Rapid antidepressant effects of psilocybin without increased SV2A binding: baseline binding predicts response

In 35 participants with moderate-to-severe recurrent major depressive disorder, a single 25 mg psilocybin dose improved symptoms without any group-level increase in hippocampal or frontal SV2A binding on [11C]UCB-J PET.

• Why it matters: Synaptic loss is implicated in major depressive disorder, and psychedelics can remodel synapses quickly in preclinical models, so it was unclear whether psilocybin’s rapid antidepressant effects reflect increased synaptic density in humans.
• What they did: A pre-registered [11C]UCB-J PET sub-study of a randomized trial measured SV2A binding (VT and BPND) 2–7 days before and 15 (+/-7) days after dosing with 25 mg psilocybin versus 100 mg niacin placebo, both with psychotherapeutic support.
• The result: Baseline SV2A VT predicted greater subsequent clinical improvement in the psilocybin group at Day 8 and Day 15 after FDR correction, suggesting baseline synaptic marker levels may help identify likely responders despite no detectable group-level binding increase.

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