Serotonergic psychedelics, such as lysergic acid diethylamide, and psilocybin, and the entactogen 3,4-methylenedioxymethamphetamine exhibit agonist activity at the 5-hydroxytryptamine 2B receptor, a signalling pathway known to mechanistically mediate drug-induced valvular heart disease. This systematic review evaluates whether chronic or repeated use of psychedelics and 3,4-methylenedioxymethamphetamine may contribute to valvular heart disease through sustained 5-hydroxytryptamine 2B receptor activation. A systematic search of Google Scholar, OVID and PubMed was conducted from inception to June 1, 2025. We sought to include studies that reported an association between psychedelics or 3,4-methylenedioxymethamphetamine at 5-hydroxytryptamine 2B binding and molecular, cellular, structural, and/or functional evidence of cardiac valvulopathy. Seventeen studies were included in this review. No studies were found on psilocybin, dimethyltryptamine or mescaline. Both lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine have high affinity for 5-hydroxytryptamine 2B receptors and promote downstream signaling linked to mitogenic and fibrotic changes in valvular tissue. In vitro and structural studies show that lysergic acid diethylamide exhibits high affinity and induces β-arrestin-biased signaling in valvular interstitial cells, while 3,4-methylenedioxymethamphetamine displays moderate affinity and similar functional responses. In vivo studies confirm serotonin-induced valvulopathy, and chronic 3,4-methylenedioxymethamphetamine use has been associated with valvular abnormalities in humans. No clinical cases of lysergic acid diethylamide-induced valvulopathy have been reported, but preclinical data support its potential to engage fibrotic signaling pathways under sustained exposure. Preliminary converging mechanistic and preclinical evidence suggests that lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine may promote cardiac valvulopathy via 5-hydroxytryptamine 2B receptor signalling. This is consistent with existing Food and Drug Administration concerns and supports the need for ongoing cardiac and valvular safety monitoring in psychedelic research.
Psychedelic Science