Psilocybin therapy shows similar benefits for patients with and without recent antidepressant use

A new study published in The Canadian Journal of Psychiatry suggests that individuals with treatment-resistant depression may benefit equally from psilocybin-assisted psychotherapy whether or not they recently discontinued antidepressant medications. The study found no significant differences in depression, anxiety, or suicidality outcomes between participants who tapered off antidepressants before treatment and those who were not on antidepressants at all.

Psilocybin, a compound found in certain “magic” mushrooms, is increasingly being studied as a treatment for depression when combined with psychological support. The researchers behind this study sought to clarify whether stopping antidepressants before starting psilocybin-assisted psychotherapy influences how well the treatment works. This question matters because many psilocybin trials require participants to taper off their medications, which can cause withdrawal symptoms and may even worsen depression. But it’s still not clear whether such tapering is necessary.

“The exact influence of tapering off antidepressant medications on the efficacy of psilocybin-assisted psychotherapy is currently unclear. Previous research has shown that participants unmedicated in terms of antidepressants before psilocybin-assisted psychotherapy had a greater therapeutic response than those who had to taper off before treatment,” said lead author Noah Chisamore, a PhD student at the University of Toronto.

“However, tapering off antidepressants can be challenging, as it can lead to side effects and worsening depression symptoms—especially in a treatment-resistant depression population we work with. It is important to examine and weigh the adverse effects of tapering medications against a potentially increased therapeutic effect of psilocybin.”

Joshua D. Rosenblat, an associate professor at the University of Toronto and senior author of the study, added: “We are working on optimizing protocols for psilocybin-assisted psychotherapy and want to know about any predictors of response (or non-response). Medication tapering before trials is one factor we were quite interested in to see if this had a negative impact on outcomes.”

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The research team used data from a clinical trial conducted at Braxia Health, a Canadian clinic specializing in mood disorders. The trial was originally designed to evaluate the feasibility and safety of psilocybin-assisted psychotherapy in adults with treatment-resistant depression. For this specific analysis, the researchers looked only at participants diagnosed with major depressive disorder who received at least one 25-milligram dose of psilocybin and completed follow-up assessments within two months. They excluded individuals with bipolar disorder to avoid confounding effects from mood-stabilizing medications.

The participants were divided into two groups: one group had not been taking antidepressants at the time they joined the study, while the other group had recently discontinued their antidepressants under medical supervision. A total of 26 participants were included—9 in the unmedicated group and 17 in the group that tapered off medications before receiving psilocybin.

Each participant received a single oral dose of 25 milligrams of synthetic psilocybin, provided by the Usona Institute. The dosing session was supported by a team of licensed therapists trained in a specific psychedelic therapy approach. Before the dosing day, participants had one preparatory therapy session to establish rapport and discuss expectations. Following the dosing session, they completed two integration therapy sessions to reflect on their experiences and apply insights to their daily lives.

Participants were assessed for depression, anxiety, and suicidal thoughts using several well-known clinical and self-report scales. Depression was measured by the Montgomery-Åsberg Depression Rating Scale and the Quick Inventory for Depression Symptomatology. Anxiety symptoms were assessed using the Generalized Anxiety Disorder 7-item scale. Suicidal thoughts were measured using a specific question from the depression rating scale. To capture the intensity of the psychedelic experience itself, the study used the Mystical Experience Questionnaire, a widely used tool in psychedelic research.

Both groups showed substantial improvements in depression and anxiety scores over the two-month follow-up period. Statistical analyses revealed that the improvements were not significantly different between the groups. For example, average depression scores dropped by about 10 to 12 points on the Montgomery-Åsberg Depression Rating Scale in both groups, moving participants from moderate to mild levels of depression. Self-reported depression and anxiety also declined over time, and again, these changes were similar regardless of whether someone had recently taken antidepressants.

“The results in general surprised us a bit, as we were expecting that the unmedicated participants would have a greater antidepressant response,” Chisamore told PsyPost.

“I thought the unmedicated group of patients would have done better,” Rosenblat said.

Participants in both groups reported comparable psychedelic experiences, as measured by the Mystical Experience Questionnaire. While the unmedicated group had slightly higher average scores, the difference was not statistically significant. This suggests that the intensity of the psilocybin experience was not diminished by recent antidepressant use.

Importantly, no serious adverse effects were reported during the study. Mild to moderate side effects—such as nausea, anxiety during the session, or headaches—were transient. There were no significant increases in suicidal thinking in either group, and a slight trend toward decreased suicidality was observed, though this was not statistically meaningful.

These findings challenge earlier research suggesting that recent antidepressant use might blunt the therapeutic or psychedelic effects of psilocybin. One earlier analysis, conducted as part of a randomized controlled trial comparing psilocybin to the antidepressant escitalopram, found that individuals who had tapered off serotonergic medications showed weaker antidepressant responses to psilocybin compared to those who were unmedicated. However, that study focused exclusively on selective serotonin reuptake inhibitors and was conducted in a different clinical context with different inclusion criteria.

In contrast, the present study included participants who had taken a wider range of antidepressants and allowed for individualized tapering under supervision. That might explain why the discontinued group responded just as well as the unmedicated group. The results also suggest that downregulation of serotonin receptors from previous antidepressant use may not be the only factor influencing how psilocybin affects the brain and mood.

“My takeaway is that while psilocybin and other psychedelics are a very promising and exciting treatment for depression, we are still working to optimize and improve psilocybin-assisted psychotherapy. There are a lot of expectations surrounding psilocybin-assisted psychotherapy research, and so I think it is important to recognize just how many factors are at play for its antidepressant effects.”

As with all research, the study comes with limitations. The sample size was small, especially in the unmedicated group, which limits the statistical power to detect subtle differences. Because the analysis was based on a post-hoc comparison within a trial that was not originally designed to answer this specific question, the findings should be viewed as exploratory.

“The study itself was a waitlist-controlled trial, so it lacked a placebo control group,” Chisamore noted.

Another limitation is that the study looked only at outcomes up to two months after the first psilocybin session. While this was done to control for differences in how many sessions participants received, it limits our understanding of the long-term benefits or potential risks of treatment.

Future studies with larger, more balanced samples are needed to confirm whether antidepressant tapering is necessary for psilocybin-assisted therapy to be effective. Trials specifically designed to compare different tapering schedules or include participants on stable doses of antidepressants could provide more definitive guidance for clinical practice. Additionally, more research is needed to understand whether certain types of antidepressants or durations of use influence psilocybin’s effectiveness.

“I think it would be very interesting to directly compare participants who are medicated and unmedicated with antidepressants in a small pilot study,” Chisamore said. “For me personally, I will continue to look at medication tapering in psilocybin-assisted psychotherapy for depression using data from other studies for my PhD thesis.”

The study, “Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation,” was authored by Noah Chisamore, Erica S. Kaczmarek, Zoe Doyle, Danica E. Johnson, Geneva Weiglein, Shakila Meshkat, Ryan M. Brudner, Marc G. Blainey, Jeremy Riva-Cambrin, Roger S. McIntyre, and Joshua D. Rosenblat.