Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice

Introduction

Psychedelic compounds such as psilocybin and LSD are increasingly used and, in some jurisdictions, decriminalised, prompting rising public interest in microdosing—the repeated ingestion of subhallucinogenic amounts of these drugs. Because many classical psychedelics are potent agonists at serotonin receptors including 5-HT2A and 5-HT2B, there is a safety concern: chronic activation of 5-HT2B receptors has previously been implicated in drug-induced valvular heart disease and pulmonary hypertension (for example, with d-fenfluramine). Although a single high dose of a psychedelic is unlikely to produce cardiac damage, the cardiovascular consequences of prolonged low-dose (microdose) use remain poorly characterised. This preclinical study set out to assess whether chronic microdosing with LSD produces structural or functional cardiac changes in mice. The investigators compared two low LSD doses against vehicle and positive controls (serotonin and d-fenfluramine) using serial echocardiography, measured behavioural evidence of psychedelic activity to define subhallucinogenic doses, characterised agonist activity at mouse and human 5-HT2B receptors in vitro, and modelled 5-HT2B receptor occupancy over time using published human pharmacokinetic data. The work aims to elucidate whether the pattern and magnitude of 5-HT2B activation with microdosing are sufficient to produce cardiotoxic effects in this mouse model.