Delivering Effective Psychedelic Clinical Trials: Overcoming Challenges for Meaningful Outcomes
The field of psychedelic research is progressing apace. As we start to discern the signal from the noise, and as various jurisdiction move towards licensing these drugs for use in the treatment of mental ill-health, it is more important than ever to redouble our efforts towards thoughtful, careful research that addresses the validity threats that affect research into psychedelic treatments.
Research into many treatments for mental ill-health, including psychedelics, psychotherapy, and exercise, will suffer from challenges related to internal and external validity unless designed in such a way as to mitigate the risks. Psychedelic research can learn much from other fields and other professional and scientific groups.
Internal Validity & External Validity
Blinding and the ‘disappointment’ factor
A primary concern in psychedelic clinical trials is maintaining blinding - the ability to prevent participants and researchers from knowing who receives the active treatment versus a placebo. There are many reasons why unblinding may invalidate the results of a study. In psychedelic trials, just as in studies of psychotherapy or exercise, blinding is extraordinarily challenging due to the dramatic subjective effects of these drugs, effects which are thought to be causally important in their effect. Clinicians who know or believe that participants have taken active compound may treat those participants differently. Participants who know or believe that they have received active compound are highly likely to respond differently to those who believe they have received placebo.
The hype and expectation surrounding psychedelics probably exacerbates the dynamics described above considerably. In any study where the comparator arm is ‘disappointing’ - for example waitlist in psychotherapy research – the effects of the active treatment arm are inflated. Open-label extensions are now commonly used to address this ‘disappointment’ factor. In studies of groups of people with a label of ‘treatment-resistant depression’ or similar groups where a criterion for inclusion is a history of failed treatments, participants may feel that they have tried everything
To mitigate these issues, researchers should deploy methods for maintaining blinding and managing participants' expectations, such as using active placebos, variable dosing regimens, recruiting from a more representative pool, by comparing to other treatments known to be effective instead of using placebo, or using smaller doses in the comparator arm. Blinding questionnaires, which ask participants which arm they believe they are in, and expectancy questionnaires, which ask participants how likely they think the active treatment is to help, are increasingly common and assist in analysis of how much expectancy and functional unblinding affects results, but do not change the relative effect of active compound versus placebo.
External Validity
38% of clinical research studies in mental health close early because they are unable to reach their target number of participants. Psychedelics may additionally suffer from the stigma of being controlled substances, and the typical indications – mental health problems – can make participation challenging for participants. The sometimes intrusive nature of screening and ongoing assessment can be exposing and upsetting which can further increase the difficulty of participant selection. Burdensome study schedules can also make it difficult for study participants to manage and balance with other personal and professional commitments.
Phase II and III psychiatric trials often have strict eligibility criteria, often requiring multiple failed treatments attempts, restrictions on comorbidity (which is the rule in mental disorders), severity, and exclusions regarding concurrent treatments. For example, most people with a history of depression are taking antidepressant medication which is usually exclusionary in psychedelic trials. In fact, up to 90% of those diagnosed with depression will be excluded from clinical trials. These exclusions are designed to minimize risk but also limit the applicability of the findings to broader populations. In Phase II studies, participant recruitment is very specific, whereas Phase III studies tend to be more inclusive. As evidence on safety grows, we hope that psychedelic treatment admission criteria will become more relaxed.
Therapeutic Components and The Role of the Therapist
Clerkenwell Health is currently delivering six trials of psychedelics and related medications, and four more are planned in the coming months. These studies are investigating treatments for multiple indications including alcohol use, depression, bipolar II disorder, postnatal depression, and chronic pain. We are investigating a range of compounds, both with and without psychotherapeutic intervention, such as methylone, psilocybin, 5-MeO-DMT, LSD, and others.
The duration and degree of therapeutic involvement varies greatly across studies. Some involve only a few hours of preparation and integration sessions, while some involve dozens of hours of psychotherapy. For instance, PTSD treatments may involve multiple weekly sessions, each lasting several hours.
Because the success of psychedelic therapy is highly dependent on the therapeutic alliance and the skill of the therapist, we use various strategies to ensure safety and quality in our therapeutic interventions: we carefully recruit our therapists and hold them to a very high standard; all sessions are recorded for review; and therapists have regular supervision to support their work.
Going Forward
As we continue to explore the therapeutic potential of psychedelics, it is essential to stay abreast of emerging evidence, continue to prioritize the safety of our participants, and continue to develop rigorous, inclusive, and innovative research methodologies which pave the way for patients and healthcare professionals to make the best and most informed decisions about care.
