Psychedelics in the treatment of unipolar mood disorders: a systematic review

This meta-analysis (n=423) of studies before prohibition (1949-73) of treating unipolar mood disorders (depression) showed that, besides the many flaws of the studies, the results were positive (79% of participants showed improvements, few side-effects).

Abstract

“Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. They are relatively safe when used in medically controlled environments, with no reported risk of dependence. Here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined UMD, and consider their place in psychiatry. Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. A recently completed pilot study in the UK favours the use of psilocybin with psychological support in treatment resistant depressive disorder. The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.”

Authors: James J. H. Rucker, Luke A. Jelen, Sarah Flynn, Kyle D. Frowde & Allan H. Young

Notes

This paper is included in our ‘Top 10 Articles on Psychedelics in the Treatment of Depression‘

“A total of 21 studies published between 1949 and 1973 were included. LSD was, by far, the most commonly used psychedelic. Mescaline was occasionally used. The absence of psilocybin is discussed below. The sample size ranged from 5 to 77, with a total aggregated sample size of 423 across all the studies where this was clearly defined. The number of psychedelic sessions ranged from 1 to 58 and the therapeutic paradigms applied were variable. The dose of LSD used ranged from 20 to 1500 µg. Mescaline was used at doses of 200–400 mg, in combination with LSD. Many studies used titrated dosing schedules that took account of individual patient responses to the drug.”

Of the studies, only four had any control group, of which – the authors argue – only one was representative.

In the discussion the authors make an interesting observation about the use of LSD (pre-prohibition) and now psilocybin. Where in the second half of the 20th century clinicians wanted to stick to what they knew (LSD), nowadays the social stigma of this substance is partially responsible for the popularity of psilocybin in study protocols. The duration of LSD (requiring an overnight stay) and possibly larger change of negative effects are also mentioned as reasons for the switch of preference.

“There is a pressing economic need for such interventions. Unipolar depressive disorder costs the United States alone over US$210 billion annually (Greenberg et al., 2015). Response to treatment is often suboptimal and entrenched, maladaptive patterns of thought, feeling and behaviour are the hallmark of resistance to treatment. Whilst long, detailed forms of dynamic, analytical and behavioural psychotherapy may change such patterns over the course of years, they are expensive and time consuming. Psychedelic therapy may represent a form of catalysed psychotherapy whereby the drug acts to hasten the breakdown of habitual maladaptive templates of thinking and behaviour in supportive therapeutic environments. The evidence from the pre-prohibition literature, whilst unsystematic and methodologically suboptimal, suggests that this is worth re-investigating.”

This paper provides a reflection on the earlier research in regards to depression and in its conclusion highlights why it’s relevant to study it within our modern context.

Summary

Introduction

Unipolar mood disorders (UMD) include major depressive disorder (MDD) and persistent depressive disorder (PDD), which are common psychiatric disorders associated with high morbidity, high socio-economic burden and high rates of completed suicide. UMDs are frequently recurrent and often unremitting, and 80% of patients will have another episode. There are few novel agents in development and many pharmaceutical companies have ended research efforts into psychiatric disorders, leading some to look to history for inspiration.

Recently, has been investigated as an antidepressant, but the effects are transient, and the drug has a potential for abuse.

Psychedelic compounds, such as LSD and psilocybin, were used and researched extensively in psychiatry before legal prohibition in 1967. They were initially noted to induce a temporary state of mind that was not dissimilar to psychosis.

Psychedelic drugs were used extensively in the treatment of mood disorders, including major depressive disorder and persistent depressive disorder, before their prohibition in the late 1960s. A systematic review of published clinical treatment studies using psychedelics in patients with broadly defined unipolar mood disorders shows promising results.

Psychedelics have been used in therapeutically supportive settings to treat neuroses, alcoholism, and the physical and existential pains experienced with terminal cancer. The quality of many studies was suboptimal by modern standards, with the best quality research found in alcoholism.

The demonization of psychedelics in the 1960s and 1970s was accompanied by medical concern for the occasionally harmful sequelae of recreational use in psychologically destabilizing environments. However, modern population studies have associated their use with a lower incidence of mental health problems.

There has been an upsurge in interest in the mechanism of action of psychedelics and their therapeutic utility in a broad range of mental health problems, including unipolar mood disorder. The reviews of Nichols are particularly comprehensive.

Contemporary depressive disorder with co-morbid anxiety, as well as disorders grouped under the old-fashioned terms ‘neurotic’ and ‘psychoneurotic’ disorders are described.

Methods

The PsycINFO and MEDLINE databases were searched using the terms LSD, lysergic acid diethylamide, psychedelic or hallucinogen and therapy, psychotherapy or treatment. A total of 2303 papers were identified, of which 109 were screened in more detail for eligibility.

Search results were screened to identify clinical studies referring to the use of LSD in the treatment of ‘Depressive’, ‘Neurotic’ and ‘Psychoneurotic’ patients.

Description of studies

LSD was first used as an antidepressant in 1949, but the results were not convincing. Savage reported that 3 patients recovered fully and 4 others improved after 1 month of treatment.

Busch and Johnson (1950) used LSD as an adjunct to traditional psychotherapy on five psychoneurotic patients, with two of the patients improving sufficiently to discontinue treatment.

Sandison and colleagues treated 36 patients with psychoneuroses in a hospital setting with periodic low dose use of LSD combined with psychotherapy. 12 patients recovered and 15 others showed some degree of improvement.

This team published a subsequent paper 3 years later with further results from 100 patients that had been treated to date. They concluded that LSD appears to be of ‘utmost value in psychotherapy’.

Sloane and Lovett Doust administered LSD to 11 healthy controls, 12 patients with predominant depression and 7 patients with schizophrenia.

Langner and Kemp give a brief report on their results of over 500 LSD psychoanalytic treatment sessions in 40 patients.

Martin describes promising results from the use of LSD in the treatment of chronic psychoneurotic disorders under day-patient conditions. The authors note that some patients became more readily ‘accessible’ under LSD and suggest that its therapeutic effect is due in part to the reliving of early experiences and release of repressed feelings.

Lewis and Sloane reported no better results than other treatments with LSD in a group of 23 psychiatric inpatients, but Eisner and Cohen reported better results with LSD in 22 patients suffering from depressive reactions.

Chandler and Hartman report on their work with 110 patients in whom LSD was utilized as part of their treatment. The authors report that 80% of patients showed improvement, and that only three patients did not show improvement.

Maclean and colleagues used a different therapeutic method, the ‘psychedelic’ approach, in the treatment of 100 patients. This method involved administering larger doses of LSD in a one-off session.

Sherwood and colleagues administered simultaneous doses of LSD and mescaline to 25 patients with various problems, and found improvement in 84% of the cases, but specifically in 4 out of 7 patients with neuroses.

A method of LSD treatment for neurotic disorders is described by Martin, who reports impressive results in 95% of patients receiving weekly analysis for an average of 20 sessions.

Geert-Jörgensen et al. (1964) report a total improvement rate of 55% in 129 patients treated with LSD, increasing to 68% in 19 out of 28 patients.

Whitaker describes his findings in the use of LSD in psychotherapy in 100 patients, where 47% of cases were successful, 18% were borderline successful and 35% were failures. In the control group only 12% of cases were successful, 30% were borderline successful and 58% were failures.

Baker and Leuner found similar effective results using LSD in the treatment of depressive patient groups.

The largest studies of psychedelic drugs and psychotherapy were carried out at Spring Grove State Hospital and the Maryland Psychiatric Research Center. Following a period of extensive preparation involving weekly interviews for 4 – 8 weeks, patients would undergo a single high-dose ‘psychedelic’ session. The authors report improvement in 80% of patients following an evaluation at 6 months.

A study at the Spring Grove State Hospital investigated the effects of LSD-assisted psychotherapy on 96 patients with severe chronic neuroses. The study found that high-dose LSD treatment was superior to conventional treatment in 19 out of 50 test variables.

Discussion

We have collated and summarized 21 studies published between 1949 and 1973 on the use of psychedelics in the treatment of broadly defined UMD. LSD was the most commonly used psychedelic, with mescaline being used occasionally.

In the pre-prohibition studies of psychedelics, only 4 studies mention a control group, and in only 1 study could the control group be deemed to be adequately selected and described. The outcome measures were generally so vague that the only meaningful grouping was a dichotomous variable reflecting those who were felt to have improved.

In an attempt to delineate classical depressive disorders from wider clinical definitions of ‘anxiety’ and ‘neurotic’ disorders, we repeated this analysis restricted to cases classified as ‘depressives,’ ‘depressive reactions,’ and ‘depressive neuroses,’ where this was specified. The degree of improvement is notable even if the presumption must be that it is biased in favour of a therapeutic effect.

Modern trial designs for psychedelics are problematic because they attempt to isolate the drug from variables such as psychological state and setting, and because patients diagnosed with UMDs have a wide variety of factors contributing to their clinical picture.

In a randomized, double blind trial using psilocybin in psychedelic-nave volunteers over two or three sessions to investigate mystical experiences, 23% of sessions were misclassified as psilocybin or methylphenidate. However, when psilocybin was given but the clinician did not accurately guess this, most participants still reported deeply meaningful, mystical experiences. A study in 1973 by Savage et al. partially implemented a design strategy of randomising patients between low and high doses of psychedelic, and showed that high dose LSD was superior to conventional treatment.

Attempts to standardize the context of the psychedelic experience are possible in controlled trials, but a significant degree of variation is unavoidable. Defined training programs in psychedelic research and psychotherapy are now being set up to provide some structure, but a raft of questions remain to be answered.

Carefully designed clinical trials that incorporate biological mechanism studies may help resolve some questions about the use of psychedelics. If the two paradigms appear mechanistically distinct, they may have different therapeutic efficacies in different disorders and, perhaps, different personality types.

In summary, psychedelics studies require a careful balance between the needs of the participants and the needs of the trial. Funders and research ethics committees need to understand the inherent difficulties discussed above, and trial designers need to be explicit about the environmental and psychotherapeutic milieu.

Psilocybin was marketed under the trade name ‘Indocybin’ by the same pharmaceutical company that marketed LSD. It was not used in clinical trials for broadly defined mood disorder, and is favoured over LSD because of its shorter duration of action and less liable to occasion highly distressing psychological reactions.

Psychedelic drugs are safe to use in medical and recreational settings. Their toxicity ratio is 1000 or more compared to alcohol, cocaine, ketamine and fluoxetine.

Recreational use of psychedelics is generally safe, but prolonged psychotic reactions are reported by 1.3% of LSD users and 1.6% of psilocybin users in a web-based self-report questionnaire. Three large population studies have found that psychedelic use is associated with a lower relative risk of suicide, need for psychiatric medication and psychological distress, and recidivism.

Cohen noted one case of prolonged psychosis in 1200 participants, and Savage et al. (1973) noted two cases of psychosis in 500 participants. The first two participants would have been excluded from participation in modern trials, whilst the third would not have.

While the research on psychedelics is certainly worth repetition, the evidence suggests that the risks associated with medically controlled and supervised use of psychedelics are low and that evidence-based guidelines improve safety even further.

A pilot study in the United Kingdom of psilocybin in the treatment of resistant MDD was completed with good results.

If psychedelic psychotherapy can help resolve unresolved traumas and emotional conflicts from the past, it can help some patients with UMD.

There is a pressing economic need for such interventions, as unipolar depressive disorder costs the United States alone over US$210 billion annually. Psychedelic therapy may represent a form of catalysed psychotherapy, whereby the drug acts to hasten the breakdown of habitual maladaptive templates of thinking and behaviour.