘not improved’.

Chandler and Hartman gave LSD to 110 patients with predominantly ‘psychoneurotic’ and ‘personality disorder/trait’ diagnoses. 50 patients showed ‘considerable, ‘marked or ‘outstanding’ improvement, 38 showed ‘some or ‘slight’ improvement and 22 showed ‘little or no change’ or were ‘slightly worse’.

Whitaker compared 100 patients with a control group, and found that 47 patients with ‘psychoneuroses’, 27 with ‘personality disorder’, 21 with ‘sexual disorders’ and 3 with ‘residual schizophrenia’ improved after LSD therapy, compared to 18 borderline and 35 failures in the control group.

A total of 243 patients with a variety of non-psychotic psychiatric diagnoses were administered LSD without the context of formal psychotherapy. 83% reported ‘lasting benefit’ and this was ‘highly correlated (tetrachoric r 1 4 0.91) with the report of a greater awareness of an ultimate reality’. 197 of 243 patients showed improvement in retrospect, with 35.8% showing ‘some’ improvement, 26.3% showing ‘substantial’ improvement and 18.9% showing ‘marked’ improvement.

2.4. 1940e1970. Studies with alcoholism

Clinical studies using LSD in the treatment of alcoholism before 1970 benefited from a more systematic approach than other disorders, but initial studies were usually uncontrolled.

Jensen gave LSD to 58 alcoholics on an inpatient unit in Ontario, Canada, and reported a significant difference in rates of abstinence between those given LSD and those given group psychotherapy and standard care.

In 1966, Smart et al. reported that 30 alcoholics were randomised to receive standard care plus a 60 mg dose of ephedrine sulphate, or standard care plus an 800 mcg dose of LSD. No significant differences were observed between the groups in terms of pragmatic measures of alcohol misuse.

Hollister et al. conducted a controlled trial of 72 male inpatients with alcoholism, randomised to a single dose either of 600 mcg LSD or 60 mg of dextroamphetamine. The results showed that the LSD group significantly improved over the dextroamphetamine group, but the difference was not significant at 6 month follow up.

Ludwig et al., working at the Mendota State Hospital in Wisconsin, USA, found that 176 male inpatients with alcoholism received 3 mcg per kg of body weight of LSD, with no significant difference found between the LSD groups and the control groups.

3. Clinical trials prior to prohibition: discussion

Studies of the clinical utility of psychedelics published prior to 1970 were methodologically sub-optimal and often reported inconsistently or without adverse outcomes.

Pre-prohibition research suggested that psychedelic drugs were not useful for those with established psychotic disorders and should probably be avoided in those liable to develop them.

In trials with so-called ‘psychoneurotic’ disorders, such as anxiety and depression, nearly 80% of participants were judged to have ‘improved’ by their clinicians. However, in controlled trials with alcoholism using quantitative measures of alcohol use, borderline or non-significant findings were often reported.

Adverse events were generally not reported systematically, and their aetiology varied according to research team. Immediate adverse events were more often reported than delayed adverse events, and included headaches, palpitations, gastrointestinal disturbances, changes in temperature perception, feelings of tremulousness or dizziness, and other somatic complaints.

Subjective reports of physical symptoms were inconsistent with objective clinical signs, which may represent both increased subjective awareness of bodily sensations and drug induced changes in the autonomic nervous system itself.

Sidney Cohen sent a questionnaire to 62 investigators who were using LSD or mescaline in healthy subjects or patients, and 44 investigators replied. No instance of physiological toxicity was reported, and the rate of attempted suicide, completed suicide and psychotic reactions lasting over 48 h was rather low.

Cohen and Ditman concluded that complications were more likely to occur after unsupervised or inexpert use of LSD, and Strassman echoed this view in his review of adverse events to psychedelics.

As recreational use of LSD and mescaline increased in the 1960s, evidence of toxic psychological reactions in sensitive individuals accumulated. This paralleled investigation of psychedelics as so-called ‘truth drugs’ or chemical weapons by the Central Intelligence Agency, and a hardening of socio-political attitudes towards psychoactive drugs.

The research conducted prior to 1970 suggests that psychedelics had therapeutic potential, but a firm conclusion about efficacy and safety was not reached.

4. Modern clinical studies

In 1967, psychedelics were classified under Schedule I of the UN Convention on Drugs, and medical use ceased quickly. Without a clinical focus, research dwindled almost to a standstill in the late 1980s and 1990s.

Three papers in 1998 by Hermle et al., Strassman et al., and Vollenweider et al., formed the basis for a resurgence of studies in healthy volunteers using psychedelics.

A clinical trial was conducted on nine subjects with treatment resistant obsessive compulsive disorder and no other major psychiatric pathology. Significant reductions in OCD symptoms were observed in all dosing conditions, although the trial was likely underpowered to detect an effect.

Matthew Johnson and colleagues gave moderate and high doses of psilocybin to 15 otherwise psychiatrically healthy subjects with tobacco addiction undergoing a structured 15-week smoking cessation treatment. 12 of 15 participants were abstinent from tobacco as measured by biological markers at 6 month follow up.

In a further open-label pilot study, 10 alcohol dependent patients (4 women) were given psilocybin in addition to standard motivational enhancement therapy. They saw large and statistically significant improvements in drinking behaviour immediately after treatment.

Four separate studies have been published on the use of psychedelics in end-of-life anxiety associated with life threatening illness. All four studies observed non-statistically significant trends towards improvements in mood.

Peter Gasser and colleagues gave LSD to 12 patients with anxiety associated with life threatening disease in a double-blind, randomised, active placebo controlled pilot study. The treatment was delivered safely with no serious adverse events.

Stephen Ross and colleagues gave 29 patients a single dose of 0.3 mg/kg psilocybin or 250 mg niacin, both in conjunction with psychotherapy. The group receiving psilocybin showed immediate and sustained reductions in anxiety and depression, with the effect sustained at follow up at 6 and half months.

Roland Griffiths and colleagues gave psilocybin to 51 patients with life threatening cancer and associated anxiety and depressive symptoms. The high dose was superior to the low dose in terms of the primary outcome measures and self-reported measures at 5 weeks.

The effect size of psilocybin in these studies may have been inflated due to the crossover design and psychotherapy provided around the psilocybin experience.

5. Pathways to licensing: modern clinical trials & regulatory frameworks

Clinical trials with investigational medicinal products (IMPs) aim to provide objective data to determine whether the IMP is safe and efficacious enough to justify a license.

A license for an investigational medicinal product (IMP) results from approval from national medicine’s regulatory bodies. The licensing decision is made based on a balanced judgement of the risks and costs of treatment with the IMP weighed against the risks and costs of the disease itself.

In the modern era, clinical trials are divided into phases 1, 2, 3 and 4. Phase 1 trials are open-label and investigate safety in small numbers of healthy human volunteers, phase 2 trials investigate safety and feasibility in modest numbers of patients, and phase 3 trials investigate safety and efficacy in large numbers of patients.

5.1. Safety

To date, 146 patients with psychiatric problems have been treated with psilocybin and no serious adverse events have been reported. A single consolidated database of adverse event information is necessary for regulatory approval of psilocybin for treatment resistant depression.

We have collated the most common immediate and delayed adverse events reported in the literature for psilocybin, ayahuasca and LSD. No cases of prolonged psychosis or hallucinogen persisting perception disorder have been reported in modern trials with these drugs.

5.3. Feasibility and validity of RCTs with psychedelics

The RCT was developed in response to the thalidomide tragedy, however many studies have shown that psychedelics are therapeutic within a psychologically supportive context, rather than therapeutic per se. Therefore, some have argued that RCTs with psychedelics are fundamentally flawed and therefore not feasible.

A large dose of LSD was given to participants before a 3-way interview about their alcohol use, and negative results were reported. However, one pilot study using psilocybin in alcoholism found encouraging results.

The relative contribution of psychedelic and its context to the putative therapeutic effect is difficult to determine, but trials that focus primarily on the drug itself may be of more value.

Although the RCT design is not ideal, carefully designed clinical trials with psychedelics are feasible and valid, although the nature and extent of psychological support provided will attract differing opinions.

5.4. Commercial viability

Phase 2 trials are relatively inexpensive in comparison to phase 3 trials, which often cost millions of dollars. However, the patent on psilocybin has long expired, and there is no commercial potential to incentivise funding for phase 3 trials.

The answer to this question is multi-faceted. A UK based company has announced a multi-center phase 3 trial of psilocybin in 300 patients with treatment resistant depression in Europe, with significant financial backing from investors, suggesting that the commercial potential does exist, at least in principle.

5.5. Schedule I

Schedule I drugs are subject to strict security protocols and must be monitored by closed circuit television at all times. Research groups that have already conducted trials with psilocybin have implemented these requirements and are thus in a good position to conduct further research.

Psilocybin, a Schedule I drug, is being developed for medical use. If efficacy and safety are confirmed, the drug could be rescheduled and become available to medical doctors without the need for a special license.

5.6. Patient groups

If trials using psychedelics are commercially and legally viable, the most logical initial focus is probably unipolar depressive disorder, with treatment resistant depression a priority. Unipolar depressive disorder confers startlingly high socio-economic burden, is under-researched relative to disease burden, and is associated with a 20 fold increased risk of completed suicide.

The largest modern trials of psychedelics have been in psychological distress associated with terminal illnesses. However, evidence of efficacy is still required and funding is not yet clear.

Given the mechanism of action of psychedelics, their potential scope of application could be wide. However, informed consent is required before using psychedelics.

5.7. Practical considerations in clinical trials with psychedelics

While their physiological safety is relatively well established, psychedelics elicit acute sensitivity to context and psychologically toxic reactions do occur. There are practical steps that can be taken to minimise risks in psychedelic trials.

5.7.1. Recruitment

Recruitment in trials of psychiatric disorders is difficult, but can be overcome by using clinical databases of patients that have consented to research contact. However, self-selecting volunteers may be less liable to experience adverse events to psychedelics.

5.7.2. Screening

Clinical trials with psychedelics should include adequate procedures to screen out high risk individuals, including those with serious neurological, renal, liver or cardiac disease. Women who are pregnant, at risk of becoming pregnant or breast feeding should also be excluded.

5.7.3. Concomitant medications

Several commonly prescribed psychiatric medications should be withdrawn prior to use of psychedelics, including fluoxetine, haloperidol, lithium, tricyclic antidepressants, selective serotonergic reuptake inhibitors, and monoamine oxidase inhibitors.

5.7.4. Psychiatric & psychological support

A psychiatrist with an appropriate Schedule I license is required to prescribe and administer the psilocybin and manage other medication, as well as provide assessment and management of mental state and risk during the participant’s journey through the trial.

Participants should be accompanied at all times, preferably by those who provided psychological preparation, and a comfortable, supportive environment with easy access to the lavatory is recommended.

Dysphoria, confusion, anxiety, agitation, panic and paranoia are all expected reactions to psychedelic experiences. Rescue medications are a last resort, given under the supervision of the psychiatrist.

Participants should receive at least one session of psychological support with the therapist that has accompanied them through the trial. This support should be minimal, given the requirements of regulatory bodies.

Ratings of primary outcome measures should be taken by trained raters who are blind to treatment allocation and preferably independent of the trial. Active placebos should be considered, such as subthreshold doses of the investigational drug or a different drug with a similar (but non-therapeutic) psychoactive effect.

6. Conclusions

Psychedelics have a long history of use, but they attract emotive and polarised opinions in modern Western society. They may have a place in the treatment of refractory neurotic disorders.

Modern pilot studies have shown promise, but RCTs with classical psychedelics will need to stand up to the scrutiny of the design, which itself poses significant challenges. If safety and efficacy is confirmed, licensing and rescheduling will likely follow.

Funding

This study was part-funded by the National Institute for Health Research (NIHR) and King’s College London. The views expressed are those of the authors.