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In this open-label trial, a single 25-mg dose of psilocybin given with structured psychological support was associated with a large reduction in chronic suicidal ideation by week 3. The mean Modified Scale for Suicidal Ideation (MSSI) score decreased by 13.95 points from baseline, with a within-subject effect size of Cohen d = 1.73. Improvements were already significant by week 1 and remained significant through week 12.

Suicidal ideation improved rapidly, with significant benefit evident at the first posttreatment assessment at week 1, and the reduction remained significant through week 12. The mean MSSI score was 3.4 at week 1, 4.6 at week 3, and 5.5 at week 12, suggesting strong early improvement with some later symptom return while remaining below baseline. The study found no significant differences among the postbaseline assessments.

At the week 3 primary end point, 15 of 20 participants (75%) had an antisuicidal response, defined as at least a 50% reduction in MSSI score, and 9 of 20 (45%) had full remission of suicidal ideation, defined as MSSI = 0. By week 12, 7 of 20 participants (35%) still had full remission, and another 7 of 20 (35%) had minimal residual ideation with an MSSI score of 1 or 2.

Yes. Depressive symptoms improved significantly across follow-up, and changes in depression and suicidal ideation were strongly linked. Baseline-to-week 3 change scores on the MSSI and Montgomery-Asberg Depression Rating Scale (MADRS) were strongly correlated (r = 0.70, P < .001).

At week 3, 12 of 20 participants (60%) met the criterion for MADRS response, defined as at least a 50% reduction from baseline, and 9 of 20 (45%) achieved MADRS remission, defined as a score of 10 or lower. At week 12, 10 of 20 (50%) still met MADRS response criteria and 5 of 20 (25%) remained in remission.

Psilocybin was generally well tolerated in this small high-risk sample, with no serious adverse events and no discontinuations due to adverse events. Most treatment-emergent adverse events judged related or possibly related to treatment were transient and mild to moderate in severity. There was no evidence of treatment-emergent psychosis or sustained manic or hypomanic symptoms in any participant.

However, safety concerns were not absent. Two of 20 participants (10%) had an increase in MSSI score above baseline during follow-up; for one, the worsening was transient, while for another the MSSI score increased from 17 at baseline to 23 at week 12.

Yes. One participant with comorbid posttraumatic stress disorder required a rescue dose of lorazepam on the dosing day to manage anxiety and then used as-needed clonazepam for 3 weeks afterward. The authors noted this as a reminder that careful monitoring is especially important in participants with high baseline anxiety or trauma-related disorders.

The study enrolled 20 adults aged 18 to 65 years with DSM-5 major depressive disorder, chronic suicidal ideation, and treatment resistance. Chronic suicidal ideation was defined as active suicidal thoughts on more days than not for at least 3 months, each episode lasting at least 1 hour, and participants had to have insufficient response to at least 2 adequate antidepressant trials.

Participants also needed Columbia-Suicide Severity Rating Scale scores of 3 or 4 within the past year at both screening and baseline. People with a score of 5, indicating active plan and imminent intent, within the preceding 3 months were excluded.

Participants received a single oral 25-mg dose of COMP360 psilocybin after tapering and washing out psychotropic medications for at least 2 weeks or 5 half-lives, whichever was longer. Treatment was delivered within a structured psychological support model that included 3 preparatory sessions totaling at least 6 hours, an approximately 8-hour supervised dosing session with 2 therapists present, and 3 integration meetings after dosing.

The 12-week findings suggest sustained benefit, but they should be interpreted cautiously because 12 of 20 participants (60%) restarted or initiated at least 1 psychotropic medication for major depressive disorder at or after week 3. The authors noted that improvements through week 3 occurred before these medication changes, but adjunctive pharmacotherapy complicates attribution of longer-term outcomes to psilocybin alone.

The main limitation is that this was an open-label, single-arm study, so it cannot control for placebo effects, expectancy, or other nonspecific contributors to improvement. The sample size was small (N = 20), the study was conducted at a single specialized academic center, and more than half of participants restarted or began other psychotropic medications after week 3, which complicates interpretation of long-term durability.

The exploratory responder-versus-nonresponder analyses were also limited because only 5 participants were nonresponders at week 3. The authors concluded that controlled trials with an adequate comparator group are needed to separate specific psilocybin effects from expectancy and other nonspecific factors.