Molecules, meaning, and physiology: disentangling the active ingredients of psychedelic therapeutics.

Abstract

Psychedelic-assisted therapy has shown rapid and durable benefits across multiple psychiatric conditions, yet the mechanisms underlying these effects remain incompletely understood. Full-dose psychedelic sessions simultaneously engage serotonergic neurochemistry, high-intensity subjective experience, and autonomic-interoceptive physiology, making it difficult to determine which components are necessary or sufficient for therapeutic change. This perspective proposes that three partially separable research approaches, a single low dose of a psychedelic, high-ventilation breathwork, and vagus nerve stimulation (VNS), offer complementary mechanistic probes for disentangling these pathways. A single, sub-psychedelic dose provides a model of low-intensity 5-HT2A engagement that isolates pharmacological and early plasticity-related effects while minimizing experiential and autonomic confounds. Breathwork induces robust experiential and autonomic shifts through CO₂-driven physiological perturbation and interoceptive amplification, enabling investigation of experiential and autonomic contributions in the absence of serotonergic pharmacology. VNS, in turn, modulates vagal-autonomic and interoceptive circuits without inducing altered states of consciousness, offering a controlled method for probing autonomic influences on affective and cognitive processes. Examining these perturbations within shared experimental frameworks may clarify how neurochemical plasticity, experiential meaning-making, and autonomic recalibration interact to support psychological change. This mechanistic precision can guide the development of interventions that are safer, more scalable, and more individually tailored than current full-dose psychedelic protocols.

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