Rapid antidepressant effects of psilocybin without increased SV2A binding: baseline binding predicts response
- 1Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm
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.
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BibTeX
@misc{yngwe2026rapid,
title = {{Rapid antidepressant effects of psilocybin without increased SV2A binding: baseline binding predicts response}},
author = {H. Yngwe and P. Plaven Sigray and M. Andersson and M. Bolin and M. Beckman and C.-J. Ekman and M. Tiger and J. Lundberg},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.26367247},
url = {https://www.medrxiv.org/content/10.64898/2026.11.06.26367247v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Rapid antidepressant effects of psilocybin without increased SV2A binding: baseline binding predicts response
AU - H. Yngwe
AU - P. Plaven Sigray
AU - M. Andersson
AU - M. Bolin
AU - M. Beckman
AU - C.-J. Ekman
AU - M. Tiger
AU - J. Lundberg
PY - 2026
DA - 2026/11/06
PB - medRxiv
DO - 10.64898/2026.11.06.26367247
UR - https://www.medrxiv.org/content/10.64898/2026.11.06.26367247v1
AB - 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.
ER -