A single 25-mg dose of synthetic psilocybin (COMP360) produced larger and more durable reductions in depression severity than a 1-mg control in adults with treatment-resistant depression. Dose-dependent improvements on the Montgomery-Asberg Depression Rating Scale were evident from day 2, remained statistically significant through week 6, and were numerically still present at week 12. The intensity of the psychedelic experience, particularly feelings of boundlessness, was linked to better clinical outcomes. Over 90% of adverse events were mild or moderate. The findings suggest COMP360 may become a useful treatment for treatment-resistant depression, though suicidality remains a concern.
Psilocybin, once metabolized to psilocin, activates 5-HT2A receptors, enhancing cortical GABA function and brain connectivity. The largest randomized controlled trial of psilocybin in treatment-resistant depression (COMP 001) showed a dose-effect relationship: 25 mg of COMP360 produced significantly greater reduction in depressive symptoms than 1 mg at 3 weeks, with 10 mg intermediate. The psychedelic experience is variable, making unblinding unlikely to explain results. Psychological support—preparation, minimal guidance during the session, and integration—differs from psychotherapy, and mood improvement was evident the day after drug administration, before integration. The author argues psilocybin's antidepressant effect is primarily drug-driven, not psychotherapeutic.