From the Editor

“Severe depression eased by single dose of synthetic ‘magic mushroom’”

– CNN, 3 November 2022

For its proponents, psilocybin could be the breakthrough we have been waiting for in depression treatment. For its critics, psilocybin lacks evidence.

What to make of psilocybin? Dr. Guy M. Goodwin (of the University of Oxford) and his co-authors attempt to answer that question with a phase 2 double blind trial focused on those with treatment-resistant depression, offering participants psilocybin at three different doses, in addition to therapy. The resulting paper was just published in The New England Journal of Medicine and has received much attention (including, yes, coverage by CNN). They find: “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.” 

The future of depression treatment?

We discuss the big paper and the review the accompanying Editorial by Bertha K. Madras (of Harvard University). We also have comments from Dr. Ishrat Husain (of the University of Toronto), one of the study co-authors.

So does psilocybin offer a breakthrough? Read on and decide for yourself.

(Note that there will be no Reading next week.)


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

Guy M. Goodwin, Scott T. Aaronson, Oscar Alvarez, et al.

The New England Journal of Medicine, 3 November 2022

Treatment-resistant depression is a challenging disorder to treat, as shown in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Incidences of remission became progressively lower from the first course of antidepressant treatment (36.8%) to the second course (30.6%), third course (13.7%), and fourth course (13.0%)… Patients with treatment-resistant depression have greater severity and duration of illness, 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. Its potential antidepressant efficacy was suggested by preliminary studies involving patients with life-threatening cancer. Amelioration of symptomatic depression in pilot studies of major depressive disorder, including those that compared psilocybin with escitalopram and that investigated its use in treatment-resistant depression, has suggested therapeutic potential for this agent..

So begins a paper by Goodwin et al.

Here’s what they did:

“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 at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point 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 end points 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).”

Here’s what they found:

  • A total of 428 participants were screened, and 233 were enrolled with 79 participants in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group.
  • Demographics. Participants tended to be female (52%), with a mean age of 39.8, and White (92%). In terms of their depression experience, the vast majority had past depressive episodes (95%) with a mean of 6.9 past episodes.
  • Efficacy. “The least-squares mean change from baseline to week 3 in the MADRS total score was −12.0 points in the 25-mg group, −7.9 in the 10-mg group, and −5.4 in the 1-mg group.” In terms of response: “The incidence of response at week 3 was 37% in the 25-mg group, 19% in the 10-mg group, and 18% in the 1-mg group (odds ratio in the 25-mg group vs. the 1-mg group…).” And, “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. “Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness.” Adverse events were most common in those on the highest dose: 84%. “Suicidal ideation or behavior or self-injury occurred in all dose groups.”

A few thoughts:

1. Psilocybin. The New England Journal of Medicine. A double-blind trial involving 22 sites in 10 countries. A primary end point of three weeks, and follow up to 12 weeks. 

This is a big paper. (It could only be bigger if it somehow tied to Elon Musk.)

2. And this is a smart paper, offering a solid design with reasonable measures – thus more credible than past work. Speaking to the last point, it “included a trial population in which more than 90% of the participants did not have previous exposure to psilocybin.”

3. The results in a sentence: At three weeks, 25 mg psilocybin, not 10 mg, reduced depression scores more than 1 mg.

4. Like all studies, there are limitations. The authors note several, including: “We did not assess participants’ ability to guess their dose assignment, and ensuring blinding is an inherent limitation of studies of drugs that produce psychedelic subjective effects.”

5. In an accompanying Editorial, “Psilocybin in Treatment-Resistant Depression,” Bertha K. Madras discusses the paper with a balanced view.

Bertha K. Madras

“The findings are both intriguing and sobering. The highest dose (25 mg), but not the intermediate dose (10 mg), resulted in significantly lower levels of depressive symptoms after 3 weeks than the lowest dose (1 mg, which served as a control), but the 37% incidence of response with the 25-mg dose was numerically lower than that in large trials of conventional antidepressants for major depression and less robust than in a small pilot study involving participants with treatment-resistant depression or a larger study showing similar efficacies of psilocybin and a selective serotonin-reuptake inhibitor…”

She also raises significant practical issues:

“Can protocols for administering hallucinogens be scaled and retain fidelity to the plans used in trials? Because psilocybin produces unpredictable hallucinogenic effects, administration is necessarily coupled to an extensive, nontraditional psychotherapy program. Sessions of 6 to 8 hours’ duration are conducted in a nonclinical, calming living-room environment, with participants listening to a specially designed music playlist and isolated by eyeshades and earphones to help direct attention internally. Hosted by a lead therapist and an assistant, sessions are preceded by rigorous preparation for the experience and followed by integration discussions. Therapist training is intensive, and requirements for a cadre of qualified therapists may be difficult to achieve.”

The Editorial can be found here:

6. We asked Dr. Ishrat Husain, who is a study co-author, to comment:

“As the Canadian investigator on this international, multi-centre phase IIb trial, it was very exciting to see the results published in The New England Journal of Medicine. The intricate procedures involved in executing a trial of psilocybin, particularly for the first time in Canada, took Herculean efforts to execute during a global pandemic. 

Dr. Ishrat Husain

“This was a dose-finding study, aiming to assess the efficacy of three doses of psilocybin: 25 mg vs 10 mg vs 1 mg (a placebo-like dose). With regards to the results, I believe they add to the evidence-base for psilocybin’s putative antidepressant effect at the ‘psychedelic’ dose of 25 mg. Unlike other RCTs, this is first to focus on patients with treatment-resistant depression (TRD). It is also the largest trial of psilocybin in depression to date, and was adequately powered to detect differences between the different treatment conditions. There was a statistically significant difference of around 7 points in depression (MADRS) scores between the 25 mg and 1 mg, in favour of the higher dose at the primary time point (week 3). There were also significantly higher rates of response and remission in the 25 mg arm at the primary time point. Although these results are encouraging, it looks like these improvements were not sustained suggesting that a single dose may not be adequate for sustained improvement. Other issues relate to the number of adverse events especially the higher rates of suicidality in the 25 mg arm. This could suggest a dose-related adverse effect, however, given the number of participants in each arm, a definitive conclusion cannot be drawn and larger studies are needed with longer follow up to adequately assess safety. Interestingly, 3 participants experiencing suicidality were non-responders to the 25 mg dose which may explain the increased rates of this SAE.

“Like all other studies of psychedelic drugs, the study is likely to be limited by a lack of adequate blinding, however there was no assessment of blinding included. Furthermore, treatments like psilocybin have garnered substantial public attention and expectancy bias is likely to have played some role in the results – again, this was not assessed and future studies should be seeking to include a validated assessment of expectancy. The short duration of follow up does not allow for comment on the longer term safety and efficacy of psilocybin. Each participant received approximately 10-12 hours of psychological support, and the fidelity to this component of the treatment, or what it even comprised of, was not adequately reported in the main paper (details are in the Supplement though). I do wonder how psilocybin will be adopted in already strained health services if it is shown that it is safe and effective but requires such specialised and resource-intensive psychological support. In summary, many critical questions remain unanswered, and as such I do not think this approach is yet ready for clinical translation. At the same time, this is a pivotal study that adds to the evidence for psilocybin’s safety and efficacy in TRD. The results will inform future trials to address some of the issues highlighted above. Only when such studies have been completed can we confidently conclude that psilocybin is ready to join evidence-based treatments like ECT as part of treatment guidelines for TRD.”

The full NEJM paper can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.