Did Compass minimize adverse experiences in its psilocybin trial?

One of the trial participants thinks so

In 2022, Compass Pathways, one of the leading psychedelic companies in the world, published a paper in the New England Journal of Medicine, called ‘Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression’. It was the largest study of psilocybin therapy ever, and claimed that in a study of 233 patients, there was a highly significant and sustained impact on their levels of depression.

Nonetheless, the publication of the paper sparked a decline in the stock price of Compass and the entire psychedelic sector, partly because of media and investors’ focus on 12 serious adverse events in the trial, including three instances of increased suicidality in the high dose group. One investor summed up the bearish case against psychedelics:

Recent results of the Compass Phase 2b study showed an unacceptable level of serious adverse events in the higher dose (25mg) treatment group, particularly suicidal ideation. Such problematic effects will prevent psychedelics from being used as first-line treatments for people with depressive disorders. Therefore, all psychedelic startups are focused on a small addressable market (less than $1bln).

Compass came out swinging in defence of the results, and sought to downplay the adverse events and dissociate them from the effects of psilocybin. A Compass email statement to one media outlet declared ‘it is not clear there is a direct link with [the increased suicidality and the] administration of the drug’. Compass added:

treatment-resistant depression is directly associated with higher rates of suicidal thoughts, suicide attempts and completed suicide, so these adverse events may be related to the illness rather than the drug. None of the 12 patients who experienced serious adverse events achieved remission in this trial, so it is not unreasonable to suggest that this might be linked to the occurrence of these adverse events.

Professor David Nutt, an advisor to Compass, told the Guardian that the cases of increased suicidality ‘were probably random events and unrelated to the dose of psilocybin, which would have been fully cleared from the patient’s bodies’.

Professor Guy Goodwin, Compass Chief Medical Officer, told WIRED  - “All three participants [who reported increased suicidality] had not responded to COMP360 psilocybin and had a previous relevant history of suicidality or self-harm. This suggests that the emergent suicidality is due to the nature of treatment-resistant depression, rather than the drug,”

All three instances of increased suicidality were classified as ‘non-responders’, a point stressed by Professor Goodwin in investor calls – ‘they were all essentially non-responders’.

Psychedelic investors took up this line of argument and used it to promote the investment case not just of Compass but of the entire psychedelic industry. Ken Belotky, founder of $30 million psychedelic fund Negev Capital, which invests in Compass, published a LinkedIn Post called ‘Don’t bet against the psychedelic renaissance’, in which he wrote:

The suicidality that was noted in the [Compass] study occurred well after the treatment day, and only in non-responders. It is unlikely that the small number of patients who described suicidal ideation were exhibiting a psilocybin-related side effect, as this has not been seen in any other studies.

I interviewed one of those three ‘non-responders’ in the trial, a British lady called Maryam.

She told me the post-trip suicidality she felt was connected to the psychedelic experience. She did respond to treatment – she had a terrifying existential trip that left her identity in tatters. She came through it,  and eventually felt better than she did before the treatment. She doesn’t regret the treatment and would like to try psychedelics again. But Maryam doesn’t appreciate how Compass minimized and dismissed her experience. And this is the crucial point - Maryam thinks she might not be here today if she didn’t have a lot of additional support. The post-trip safety net is crucial, and at the moment it doesn’t exist. At the end of the article I’ll make a suggestion about a very basic safety net that could be created.

Maryam has suffered from depression since high school. She had tried CBT and anti-depressants but neither had worked. She read about the potential benefits of psychedelic therapy and signed up for the Compass trial having had no previous psychedelic experiences (like the majority of British people). She says Compass informed participants there was a tiny risk of symptoms worsening but said this had never happened on any previous trial.

She then had an extremely challenging experience. Here’s a paragraph from her eloquent trip description:

I drew back and saw the Pattern. It looked more like the Mandelbrot set now, perpetually churning and roiling within itself constantly but never changing shape. A huge eye opened in the middle and looked around, echoed by a multitude of smaller eyes refracting into its depth, horrified to be beheld…I felt as though I had discovered a sick truth of life: That no matter how hard you try to climb to better things, you will never succeed; and if you don’t work, thing will spiral into deeper and darker depression. The only way out is death.

So, yes, Maryam may have had a latent and unconscious suicidality before, but the mushrooms amplified it and projected it in 10,000-ft technicolour.

She emerged from the psilocybin experience feeling like her identity and even her faith in God was torn apart. In the days and weeks afterwards, she felt suicidal, and describes going to nearby train tracks, struggling with the urge to throw herself in front of a train. She came through in part thanks to intensive support from the doctors and therapists on the Compass trial – she phoned them around six times asking for emergency help, received two extra sessions of therapy, and was also referred by them to an emergency crisis line. She says this extra support may have saved her life.

Even after all this extra support, she found it difficult when the trial ended three months after the psychedelic experience. She says the depression had gone down, but anxiety had intensified. She was prescribed anti-psychotics for the anxiety by an NHS psychiatrist, but the side effects were horrible. Today, she feels in a better place and is enjoying some of the benefits and occasional epiphanies of post-psychedelia, but also still struggles with aspects of the experience.

Maryam was dismayed to discover she was reported as a non-responder in Compass’ results:

I remember it very vividly, because it was Boxing Day when I discovered the article had been published. And I was really upset.  In a phone call I had with the one of the doctors, I specifically said, they're not going to just write me off, are they? Because I have this twofold fear of like, I don't want them to dismiss my case as an outlier. But I also don't want my numbers to be negative for the trial as a whole. And he was like, no, no, they'd be really silly if they wrote you off. And then they did.

I put this to Professor Guy Goodwin of Compass. He said ‘non-responder’ doesn’t mean ‘no response’. It means Maryam’s MADRS depression scores didn’t go down 50% in the time frame of the trial. It’s not clear if everyone in the market understands that ‘non-responder’ doesn’t mean ‘no response at all’ and could mean  ‘extremely challenging trip that left one suicidal’.

Compass also suggested the suicidality was a consequence of the Treatment-Resistant Depression rather than the drug. I asked Maryam, had she ever felt suicidal prior to the trip? She replied:

I have, but in this instance it was directly due to the experience. Before it was mostly just ideation etc whereas this was very strong desire and was because of what I had gone through. The way I think of it is like “would I have felt suicidal again without the drug? Yeah probably, but would I have felt suicidal that particular day and in the way I had if I hadn’t taken it a few days prior? No.”  It feels a bit silly to dismiss acute suicidality from challenging experiences as just a normal part of Treatment Resistant Depression; kind of like saying “if you have a car then car accidents are not an unlikely occurrence; adding ice to the road is unrelated and not necessarily connected to this crash”.

She was disappointed by David Nutt’s comments to the Guardian as well – that this couldn’t be connected to the drug as it would have been out of her system in a few hours.  His comment not only dismissed Maryam’s actual experience but spreads the false information that psychedelics can’t negatively affect people beyond the acute effects of the drug.

Professor Nutt , by the by, then persuaded Australia’s health regulator to legalize psychedelic therapy because, in his words, ‘no one’s ever come out [of a clinical trial] more depressed’ [listen to this interview with Australian media, seven minutes in].

To be clear, if offered the opportunity Maryam would take part in the trial again,  and would also like to try psilocybin therapy again. There are a lot of positives to take from the Compass trial in general, and from Maryam’s journey. There are reasons to be hopeful about the potential of psychedelic treatments.

But Maryam offers some important reflections on how to prepare people for psychedelic treatments – inform them about the risks of challenging experiences and post-psychedelic difficulties, make sure they have strong support networks in place afterwards including specialist help that understand psychedelic experiences, and don’t try to sugar coat it if people are really struggling afterwards. Be honest about adverse effects to patients, regulators, the market and the general public. Include qualitative studies as well as quantitative, to capture people’s messy non-linear journeys towards more fulfilling lives.  

Finally, her case raises a difficult question for the field. If a percentage of people experience post-psychedelic difficulties and need intensive therapeutic support after challenging psychedelic experiences, how likely is it they will receive that support on the NHS, or in any other healthcare system? Who will pay for that support?  

Maryam says:

I think if I was going to talk about psilocybin to somebody, I would say ‘don't think of it as a treatment, I would think of it as exploratory surgery for your mind. You might open up your self and find something that is easy to treat. But you might find stage four metastatic cancer… If you introduce psychedelic therapy, and there's no support set up once the treatment finishes, you shouldn't go ahead with it.

My brief suggestion is that every country with a legal psychedelic market should have at least one specialist medical clinic to offer support to people dealing with post-psychedelic difficulties, similar to what Cheetah House does with adverse meditation experiences. It should be part-funded by the market. This would a much better way of defending the investment case for psychedelics than denying adverse experiences. 

After the pay-wall, the full interview with Maryam. The more the psychedelic industry listens to and learns from people who have challenging experiences or post-trip difficulties, the safer and more effective the industry will be.