2026 ECNP Congress

PS03-3222

Disentangling pharmacological and experiential contributions to psilocybin’s antidepressant effects: A mechanistic sub-analysis of a randomized controlled trial in treatment-resistant depression

Lea J Mertens — D. Scharf, M. Spangemacher, L. Kärtner, M. Koslowski, M. Böttcher, M. Berger, G. Gründer · Central Institute of Mental Health, Department of Molecular Neuroimaging, Mannheim, Germany

2026 ECNP Congress

Introduction

Psilocybin, a partial 5-HT2A receptor agonist, has demonstrated robust antidepressant effects, with clinical outcomes consistently associated with the acute psychedelic experiences [1, 2]. Neuroimaging studies have linked psilocin plasma levels – the active metabolite of psilocybin – to 5-HT2A receptor occupancy, with both correlating with the acute subjective experiences [3]. Relatedly, whether psilocybin therapy is best conceptualized as a pharmacological intervention or as psychedelic-assisted psychotherapy, where pharmacological and psychological processes interact, remains an unresolved debate.

Objectives

This study aimed to disentangle the contributions of pharmacological (psilocin plasma levels) and psychological (acute subjective experiences) processes in psilocybin’s antidepressant effects in treatment-resistant depression (TRD).

Methods

As part of mechanistic investigations of a phase 2b, randomized active placebo-controlled trial in treatment-resistant depression (TRD), participants received two dosing sessions with adjunct psychotherapy, administering active placebo (100 mg nicotinamide), 5 mg or 25 mg psilocybin (dose 1; administered at week 0) or 5 mg or 25 mg psilocybin (dose 2; administered at week 6). During each dose, psilocin plasma levels were assessed after two (T1) and three (T2) hours (N=128); individual peak levels were derived from these time points. Acute subjective effects were assessed using the 11D-Altered States of Consciousness Rating Scale (11D-ASC), the Emotional Breakthrough Inventory (EBI) and the Challenging Experience Questionnaire (CEQ) at the end of dosing days. Depression severity was assessed with the Hamilton Rating Scale for Depression (HAMD17) at baseline, as well as one week and six weeks after each dose. Two regression models were estimated: a repeated-measures model of psilocin levels at T1 and T2, and a multiple regression modeled of individual peak levels, each including dose, sex, age, body weight and time. Mediation analyses tested whether the effect of peak psilocin levels on antidepressant outcomes (HAMD17 change from baseline) was mediated by the acute psychedelic experiences (EBI, CEQ, 11D-ASC).

Results

Mean (SD) peak psilocin plasma levels were 16.9 (5.12) and 3.90 (1.47) ng/mL after 25 mg psilocybin and 5 mg psilocybin (dose 1), respectively. Psilocin plasma levels were strongly predicted by dose, with weak evidence for a sex effect. Peak psilocin levels significantly predicted changes in HAMD17 scores from baseline at one (β = -0.31, 95% CI, -0.51 to -0.12, p<0.003) and six weeks (β = -0.33, 95% CI, -0.52 to -0.14, p<0.001), with model fit comparable to models using dose as predictor. Across time points, female sex was associated with higher HAMD17 scores, with estimated mean differences of 4.38 (95% CI: 0.34 – 8.43, p = 0.029) at one week and 4.72 (95% CI: 0.89 – 8.56, p = 0.019) at six weeks. Crucially, most of the total effect of peak psilocin levels on HAMD17 change from baseline at one and six weeks was mediated by the EBI. Additional experiential dimensions are currently under investigation.

Conclusions

These preliminary findings from a large TRD sample highlight the interplay between pharmacological and psychological processes in psilocybin’s antidepressant effects. This has important implications for clinical implementation and treatment optimization and should guide future mechanistic studies.

References

  1. Mertens LJ, Koslowski M, Betzler F, Brand M, Evens R, Kärtner L, Jungaberle A, Jungaberle H, Majic T, Schmitz CN, Ströhle A, Scharf D, Spangemacher M, Wolff M, Assadi Z, Bahri S, Becher L, Färber LV, Kirchen N, Kulakova E, Kunz L, Meijer A, Rohrmoser B, Wellek S, Berger MM, Gründer G. Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial. JAMA Psychiatry. 2026 Mar 18:e260132. doi: 10.1001/jamapsychiatry.2026.0132.
  2. Romeo B, Kervadec E, Fauvel B, Strika-Bruneau L, Amirouche A, Bezo A, Piolino P, Benyamina A. The intensity of the psychedelic experience is reliably associated with clinical improvements: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2025 May;172:106086. doi: 10.1016/j.neubiorev.2025.106086.
  3. Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbæk DS, Kristiansen S, Johansen SS, Lehel S, Linnet K, Svarer C, Erritzoe D, Ozenne B, Knudsen GM. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019 Jun;44(7):1328-1334. doi: 10.1038/s41386-019-0324-9. Epub 2019 Jan 26. Erratum in: Neuropsychopharmacology. 2019 Jun;44(7):1336-1337. doi: 10.1038/s41386-019-0360-5.