By Caroline Hayes
The psychedelic renaissance is well underway, with hundreds of clinical trials currently looking into a plethora of different mental health conditions. I was a sub-investigator on a clinical trial researching a psychedelic study drug to treat depression, but I have since stepped back from psychedelic clinical trials due to personal ethical concerns about the way the field is evolving. Despite the seemingly boundless optimism for their potential as pharmacological treatments, there are a number of unique issues that psychedelics present in a clinical setting that are yet to be adequately addressed. I believe it is essential that these issues are rectified to minimize the potential harm to those desperately seeking relief from their mood symptoms.
The methodology of current clinical psychedelic research seems particularly vulnerable to bias. Many subjects self-refer into trials having seen the extensive positive coverage in the lay media. Although this may help with recruitment, it can have a problematic effect on the data. Participants attend with a firm set of expectations about the study drug and the impact it will have, often pinning all their hopes on it alleviating symptoms that have caused suffering for many years. This creates an expectancy bias, which means that there is an inflated difference between the relative treatment effects of the active and the placebo arms. This is not helped by the inherent difficulty in blinding psychedelics. This may have the overall effect of making the study drug seem more effective in the trial data than it may be in practice.
Further, there is a striking lack of diversity among subjects partaking in psychedelic clinical trials. In the vast majority (70.6%) of psilocybin trials, 75% of participants were white, and have been described as “mainly Caucasian, highly educated living in major urban centers with access to tertiary medical care.” The promising results lauded by both the media and sponsors of clinical trials simply may not apply to a more diverse population. This may well be of clinical significance to the target population of patients with difficult-to-treat depression, given that the condition is associated with lower socio-economic status. Although lack of diversity in clinical trials is an issue in other fields, it is particularly pertinent to psychedelics, as psychedelic experiences can be both deeply personal and culturally specific. This lack of diversity can perpetuate mistrust of medical institutions by minority groups. We must also consider whether or not there is actually much interest in psychedelics as pharmacological treatments in the broader population, especially if they are not already participating in clinical trials.
The theme of perpetuating mistrust is also relevant when considering the complex issue of informed consent in psychedelic research. One of the founding principles of research ethics, informed consent requires participants in clinical trials have a full understanding of what it is they are agreeing to. The main barrier to the informed consent process involves the mystical experience, which is often associated with the psychedelic experience and tied to clinical outcomes. The Mystical Experiences Questionnaire (MEQ30) that is used in psychedelic clinical trials boils this historically and culturally ubiquitous human experience down to four domains. These are: a sense of unity with all that exists, a sense of sacredness, noetic quality; deeply felt positive mood; transcendence of time and space; and ineffability. It is the ineffability, or inability to put the experience into words, that presents the issue for informed consent. If I as the clinician consenting a participant cannot fully convey the backbone of the psychedelic experience in words, then how can I possibly get consent that meets the robust medico-legal standard? Consent is even more of an issue in the clinical setting than in the naturalistic setting due to the asymmetry in the relationship between doctor and patient, and people who just want some relief from their symptoms are all too ready to accept something that they are told may help from someone in a position of trust.
Perhaps the most concerning issue bubbling to the surface is that of suicidality. In the recent Compass Pathways study looking at psilocybin for treatment-resistant depression, there were 3 patients in the group receiving the highest dose (n=79), 25mg, who reported suicidal behavior and were classified as “non-responders” to treatment. There was no suicidal behavior in either the 1mg (n=79) or the 10mg (n=75) groups. This is concerning to see in subjects who have been heavily screened to minimize such outcomes. As a result, we have to ask whether this rate would increase in an unscreened population. It is disingenuous to label these participants as “non-responders,” as they have certainly responded to the study drug, just not in a positive manner. In these cases, was the so-called “pearl of wisdom” that the participants found during their journey too much to bear? It seems naïve to assume that new insights will always be helpful and easily integrated. In order to ascertain the cause of distress in these cases, clinical trials need to start collecting more qualitative data on participants’ experiences to see if there are any similarities in those who go on to display suicidal behavior. Future participants should also be adequately counseled around the risk of destabilization of their condition and potential for increase in suicidality.
Even if participants feel that psychedelics have had a positive effect on their mental health, they may find that this effect is much more short-lived than they were led to believe. Good mental health isn’t just a headspace, but — additionally — a reflection of lifestyle and socioeconomic conditions. Psychedelics aim to provide rapid relief of symptoms that may have been present in some for many years. This rapid change means that people may not have the time to make the requisite lifestyle changes, such as regular exercise and a consistent sleep routine, to maintain the positive impact. This means participants could return to being depressed relatively soon after dosing. The process of getting better and unwell again quickly can be very traumatic and destabilizing for participants, and raises the question of whether it would have been less distressing to have had no intervention at all.
Psychedelics still have a long way to go before becoming accepted treatments for mental health conditions, and it remains to be seen whether they will live up to the brouhaha and find a role in psychiatric care. Upcoming phase three trials have a responsibility to address these issues to ensure minimal harm to research participants and potential future patients.
Caroline Hayes is a physician-researcher at the Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust.
