Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats

Introduction

Psilocybin, a serotonergic psychedelic prodrug that is converted to the psychoactive psilocin, has shown efficacy in treating depression, end-of-life anxiety and substance-use disorders when given as single high doses combined with psychotherapy. An alternative practice, commonly called microdosing, consists of repeated administrations of very low doses that do not produce overt psychedelic effects; human observational studies report mood, well‑being and cognitive benefits but are vulnerable to expectation and placebo effects and lack rigorous biological validation. The authors therefore sought to establish an objective, translational psilocybin ‘‘microdosing’’ regimen in rats based on in vivo 5-HT2A receptor occupancy, and to test whether repeated low doses produce measurable behavioural and neurobiological effects. Kiilerich and colleagues aimed to determine a dose that occupies less than 20% of brain 5-HT2A receptors (a threshold previously linked to absence of overt psychedelic effects), then to apply that dose intermittently over multiple weeks and assess behaviours relevant to anxiety, anhedonia and compulsivity, together with receptor and synaptic markers postmortem. The study combined in vivo PET receptor-occupancy experiments, in vitro receptor pharmacology and functional assays, a repeated low-dose treatment regimen, multiple behavioural tests (open-field, pre-pulse inhibition of the acoustic startle reflex, sucrose preference, elevated plus maze) and autoradiographic quantification of 5-HT receptors and synaptic vesicle protein 2A (SV2A). The authors hypothesised that repeated low doses would alter behaviours linked to mood, anxiety and compulsivity and produce detectable receptor or synaptic changes.