The prospect of using psychedelic drugs to treat people with psychiatric disorders has generated understandable excitement among mental-health professionals and the public alike. Early reports that people with severe treatment-resistant depression responded to psychedelic treatment, for example, created momentum for controlled clinical trials to definitively establish therapeutic efficacy. As those trials are planned, however, it will be crucial for their designers to anticipate how psychedelics are likely to be used in clinical treatment.

Studies of psychedelic treatment, as one review noted1, have been based on data from “highly screened research populations, which exclude many individuals potentially at increased risk for adverse outcomes”. The only randomized controlled trial so far to compare a psychedelic (in this case, psilocybin) with a standard antidepressant demonstrates the problem. Among the exclusion criteria for the study were a personal or family history of psychosis, a history of mania, a previous serious suicide attempt requiring hospitalization, and the suspected or known presence of a pre-existing psychiatric condition, such as borderline personality disorder, that could jeopardize the rapport with the therapy team2.

It is difficult to fault the investigators for this, because caution is warranted in the initial studies of any new medication. It seems prudent to exclude people with personal histories of psychosis and mania from trials of a drug that mimics the symptoms of psychosis.

The problem is that in the real world of psychiatric treatment, people with characteristics that would have excluded them from the psilocybin trial are common. People with major depression are roughly twice as likely as the general public to have a sibling with the same condition, or with schizophrenia or bipolar disorder3. According to one large meta-analysis, 31% of people with major depression attempt suicide at some point in their life4. A national epidemiological survey in the United States found an 11.5% lifetime prevalence of borderline personality disorder among people with major depression5. Another large study found that more than 80% of people with borderline personality disorder also had major depression6.

Clearly, if the only data continue to come from clinical trials with such stringent exclusion criteria, we will not learn whether people with these conditions are as likely to respond to psychedelic treatment as other people, or whether they are more or less likely to suffer adverse effects. Moreover, some of the people in these groups are those in greatest need of innovative treatments. A previous suicide attempt is one of the strongest predictors of future suicide7, so effective treatment of the psychiatric disorder underlying the attempt — with depression being the most common — is an essential public-health priority.

Restrictive entry criteria are not unique to psychedelic studies; this is a problem affecting all sorts of medication trials. However, continuing to exclude groups that are highly likely to seek treatment with psychedelics, should they be approved for clinical use, will leave physicians flying blind when these people turn up in the clinic. Once regulatory authorities approve the clinical use of psychedelic medicines, the incentive for pharmaceutical companies to sponsor trials with groups that are perceived as higher risk will plummet. It is therefore crucial that before psychedelics are authorized for clinical use, exclusion criteria are modified so clinical trials can offer guidance on how people in these groups are likely to fare.

Exclusion criteria are not the only problematic aspect of clinical trials of psychedelics, however. Another is the psychotherapeutic component of the treatment, which is currently variable, time-consuming and extensive. In the psilocybin trial mentioned above2, two therapists were assigned to each participant in the trial, and held preparatory sessions, further sessions after the drug was administered, and a series of follow-up calls by phone or videoconference to ensure their welfare. These components took up to 20 hours from each of two therapists.

Given the costs associated with such extensive use of trained therapists, it seems unlikely that this regimen will be followed in full at most clinical sites if the psychedelics are approved. Whoever pays for the treatment, be they health insurers, health services or patients, will need to know that this protocol is an essential part of the treatment process, or they might seek less-intensive and less-expensive alternatives.

Researchers who run clinical trials might see such extensive care as helping to maximize the likelihood of finding positive outcomes. However, it is incumbent on the field to identify the components that are truly essential to the success of the treatment.

Research into psychedelics for psychiatric indications is still at an early stage. The total number of participants in these studies is small, and comparative efficacy versus conventional treatments for depression remains to be established1. Now is the time to build into ongoing research the real-world questions that will suddenly become pressing if clinical use is authorized.

Competing Interests

The author declares no competing interests.



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