From Amygdala to Synapse: A Multimodal Longitudinal RCT of Psilocybin-Assisted Therapy for Major Depressive Disorder Integrating Neuroplasticity Biomarkers, Inflammatory Indices, and Acute Experiential Mediators

Abstract

Background: Psilocybin-assisted therapy (PAT) has demonstrated rapid and substantial antidepressant effects in phase 2 RCTs (Davis et al., 2021; Carhart-Harris et al., 2021), and phase 3 trials are now active (Usona uAspire, NCT06308653). However, three critical gaps remain unresolved in 2025: (1) the durability of effects beyond 12 months has not been established in a controlled design; (2) the neurobiological mechanisms — specifically the BDNF/TrkB neuroplasticity pathway (Moliner et al., 2023), glutamatergic modulation (Doss et al., 2021), and neuroinflammatory changes — have not been prospectively tested as mediators in a clinical RCT; and (3) the acute subjective experience (mystical quality, ego dissolution) has been examined only as a predictor of outcome, never as a mediator within a controlled longitudinal design. A 2025 meta-analysis confirmed large antidepressant effect sizes (SMD = −2.08) but flagged the absence of long-term data and biological mechanism testing as the field’s most urgent priorities (Menon et al., 2024). Objective: To evaluate the 24-month efficacy, durability, and multimodal biological and psychological mechanisms of psilocybin-AT for MDD, integrating neuroimaging, neuroplasticity biomarkers, neuroinflammatory indices, and acute experiential quality in a single pre-registered longitudinal RCT. Design: Randomised, double-blind, active-placebo-controlled parallel-group longitudinal RCT. Four assessment time points: T0 (baseline), T1 (6 months), T2 (12 months), T3 (24 months). Innovation: This is the first RCT to (i) use serum BDNF and MRS ACC glutamate as pre-specified human mediators of psilocybin’s antidepressant effect; (ii) include a full neuroinflammatory panel (IL-6, TNF-α, CRP, IDO-1) as secondary biomarkers; (iii) treat mystical experience quality (MEQ-30) and ego dissolution (5D-ASC) as pre-specified mediators rather than predictors; (iv) use ACC-PCC dynamic functional connectivity as an index of cognitive flexibility; and (v) employ an active expectancy-matched placebo (niacin) with blinding integrity formally assessed. Participants: N = 100 adults (18–65) with confirmed DSM-5 MDD (MADRS ≥ 20), randomised 1:1 to psilocybin-AT (n = 50) or active placebo + matched therapy (n = 50). Primary outcome: MADRS total score change from T0 to T1 (6 months). Novel secondary outcomes: Serum BDNF; ACC glutamate (MRS); IL-6, TNF-α, CRP, IDO-1; MEQ-30; 5D-ASC ego dissolution; ACC-PCC dynamic FC; cognitive flexibility (WCST perseverative errors); RRS; SRET. Power: G*Power 3.1: N = 100 provides 99% power for d = 0.80 at T1 (α = .05), adequate for 24-month durability under conservative attrition assumptions. Keywords: MDD; psilocybin-assisted therapy; BDNF; TrkB; neuroplasticity; neuroinflammation; mystical experience; cognitive flexibility; dynamic functional connectivity; 24-month RCT; precision psychiatry.

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