Rapid antidepressant effects of psilocybin without increased SV2A binding: baseline binding predicts response
Hampus Yngwe, Pontus Plavén-sigray, Max Andersson, Martin Bolin, Maria Beckman, Carl Johan Ekman, Mikael Tiger, Johan Lundberg
medRxiv November 8, 2026 preprint DOI: 10.64898/2026.11.06.26367247 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pre-registered PET sub-study of a randomized controlled trial Preregistered |
|---|---|
| Sample size | 35 |
| Population | Participants with moderate-to-severe recurrent major depressive disorder |
| Interventions | Psilocybin Niacin placebo Psychotherapeutic support |
| Dose | 25 mg psilocybin or 100 mg niacin |
| Duration | PET 2-7 days before and 15 (+/-7) days after dosing |
| Measures | [11C]UCB-J PET (VT, BPND), MADRS |
| Topics | Psilocybin |
| Key findings | Despite significant clinical improvement in the psilocybin group, there was no evidence of a group-level increase in SV2A binding (VT or BPND) relative to niacin in the hippocampus or frontal cortex. Higher baseline VT was associated with greater subsequent clinical improvement in the psilocybin group, surviving FDR correction at Day 8 and Day 15. The authors suggest substantial antidepressant improvement can occur without a detectable group-level increase in SV2A binding, and that baseline SV2A binding might help identify likely responders. |
Abstract
We report a pre-registered [11C]UCB-J PET sub-study of a recently published randomized trial in which a single psilocybin dose produced rapid and sustained antidepressant effects in major depressive disorder (MDD). Synaptic loss has been implicated in MDD, and psychedelics induce synaptic remodeling in preclinical models within 24 hours, raising the possibility that psilocybin's antidepressant effects involve increased synaptic density. We used the PET radioligand [11C]UCB-J targeting synaptic vesicle glycoprotein 2A (SV2A) to test this in thirty-five participants with moderate-to-severe recurrent MDD randomized 1:1 to a single dose of 25 mg psilocybin or 100 mg niacin placebo, both with psychotherapeutic support. [11C]UCB-J PET was performed 2-7 days before and 15 (+/-7) days after dosing. Despite significant clinical improvement in the psilocybin group, we found no evidence of a group-level increase in SV2A binding (VT or BPND) relative to niacin in the hippocampus or frontal cortex. In secondary analyses, higher baseline VT was associated with greater subsequent clinical improvement in the psilocybin group; this survived FDR correction at Day 8 and Day 15 (two of three pre-registered timepoints). Change in VT was associated with greater subsequent clinical improvement in unadjusted analyses, but these associations were attenuated after adjustment for baseline VT and baseline MADRS and did not survive FDR correction. These findings indicate that substantial antidepressant improvement after psilocybin can occur without a detectable group-level increase in SV2A binding, while raising the possibility that baseline SV2A binding could help identify individuals more likely to respond.
Comparable studies
Other randomized controlled trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Hallucinogen-naïve adults reporting regular participation in religious or spiritual... | 2006 | Double-blind study | n = 36 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
Citations in the library
Cites 12
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
and 7 more in the library