A Two-Threshold Model of Psilocybin Response Explains Variability in Psychedelic-Assisted Therapy for Treatment-Resistant Depression

Abstract

Abstract The COMP006 Phase 3 trial showed that 39% of patients with treatment-resistant depression (TRD) respond to a single 25 mg dose of psilocybin, while 61% do not — at identical dose, protocol, and pharmacological exposure. No mechanistic explanation for this heterogeneity has been established. Here we propose and validate a two-threshold model in which the psilocybin dose-response landscape is governed by two qualitatively distinct transitions: a universal first threshold at Dc1 = 18 ±1 mg and an individual-dependent second threshold near Dc2 ≈21–30 mg. Dc1 marks the pharmacological transition from ordinary to altered consciousness and is confirmed by five independent analytical methods applied to N > 700 subjects across two independent datasets, all converging within 1.5 mg. Dc2 marks the transition to transformative mystical experience and is governed not by dose but by individual psychological parameters — set, setting, and preparation — that modulate the probability of therapeutic benefit independently of pharmacology. Twelve independent lines of evidence across N > 3,000 subjects support this model, including pharmacokinetic data demonstrating that intersubject variability in subjective response is 52 times larger than variability in plasma drug levels, neural evidence from EEG showing that the two thresholds have distinct variability signatures, historical data from six randomised controlled trials of LSD for alcoholism showing near-zero inter-study heterogeneity (I2 ≈0%) predicted by the model, and direct evidence that mystical experience intensity — not dose — predicts antidepressant outcome. The primary clinical implication is falsifiable: intensive psychological preparation should increase therapeutic response more effectively than dose escalation above Dc1.