Single-Dose Psilocybin Treatment for Major Depressive Disorder

Summary & key facts

In a carefully controlled trial, a single 25 mg dose of psilocybin given with psychological support reduced depressive symptoms more than a look-alike placebo pill over about six weeks. One hundred four adults with moderate major depressive disorder were studied and the psilocybin group showed a clear drop in standard depression scores and in how much depression got in the way of daily life. There were no life-threatening safety events, but people who took psilocybin reported more side effects and more severe side effects than those on placebo, and the study did not include people with psychosis, active substance use, or current suicidal intent.

Key facts:

• The study randomly assigned 104 adults with diagnosed major depressive disorder to get either one 25 mg dose of synthetic psilocybin or a 100 mg niacin placebo, and everyone got psychological support during dosing.
• Depression was measured with a standard clinical score before treatment and up to day 43 about six weeks later.
• By day 8 and by day 43 the psilocybin group had much larger drops in depression scores than the placebo group, with an average difference of about 12 points on the depression scale in favor of psilocybin.
• Psilocybin also reduced disability related to depression more than placebo by day 43, meaning people reported less interference with daily life.
• More people given psilocybin had a sustained improvement in symptoms over the follow-up period, but psilocybin did not produce significantly more full remissions than placebo in this trial.
• There were no serious treatment-emergent events reported, but the psilocybin group had a higher overall number of side effects and a higher number of severe side effects than the placebo group.
• People with a history of psychosis or mania, active substance use disorder, or active suicidal intent were not included, so the results do not tell us whether psilocybin would be safe or effective for those groups.
• This was a single-dose study with follow-up to 43 days, so the longer-term effects and safety of one dose of psilocybin are not answered by this trial.

Abstract

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174.

Topics

Forensic Toxicology and Drug Analysis Pain Management and Placebo Effect Psychedelics and Drug Studies

Categories

Clinical Psychology Psychology Social Sciences

Tags

Adverse effect Alternative medicine Antidepressant Anxiety Bipolar disorder Depression (economics) Developmental psychology Dosing Economics Environmental health Hallucinogen Injury prevention Internal medicine Macroeconomics Major depressive disorder Medicine Mood Pathology Placebo Poison control Psilocybin Psychiatry Psychology Rating scale Suicidal ideation

Substances

Psilocybin

Conditions & symptoms

Anxiety Depression Sadness or low mood