Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
A single 25 mg dose of psilocybin, or two such doses given six weeks apart, combined with psychotherapy produced a stable and clinically meaningful reduction in depression symptoms for up to twelve months in people with treatment-resistant depression. The average improvement on the Hamilton Rating Scale for Depression was about 7.9 points at six months and 7.7 points at twelve months, with no significant difference between dosing groups. Restarting standard antidepressant medication during follow-up was strongly linked to higher depression scores. This naturalistic follow-up of a phase 2b trial is the largest and most complete long-term assessment of psilocybin for depression to date.
Classical and novel antidepressants may share a common mechanism: promoting long-term neuroplasticity and improving negative bias in emotional processing. Extrapharmacological factors—body, environment, and social interaction—appear necessary for these biological changes to produce an antidepressant effect. Rather than dismissing such factors as placebo, the authors argue they should be tested as essential components of treatment and integrated into clinical practice.