Psychedelic medicine: The biology underlying the persisting psychedelic effects

Introduction

Psychedelics such as psilocybin, ayahuasca and LSD have re-emerged as potential therapeutic agents for severe stress-related disorders, including treatment-resistant depression. Kuypers summarises preliminary clinical findings showing sustained symptom improvement after very limited dosing—acute improvement up to seven days after a single ayahuasca dose and symptom reductions lasting up to six months after two psilocybin sessions—and notes survey and naturalistic reports of lasting reductions in stress and depressive affect. The paper also highlights the growing interest in micro-dosing, the repeated use of sub-perceptual doses (often around one-tenth of a full dose), which users anecdotally report improves concentration, creativity and ADHD symptoms despite producing no overt psychedelic experience. This paper sets out to propose mechanistic hypotheses for the persisting psychological effects of both regular and low (micro-)doses of psychedelics. Rather than present new empirical data, Kuypers integrates prior findings and argues for a central role of sleep processes in the lasting effects of regular doses and for an indirect, gut-mediated route—via the microbiome and related metabolic pathways—for low doses. The author frames these as testable hypotheses and outlines experimental approaches to evaluate them, while acknowledging that multiple interacting biological systems are likely involved but are not the focus here.