Historic psychedelic drug trials and the treatment of anxiety disorders

This meta-review (2019) examined the efficacy of psychedelics combined with therapy for the treatment of anxiety disorders, across twenty studies conducted between 1940 to 2000. The review outlines individual aspects of their design, assessment methodology, and notable shortcomings, such as the lack of randomized control designs and overreliance on the therapists’ opinion. The large majority of patients of these studies exhibited improved symptoms over the course of treatment with psychedelic-assisted therapy.

Abstract

Introduction: In this paper, we systematically review literature from 1940 to 2000 relating to the combined use of psychological therapies and psychedelic drugs in the treatment of ICD‐10 anxiety disorders.

Methods: The databases Ovid MEDLINE(R), PsycINFO, and Multidisciplinary Association for Psychedelic Studies (MAPS) were searched for case reports and trials involving humans in the treatment of ICD‐10 anxiety and related disorders. Twenty‐four studies are described; four describe anxiety symptoms in diverse patient groups, 14 studies describe historic diagnoses that usefully correspond with ICD‐10 anxiety disorders, six studies pooled results or failed to detail results specific to contemporary ICD‐10 anxiety disorders. Two of the 24 studies reported are individual case reports while two of them were inadequate in terms of the reporting of outcome measures. Thus 20 studies were ultimately included in the summary analysis.

Results: Three of the 20 studies reviewed described improvements in anxiety by standardized measures (p < .05) and two studies found that this effect was dose related. Of the 20 studies included in the final analysis, 94 of 145 (65%) cases of “psychoneurotic anxiety reaction” as defined by Diagnostic and Statistical Manual of Mental Disorders‐I showed improvement that ranged from moderate improvement to full recovery. Despite methodological inadequacies, the results from previous studies are encouraging and should be used to guide and inform further investigation.

Conclusion: The majority of studies indicate that a combination of psychedelic drug administration and psychological therapy was most beneficial. We found no study suggesting that the pharmacological action of psychedelic drugs in isolation is sufficient.”

Authors: Neil M. Weston, Damian Gibbs, Catherine I. V. Bird, Aster Daniel, Luke A. Jelen, Gemma Knight, David Goldsmith, Allan H. Young & James J. Rucker

Summary

In this paper, we review literature on the combined use of psychological therapies and psychedelic drugs for anxiety disorders.

Twenty four studies are described, including four case reports, 14 historic diagnoses, six pooled results, and two inadequate in terms of the reporting of outcome measures.

Three of 20 studies reviewed found improvements in anxiety by standardized measures, and two studies found that this effect was dose related. Despite methodological inadequacies, the results from previous studies are encouraging.

sufficient.

1 | INTRODUCTION

The classical psychedelics comprise three main chemical classes: organic tryptamines, phenethylamines, and semisynthetic ergolines. The prototypic “psychedelic experience” arises from agonism at the serotonin 2A receptor subtype (5HT2AR).

Studies on the safety and therapeutic potential of psychedelics suggest that they may impact on depressive symptoms as well as anxiety associated with lifethreatening diseases.

ICD10 describes phobic and “other anxiety disorders” under “neurotic, stress related, and somatoform disorders”. Despite significant prevalence, many go undetected and those identified receive far less attention than other areas of mental health.

Patients with anxiety disorders experience substantial physical and emotional discomfort, functional impairment, reduced work productivity, elevated rates of substance use and medical illnesses, and lifelong symptoms. The natural course of anxiety states is unfavorable, with complete recovery occurring in 12 – 25% of cases.

The chronic and disabling course of anxiety disorders is associated with substantial economic and social cost, primarily arising from premature mortality, unemployment, and reduced productivity.

2 | METHODS

We searched historic publications for studies describing the use of psychedelic drugs in the treatment of anxiety disorders. We considered how to fit older diagnostic labels to the present day classification of anxiety disorders.

Although not discussed explicitly in DSMI, panic symptoms were described in DSMII under the term “anxiety neurosis”, and were frequently associated with somatic symptoms.

Four authors searched Ovid MEDLINE and PsycINFO for articles on LSD, psychedelics, hallucinogens, mescaline, peyote, DMT, dimethyltryptamine, ayahuasca, psilocybin, and therapy or psychotherapy for anxiety disorders. They selected 1,667 articles and manually searched 5,402 entries.

Twenty-four studies were eligible for inclusion in this textual narrative synthesis, which was guided by the principles of quality assessment in qualitative studies and recommendations of the Strengthening The Reporting of Observational Studies in Epidemiology (STROBE) initiative.

3 | RESULTS

A total of 24 studies published between 1940 and 2000 were included. Three studies found a significant reduction in anxiety symptom measures following LSDassisted psychotherapy from a combined cohort of 95 patients, and a dose dependent reaction was seen in these studies with the exception of Soskin (1973).

Studies in the first grouping demonstrate consistent psychological screening and preparation for the therapy.

Previous investigation found that most wellestablished selfreport measures of neuroticism or anxiety will have correlations of >0.5. The correlation between the Minnesota Multiphasic Personality Inventory and Beck Anxiety Inventory is .72, and the correlation between the EPI Neuroticism score and the Taylor Manifest Anxiety Scale is .79.

A total of 14 studies are described, including extended case series, individual case studies, and reviews. The outcomes ranged from “worse” to “recovered” for the various clinician rated outcome scales used across these studies.

Six studies are described, of which one is an individual case study. The results from the questionnaire in Johnsen (1964) and Madsen, ysleb, and Hoffart (1996) are reported some 17 years after treatment administration and thus are not included in the summary analysis due to the likelihood of misreporting and bias.

Across three groups, anxiety, depressive and phobic reactions achieved better mean improvements than obsessive or phobic reactions. The most frequently used psychedelic was LSD.

In two studies, a single large dose of psychedelic without associated psychotherapy was used to bring about psychological change following a single “transcendental experience”. Antipsychotics and barbiturates were used to help terminate the drug effect.

Across all studies, few phobic patients were included, despite greater prevalence of specific phobias in modern epidemiological studies. The combined results from this review also suggest that generalized anxiety may be more amenable to psychedelic therapy.

4 | DISCUSSION

Previous research into the effects of psychedelic drugs has been extensive, however, most studies did not follow methodology that would be considered rigorous by today’s standards.

Modern clinical trials use randomization to placebo and blinding both assessor and participants to the intervention to achieve rigor. However, these design strategies are incompatible with psychedelic research due to the subjective and objective behavioral effects of these compounds being transparent to those familiar. Rucker, Jelen, Flynn, Frowde, and Young (2016) suggested randomization between doses of psychedelic to mitigate the difficulties in blinding and randomization against controls.

In the majority of studies, psychedelic drugs were paired with psychological therapy. The therapist’s input was crucial to the treatment process, and none of the authors suggest that the positive therapeutic effect can be solely attributed to the pharmacological action of the psychedelic.

Mascher reports 62.5% success with paradigm 3, 56% with paradigm 1, 2 and 4, and 40% with paradigm 5.

The importance of psychotherapy to the treatment process extends beyond the dosing session. The psychological state and the interpersonal and physical setting within which the drug is experienced are important factors in the therapeutic effect.

Although outside the scope of this paper, we felt it important to highlight the patient narrative. This narrative describes a psychedelic experience that facilitates vivid recovery of early memories.

We note important described adverse events, such as a transient psychosis and a manic reaction, but most of these events were not reported systematically, if at all. However, modern psychedelic drug trials do not point towards frequent occurrence of concerning adverse events.

5 | CONCLUSION

Psychological therapies have some success in the treatment of anxiety disorders, but are often lengthy and expensive. LSD therapy has the potential to facilitate improvement of anxiety symptoms and disorders.

6 | LIMITATIONS

The quality of qualitative studies was assessed using Pope et al. (2000) and STROBE initiative recommendations, but few studies fit the requisite RCT design.

CONFLICT OF INTERESTS

King’s College London receives grant funding for phase 1 and 2 trials with psilocybin from COMPASS Pathways Ltd, and Allan Young receives research funding from the National Institute for Health Research.

Robinson et al. (1963)

Robinson et al report on a RCT conducted at Roffey Park Hospital, a community focused facility for inpatient treatment of those suffering from psychoneurosis. They found that individuals with anxiety prone personalities improved more so than those with dependent personalities after LSD therapy.

Hausner and Dolezal (1966)

Hausner and Dolezal conducted a nonrandomized, non blinded placebocontrolled trial in a therapeutic community, hypothesizing that LSD therapy would accelerate individual and group psychotherapy. They found that patients receiving LSD therapy had a significant improvement in N5 neuroticism score at 1 year post dosing.

Soskin (1973)

In a double blind, placebocontrolled study conducted at Topeka Veteran’s Administration Hospital, Kansas, A Soskin (1973) investigated the use of LSD as an aid to psychotherapy. Both groups showed a significant improvement in anxiety (p .01) as measured by the Wittenborn Psychiatric Scales (WPRS).

Savage et al. (1973)

Savage et al. (1973) reported on a study involving 96 patients with a psychoneurotic diagnosis that compared the overall efficacy and dose response for LSD augmented psychotherapy against conventional treatment.

All forms of treatment reduced anxiety symptoms, but highdose LSD subjects showed a significantly lower reduction than those receiving group therapy. Low dose LSD subjects also showed a significant reduction versus group therapy subjects.

Sandison and Whitelaw (1957)

Sandison and Whitelaw (1957) follow up on their paper from 1954 by including data from 58 patients introduced to psycholytic therapy with LSD. Of those with a diagnosis of Primary Anxiety neurosis, 17 showed a moderate or significant improvement while five did not improve.

Martin (1957) conducted an open label case series at the Marlborough Day Hospital with the aim of assessing the utility of LSD in chronic psychoneurotic disorders. Nine patients relapsed, mostly from the chronic tension class, 2 years after the treatment.

Eisner and Cohen (1958)

Eisner and Cohen tested whether a short series of LSD treatments combined with psychotherapy could create positive change inpatients with neurotic and/or character diagnoses.

In 1960, Ling and Buckman used LSD in psychotherapy with the hope that this might expedite the psychotherapeutic process. 27 out of 39 patients improved, with some returning to work and functioning at a higher level than before illness onset.

Chandler and Hartman (1960)

Chandler and Hartman (1960) conducted LSD therapy on 110 patients, with a mean improvement score of 2.5 for anxiety reactions and 0.7 for phobic reactions. Proper preparation was essential, and a lack of preparation had the effect of slowing down therapy.

MacLean, MacDonald, Byrne, and Hubbard (1961)

MacLean, MacDonald, Byrne, and Hubbard (1961) administered a single high dose of 4001,500 g LSD25 to 100 patients, including 61 alcoholics and 39 patients with other psychiatric conditions. Of those 23 patients with a previous anxiety reaction, 15 were much improved, 7 improved, and 1 exhibited no change.

Sherwood et al. (1962)

Sherwood et al. (1962) administered massive doses of LSD and mescaline in an open label trial, and found that of those diagnosed with anxiety neurosis both were much improved. However, one in five patients suffered from difficult experiences, including paranoia, hostility, and schizophrenic like reactions.

Ling and Buckman (1963) (individual case report)

Ling and Buckman reported on a case of severe phobic anxiety that was completely resolved after 3 weekly sessions using LSD and methylphenidate.

In 1964, Whitaker conducted an open label controlled trial to assess whether the results of psychotherapy were significantly improved by the use of LSD as an adjunct. One hundred patients, 51 male and 49 females, were selected, and LSD was given by intramuscular injection or intravenous injection together with 200 mg of nicotinic acid by mouth.

Six patients with anxiety states and four patients with phobic reactions received psychotherapy between LSD sessions. Two patients recovered, two were much improved, and one had doubtful improvement.

Costello (1964)

Costello reported on three patients with pervasive anxiety and depression and anxiety following three sessions psycholytic therapy with LSD and 100 mg of Sparine (promazine) intramuscularly. One patient made a full recovery.

Solursh (1966)

Psychoneurotic patients were treated with LSD and methamphetamine at Toronto Western Hospital. Two patients with anxiety reaction made some improvement, one patient with phobic reaction was unchanged and another was improved.

Martin describes 60 patients undergoing weekly LSD sessions with an unknown dose. One patient made a full recovery from psychoneurotic anxiety state.

In 1967, Edward Baker published the results of an open label case series using 100 – 2,000 g of LSD in 150 “functioning” nonpsychotic psychiatric inpatients. One patient was unimproved, two showed some improvement, and one made definite improvement.

Savage et al. (1968)

In 1968, Savage et al. reported on an uncontrolled, open label study with a single large dose of LSD without conventional interpretive psychotherapy. Two hundred forty three patients took part in the study, and 19 showed no improvement, seven express some improvement, nine substantial improvement and two marked improvement.

Lewis and Sloane (1958)

Inspired by the work of Sandison et al. and Sandison and Whitelaw, 23 patients were treated with LSD psycholytic therapy. Of those treated, at least six improved after treatment.

Geert‐Jörgensen, Hertz, Knudsen, and Kristensen (1964)

In 1964 and 1968, GeertJörgensen et al. used LSD with inpatients and outpatients at the Frederiksberg Hospital in Denmark. Nineteen patients improved, six remained unchanged or had deteriorated, and two completed suicides were noted.

Johnsen (1964); Madsen et al. (1996)

Gorden Johnsen treated 379 patients with LSD, psilocybin and CZ 74 at Modum Bads Nerve Sanatorium in Norway between 1961 and 1979. Patients were required to attend several assessments and preparatory sessions.

Madsen et al. (1996)

Madsen et al. followed up on the cohort studied by Johnsen in 1964, sending the patients a questionnaire. 15 out of 24 patients with obsessive neuroses answered unequivocally yes, and 13 were still well after receiving an average of 20 treatments.

Vanggaard (1964)

Thorkil Vanggaard reports on a series of open label LSD treatments at Powick Hospital England where 24 inpatients were selected at random. One patient recovered and the other was greatly improved after receiving LSD.

Leuner (1967)

Hanscarl Leuner studied 82 patients with severe and chronic psychiatric disorders over 8 years, using 30 – 200 g of LSD and other psychedelic drugs in psycholytic therapy. Two patients recovered and were able to work, 10 were greatly improved and able to work, 3 moderately improved but unable to work.

Brandrup and Vanggaard (1977) (individual case study)

A 30yearold man with “incapacitating compulsiveneurotic condition” was treated with a weekly dose of 100 g of LSD for 57 weeks. After 4.5 months, symptoms and avoidance reduced.

Study details

Topics studied
Anxiety

Study characteristics
Meta-Analysis Literature Review

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