The risk of chronic psychedelic and MDMA microdosing for valvular heart disease

Abstract

Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT2B receptor. However, this risk has not yet been comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related to the VHD risk of lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), and the non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds and some metabolites could bind to the 5-HT2B receptor with potency equal to or greater than that of the 5-HT2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk. No animal or clinical studies appropriately designed to evaluate VHD risk were found for the four psychedelics. However, there is some clinical evidence that chronic ingestion of full doses of MDMA is associated with VHD. We conclude that VHD is a potential risk with chronic psychedelic microdosing, but further studies are necessary to better define this risk.

Effects of hallucinogenic drugs on the human heart

“…From these binding data of psilocin at 5-HT 2B -serotonin receptors, one would assume that psilocin cannot activate this receptor in the normal client or patient. Likewise, there is not any proof from clinical studies for valvular damage due to psilocin (Tagen et al, 2023). However, this side effect should be looked for in prospective clinical trials.…”

“…This might lead valvular heart disease (vide supra). However, others claimed that any proofs for valvular damage through LSD from clinical studies is currently lacking (Tagen et al, 2023). However, this valvular side effect should be looked for in prospective clinical trials.…”

Cardiovascular safety of psychedelic medicine: current status and future directions

“…Activation efficacy (Emax) is relative to serotonin Ca intracellular calcium assay; G q G q dissociation assay, PI phosphoinositol hydrolysis assay 1 3 in the case of LSD, the affinity for the 5-HT2B receptor is similar to its affinity for the 5-HT2A receptor. This suggests that psilocybin may have a relatively higher risk of valvular heart disease than LSD in microdosing therapies [100].…”

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

“…Agonist actions at the 5-HT 2B R cause cardiac valvulopathy and pulmonary hypertension, as seen with the anti-obesity medication fenfluramine ( Rothman and Baumann, 2009 ; Barnes et al, 2021 ). LSD and psilocin, the active metabolite of psilocybin, exhibit similar affinity at the 5-HT 2A R and 5-HT 2B R in vitro ( Porter et al, 1999 ), but neither are projected to pose risk for valvulopathy, particularly on acute dosing ( Tagen et al, 2023 ). However, given the critical liability of off-target 5-HT 2B R agonist actions ( Horvath et al, 2004 ; Hutcheson et al, 2011 ), current efforts to identify 5-HT 2A R-selective agonists as novel chemical entities require 5-HT 2B R affinity and efficacy screening early in molecule discovery ( Cao et al, 2022 ; Chen et al, 2023 ; Cunningham et al, 2023 ).…”