Challenging Psychedelic Experiences Study & Compass' Phase III Trial Design

Greetings from NYC! I have just arrived for the Horizons Conference and looking forward to seeing many of you this weekend!

Today’s dispatch is brief but looks at Compass Pathways’ announcement of the trial design and enrollment goals for the Phase III program for COMP360 (psilocybin) for Treatment-Resistant Depression. 

Additionally, two recently announced projects are worth pointing out, the Challenging Psychedelic Experiences Project and a grant from The Tiny Blue Dot Foundation for research into The Perception Box using psychedelics, meditation, or other mind-altering tools.

Plus, some weekend reading.

Compass Pathways’ Phase III trial design

This week, Compass Pathways revealed the trial design for the much anticipated Phase III program.

You may recall that in November of 2021, the topline results from the phase II trial showed promising treatment effects while also highlighting the need for caution with 12 severe adverse events.

The phase II trial was the largest enrolling study of any psychedelic with 233 subjects—before this study, only 151 participants had enrolled in ANY double-blinded, placebo-controlled trial.

The recently announced phase III program plans to include nearly 1,000 subjects.

In short, there are two separate trials; the first will evaluate a single dose of 25mg vs placebo with just under 400 subjects. The second will compare two doses of three different dosages (25mg, 10mg, 1mg) in 568 subjects.

From the press release:

The Phase 3 program is composed of three clinical trials, two pivotal trials and one long-term follow-up, and is expected to commence by the end of 2022. The pivotal program design is as follows: 

Pivotal trial 1 (COMP 005) (n=378): a single dose (25mg) monotherapy compared with placebo. This trial is designed to replicate the treatment response seen in the Company’s Phase 2b study (n=233).

Pivotal trial 2 (COMP 006) (n= 568): a fixed repeat dose monotherapy using three dose arms: 25mg, 10mg and 1mg. This trial is designed to investigate if a second dose can increase the number of responders and/or improve response seen in the Company’s Phase 2b study and explore the potential for a meaningful treatment response from repeat administration of COMP360 10mg. 

The primary endpoint in both pivotal trials is the change from baseline in MADRS total score at Week 6.

The below image comes from the company’s Capital Markets Day, a lengthy presentation from the executive team where it unveiled the trial design.

Notably, the final data readout is planned for mid-2025. This puts the likely timeline for an FDA decision and commercialization at 2026.

Challenging Experience Study

A group based at the University of Greenwich is undertaking the important task of studying challenging psychedelic experiences, and they have launched a survey study to capture the difficulties people have experienced after psychedelic use.

“This study is investigating difficulties people experienced after using a psychedelic drug, which they believe negatively impacted their functioning for more than a day after the trip, and what they found helpful in dealing with these difficulties. 

If you have had a psychedelic experience that you believe led to difficulties that lasted for longer than a day, you qualify as a candidate experience. You must be over 18 to participate.”

As I’ve argued, even if the messaging from the media is overblown, most people I talk to who are actively involved appreciate the gravity of the psychedelic experience, these compounds are not a panacea, and each trip is unique and unpredictable. And sometimes things go south.

The Challenging Psychedelic Experiences Research Project, along with research into things like music, set & setting, and enriched environment, perhaps mark the next generation in psychedelic research—not next-generation compounds—that explores how context can either heal or harm, how to reduce risk, extend benefit and predict who will benefit and who won’t.

There is readily available precedent for the Challenging Psychedelic Experience Project and comes from meditation.

In 2007, Willoughby Britton, a neuroscientist at Brown, first learned of meditation-induced psychosis and began researching the phenomenon.

The explosion in interest in mindfulness and meditation in the West over the last 20+ years has revealed that it is not all upside; meditation has a dark side—or rather a dark night—and understanding what reduces bad outcomes and what exacerbates them is crucial.

If there is a lesson that the psychedelic field can take from the meditation/mindfulness world it is not to resist the reality that challenges, harms, and bad outcomes are part of the psychedelic package.

Donations to the Challenging Experience Research Project can be made here.

Further Reading

🧠The Tiny Blue Dot Foundation is accepting proposals for ‘outside the box’ research projects on The Perception Box

⚖️ The lads over at On Drugs published a great series on President Biden’s recent move to pardon cannabis offenders and direct a rescheduling scheme

🚀 Floris Wolsijk penned an opinion piece in Lucid News arguing that mental health conditions are just the beginning of psychedelic-based interventions

That’s it for this week—see you in NYC!

Zach