Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

This double-blind active-placebo controlled trial (n=233) tested the effect of a single dose of psilocybin (25/10/1mg) with supportive therapy for treatment-resistant depression. The primary endpoint at three weeks finds a significant reduction in depressive symptoms (MADRS, 12-point drop from baseline of 32) that was significantly greater in the 25mg group vs the 1mg (placebo) group (6.6 points larger drop). The response (>50% drop in MADRS score) in the 25mg group dropped from 37% at 3 weeks to 20% at 12 weeks.

Abstract of Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

“Background Psilocybin is being studied for use in treatment-resistant depression.

Methods In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin [COMP360] at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary endpoint was the change from baseline to week 3 in the total score on the Montgomery–Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary endpoints included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).

Results A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were −12.0 for 25 mg, −7.9 for 10 mg, and −5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P<0.001) and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P=0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.

Conclusion In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder.“

Authors: Guy M. Goodwin, Scott T. Aaronson, Oscar Alvarez, Peter C. Arden, Annie Baker, James C. Bennett, Catherine Bird, Renske E. Blom, Christine Brennan, Donna Brusch, Lisa Burke, Kete Campbell-Coker, Robin L. Carhart-Harris, Joseph Cattell, Aster Daniel, Charles DeBattista, Boadie W. Dunlop, Katherine Eisen, David Feifel, MacKenzie Forbes, Hannah M. Haumann, David J. Hellerstein, Astrid I. Hoppe, Muhammad I. Husain, Luke A. Jelen, Jeanine Kamphuis, Julie Kawasaki, John R. Kelly, Richard E. Key, Ronit Kishon, Stephanie K. Peck, Gemma Knight, Martijn H. B. Koolen, Melanie Lean, Rasmus W. Licht, Jessica L. Maples-Keller, Jan Mars, Lindsey Marwood, Martin C. McElhiney, Tammy L. Miller, Arvin Mirow, Sunil Mistry, Tanja Mletzko-Crowe, Liam N. Modlin, René E. Nielsen, Elizabeth M. Nielson, Sjoerd R. Offerhaus, Veronica O’Keane, Tomáš Páleníček, David Printz, Marleen C. Rademaker, Aumer van Reemst, Frederick Reinholdt, Dimitris Repantis, James Rucker, Samuel Rudow, Simon Ruffell, A. John Rush, Robert A. Schoevers, Mathieu Seynaeve, Samantha Shao, Jair C. Soares, Metten Somers, Susan C. Stansfield, Diane Sterling, Aaron Strockis, Joyce Tsai, Lucy Visser, Mourad Wahba, Samuel Williams, Allan H. Young, Paula Ywema, Sidney Zisook & Ekaterina Malievskaia

Analysis of Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

The COMPASS Pathways psilocybin for treatment-resistant depression is the largest psychedelic trial published to date. A year ago, the top-line results were shared, and now the full results have been published in the New England Journal of Medicine (NEJM, one of the most prestigious medical journals).

The results are promising, but far from spectacular. Of the third of the participants who received 25mg of psilocybin (the high/active dose, 79 of 230 participants), 37% responded (>50% reduction in depression, MADRS score) three weeks after the dosing session. At that time, 29% were in remission (<10 MADRS score); this went down to 20% at 12 weeks. At the 12-week mark, this change was not significant when compared to the placebo (1mg) or low-dose (10mg) groups.

Comparison to results from other studies

Though good, these results don’t compare favourably to other treatments for ‘treatment-resistant’ depression.

A meta-analysis of Cognitive Behavioural Therapy (CBT) interventions found a response of 42% immediately (26% remission), which improved over time to 61% response (26% remission) at the one-year mark.

Similarly, the real-world data on the efficacy of ketamine-assisted therapy shows a higher response. One meta-analysis (n=2.665) finds an immediate response of 45% (30% remission), but with large variability between studies. A real-world study of esketamine finds that repeated dosing (over 12 weeks) leads to a 64% response (41% remission), but this is also measured immediately at the end of treatment (i.e. not 12 weeks later).

A small study (n=24) on two doses of psilocybin for major depression (not treatment-resistant) reported even more spectacular effects over a 12-month follow-up. In this study, 71% were in remission at the 4-week follow-up (75% at 12 months), and 54% were in remission (58% at 12 months).

In the only psychedelic study that pitted psilocybin (25mg) directly against an antidepressant, the response (on the MADRS – not the primary measure used in the study) was 68% (29% remission) for the psilocybin (2 doses) compared to 21% (7% remission) in the escitalopram group.

All these studies have been conducted in different ways (e.g. blinding or lack of it, the intensity of therapy, etc.), and the numbers here are just for illustrative purposes.

A quick note on participants in the trial

The participants in clinical trials are usually a very small sub-group of those who respond to the call to join a trial. Those with other mental health issues (e.g. comorbid PTSD and depression) are commonly excluded. This is also the case in this trial, though, as we will see in a bit some did have suicidal ideation/behaviour in the past.

There is also a big expectation effect. Patients have heard about the positive findings of psychedelic treatments (also dubbed the Pollan Effect) and might be positively biased to expect positive effects. The flip side is that they can be disappointed even further when these results don’t materialise.

We can also expect – but this wasn’t measured – that nearly all participants knew if they had received psilocybin. Many words have been written about this, but see this thread for more.

Finally, treatment within a clinical trial may be worse than in real-world settings, where more long-term therapy and flexibility in treatment are possible. The sterile and protocolised environment of a trial might have also dampened the effectiveness of treatment.

Honest reporting on adverse event

Earlier psychedelic trials have made it look like there are few to no negative consequences to be expected when taking a high dose of psilocybin within a medical context. As Joost Breeksema points out in his commentary (see below), the reporting is much more rigorous than in other psychedelic trials.

The incidence of adverse events (e.g. headache, fatigue, euphoric mood, insomnia) was 77% in the trial. The acute adverse events on the treatment day were higher in the high-dose group (61%) than in the placebo group (38%).

The non-serious adverse events should be considered, but they may not throw up big barriers to implementing psychedelic-assisted treatments (i.e. euphoric mood). Serious adverse events, on the other hand, do. There were five serious adverse events in the 25mg group, of which three were suicidal behaviours.

The details are explained in the supplemental materials. The three suicidal behaviours happened between 29 and 63 after treatment and are described as an aborted suicide attempt or acquiring materials for an attempt. No completed suicide occurred in the 12 weeks patients were followed up with.

A possible explanation for the behaviours is put forth by Natalie Gukasyan, “You can imagine that, for someone who’s already demoralized, that could be another stressor for them.” Put differently, when knowing they were in the active treatment group, and without results, the participants felt without hope.

Seeking treatment during the follow-up

In the 12 weeks after treatment, an average of 38% of participants sought out other treatments. This was the same in all groups (25mg, 10mg, 1mg), but those in the high-dose group sought treatments later than the other groups (in the first three weeks, 5%, 12%, and 18%, respectively).

This is similar to the psilocybin for depression trial, where 33% of participants started daily antidepressants again in the 12-month follow-up.

The long-term follow-up study (12 months) to the MDMA for PTSD Phase II trial similarly reported continued use of medication (34% any psychiatric/psychological symptoms, 5% specifically for PTSD). Of these participants, a third reported starting a new medication. Nearly 10% also reported taking MDMA on their own accord.

Put bluntly, psychedelic-assisted treatments look less like the one-shot and done magic bullets than the field imagined them to be.

What is next for COMPASS?

COMPASS has a two-part Phase III trial planned, which will enrol 946 participants. The first trial (COMP005) will, again, only give one dose of psilocybin (25mg) and compare it directly to a placebo. The study’s primary endpoint is the MADRS score at six weeks after treatment. The second trial (COMP006) pits two doses (25mg, 10mg, or 1mg) against each other. No signal has been given that a longer-term follow-up is planned in these trials.

A treatment protocol with two doses will likely do better than one dose, and COMPASS expects a response in the 2x10mg group. The costs of delivering such treatment are higher, benefits of the increased response should be weighed against the benefits expected.

Another relatively large trial (n=144) is currently taking place in Germany. The study rationale describes a more involved therapeutic container which includes weekly check-ups. Also different is that participants will be followed for 12 months.

The results from the Phase III trial will be looked at in great detail, they could determine the future of the psychedelics as medicine field.

Other responses

• List of responses by Michael Haichin on Twitter
• expert reaction to Phase IIb Clinical Trial of Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression (Science Media Centre)
• The Harms of Psychedelics Need to Be Put Into Context (Wired), commentary by Joost Breeksema
• Analysis: COMPASS Pathways Phase 2b Psilocybin Trial Published in NEJM (Psychedelic Alpha)
• Severe depression eased by single dose of synthetic ‘magic mushroom’ (CNN)

Summary of Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

Treatment-resistant depression is a challenging disorder to treat. Patients with treatment-resistant depression have greater severity, duration, disability, physical illness, incidences of hospitalization, risk of suicide, and economic costs than patients with treatment-responsive depression.

Psilocybin is a tryptamine alkaloid found in several species of psilocybe mushrooms, and may be used to treat depression. It was tested in smaller studies on patients with a treatment-resistant major depressive episode.