Psilocybin-Assisted Supportive Psychotherapy in the Treatment of Major Depression

Peter ForsterTreatments of Depression Leave a Comment

We have been eagerly awaiting the results of controlled studies of psilocybin treatment of depression (used along with psychotherapy). A large multi-center study is still recruiting participants. Meanwhile a great deal of interest in this topic has been stirred up by Michael Pollan and his book How to Change Your Mind. But clinicians have had very little solid science upon which to base assessments of this approach to treatment.

A recent small crowdfunded study by researchers from Johns Hopkins has excited a lot of interest as the first significant study in this area not involving a very special population (such as people with cancer). Several psychiatrists emailed me to ask what I thought of it.

First the good news, this study was well designed and provides us with a wealth of information about potential benefits and adverse effects. It was published in the most prestigious journal in psychiatry, JAMA Psychiatry. And the results seemed very positive.

The authors reports rapid relief of depression and high rates of initial response and remission.

However, several limitations of the study suggest that we will still have to await the results of larger studies before making clear recommendations. The authors make this point in their conclusion.

[The study]… had a short-term follow-up, a small sample that was predominantly composed of White non-Hispanic participants, and included participants with low risk of suicide and moderately severe depression. Further research with larger and more diverse samples, longer-term follow-up, and a placebo control is needed to better ascertain the safety (eg, abuse potential of psilocybin, suicide risk, and emergence of psychosis) and efficacy of this intervention among patients with MDD. 

The study followed 24 mid-life adults with moderate depression and no suicidal ideation for four weeks. Patients with bipolar disorder (or any family history of bipolar disorder, first or second degree) and any substance use disorder were excluded. Patients had to be off all medications for up to 4 months during the trial (which would have tended to weed out more severe and treatment resistant depression patients).

The fact that the group that ended up enrolling in the study was very different from the type of people who were interested in psilocybin treatment of depression is illustrated by this figure from the study. Out of 870 people who were interested in the study, only 3% qualified and enrolled in the study. This is an unusually large exclusion rate. In a typical clinical trial 2/3rds of those assessed for the study will be excluded, a finding that has led to concerns about the generalizability of the results.

Study flowsheet

A further limitation is that there was no placebo control so the possibility that patient, and clinician, expectation and bias affected the results cannot be excluded. In fact, biases related to expectancy are a major problem even in randomized clinical trials of antidepressants.

Finally, the administration of the psilocybin was associated with a lot of clinical contact. The intervention period involved at least 18 in-person visits, including 2 daylong psilocybin administration sessions as well as preparatory meetings (8 hours in total) with 2 session facilitators before the first psilocybin session, and follow-up meetings after psilocybin sessions (2-3 hours in total). We can’t rule out the possibility that it was the combination of clinical contact and expectancy that led to the response.

One piece of good news is that there were no serious adverse events in this trial. A transient increase in blood pressure occurred during 1 session, but no medical intervention was needed, and the blood pressure increase resolved spontaneously during the session. Other nonserious adverse effects included challenging emotional (eg, fear and sadness) and physical (eg, feeling body shake or tremble) experiences. Mild to moderate transient headache was reported during 1/3rd of the sessions and after the subjective psilocybin effects had subsided in 30%.

An accompanying editorial notes both the significant response to treatment as well as some questions about the study’s limitations.

Here is a question: would a double-blind experimental design, entailing the use of pill placebo, or an active comparator with psychotropic effects (eg, an anxiolytic or an antidepressant), in a model of medication-assisted psychotherapy, yield results that are comparable with those reported by Davis et al in their single-blind, immediate vs delayed exposure to psilocybin paradigm? A second set of questions highlights the need to know for whom psychedelic-assisted psychotherapy is appropriate (or not), particularly in patients with depression who are suicidal or have a history of suicide attempts. Participants in Davis et al were noteworthy for the general absence or low level of suicide risk… A final set of questions relates to the durability and maintenance of antidepressant response, with respect to both symptom burden and major role functioning.


Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. Published online November 04, 2020. doi:10.1001/jamapsychiatry.2020.3285

Reynolds CF. Psilocybin-Assisted Supportive Psychotherapy in the Treatment of Major Depression—Quo Vadis? JAMA Psychiatry. Published online November 04, 2020. doi:10.1001/jamapsychiatry.2020.2901