Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins

The extracted text presents a narrative, comparative review rather than a report of a primary empirical study. No explicit systematic search strategy, eligibility criteria, databases searched, or formal risk‑of‑bias assessment are described in the provided extract; the authors do not clearly report a reproducible literature‑search method in the available text. Instead, the investigators synthesised evidence from several sources: receptor pharmacology (Ki values at cloned human 5‑HT2B receptors), peak plasma concentrations observed after typical therapeutic or microdoses, in vitro functional assays (e.g. calcium flux, ERK phosphorylation, arrestin recruitment), preclinical animal models of valvulopathy, and clinical/epidemiological reports and echocardiographic studies of affected patient groups. A comparative table of 5‑HT2B affinities and peak plasma concentrations for known fibrotic drugs and commonly microdosed substances is presented in the text. The review integrates mechanistic literature on downstream signalling (including phospholipase C‑β, protein kinase C, MAPK, and transforming growth factor‑β1) that has been implicated in pro‑fibrotic responses.

The authors first summarise what is known about microdosing practice and the current evidence base. Typical microdoses are reported as 10–20 μg for LSD and about 0.3–0.5 g of dried psilocybin‑containing mushrooms; doses are commonly taken 2–4 times per week for weeks to months, and sometimes for years. Controlled trials of microdosing are few (the extract notes 11 randomized trials and one open‑label study to date) and the results are mixed, with some trials finding null effects and others suggesting placebo or expectancy influences. Turning to drug‑induced VHD, the review describes the clinical phenotype as valve thickening and impaired leaflet motion (fibrosis) leading to regurgitation, arrhythmias or heart failure in severe cases. Historical examples linked to fibrosis include methysergide (and its active metabolite methylergonovine), ergotamine, dihydroergotamine (DHE), pergolide and cabergoline in Parkinson’s disease, and anorectic agents such as fenfluramine/norfenfluramine. Reported epidemiology ranges from case series (for example methysergide: 10/1000 over 5 years in one report) to larger cohorts and meta‑analyses indicating markedly increased risk after prolonged exposure to some ergot‑derived drugs. Regulatory actions (withdrawals and use restrictions) for several of these agents are noted. The authors also report that higher‑dose MDMA (not microdoses) has been associated with echocardiographic abnormalities in some user cohorts. Mechanistic evidence converges on overstimulation of the 5‑HT2B receptor as the principal driver of drug‑induced valvulopathy: valvular fibroblasts express high levels of 5‑HT2B, and chronic agonism promotes fibroblast proliferation and extracellular matrix deposition. Preclinical work is cited showing that nordexfenfluramine‑induced valve lesions are prevented by 5‑HT2B antagonism or genetic deletion of the receptor in rodents, and antagonist studies in rats similarly block drug‑induced valvulopathy. The authors acknowledge that other pathways (for example 5‑HT2A or dopaminergic signalling) may contribute, but they present broad consensus that 5‑HT2B activation is necessary for the classical drug‑induced VHD phenotype. Comparative pharmacology data are highlighted. The authors note that drugs associated with VHD generally have high affinity for 5‑HT2B (Ki < 15 nM). Reported Ki values in the extract include: LSD ~0.98 nM and psilocin (the active metabolite of psilocybin) ~4.6 nM, both well below the 15 nM threshold; by contrast, lorcaserin and ropinirole, which have not been associated with VHD, show much weaker 5‑HT2B affinity (174 nM and 380 nM respectively). MDMA’s measured affinity is substantially weaker (around 500 nM), but it may contribute to valvulopathy by provoking large serotonin release rather than direct high‑affinity agonism. The review compares peak plasma concentrations after microdoses with those of known cardiotoxins: a reported microdose of LSD (0.01 mg) produced a peak total plasma concentration of 0.28 ng/mL; a typical cabergoline dose (1 mg p.o.) reaches about 0.04 ng/mL and has been associated with VHD after repeated use. A small oral psilocybin dose (3 mg) produced peak psilocin levels of ~2.3 ng/mL, which the authors note are comparable to levels seen with pergolide. From these comparisons, the reviewers argue that microdoses of LSD or psilocybin could conceivably produce systemic exposures sufficient to stimulate 5‑HT2B. Functional assay evidence is also discussed: psilocin shows potency in calcium flux assays at 5‑HT2B similar to methylergonovine and other valvulopathic drugs, and composite potency across several functional readouts (calcium flux, ERK2 phosphorylation, arrestin recruitment) correlates with fibrotic risk. Downstream signalling via transforming growth factor‑β (TGF‑β) is proposed as a promising molecular marker of pro‑fibrotic activity; MDMA has been associated with increased TGF‑β signalling in humans at higher doses, while the extract notes an absence of data on LSD/psilocybin effects on TGF‑β in humans. Finally, the review emphasises that no controlled studies have specifically assessed the risk of VHD in people who chronically microdose, and that duration of exposure — even intermittent weekly use over months or years — has been important in previously observed drug‑induced valvulopathies.

Rouaud and colleagues interpret the assembled evidence as indicating a plausible, though currently uncertain, risk that chronic microdosing could promote cardiac fibrosis and valvulopathy. They emphasise three converging lines of concern: (1) the mechanistic link between sustained 5‑HT2B agonism and valvular fibroblast proliferation demonstrated in preclinical models, (2) the high 5‑HT2B affinities of LSD and psilocin relative to many drugs known to cause VHD, and (3) pharmacokinetic comparisons suggesting that peak plasma levels from typical microdoses may fall within ranges capable of engaging 5‑HT2B. The authors place these findings in the context of prior experience with ergoline drugs and anorectic agents, where duration of exposure rather than single doses was critical to risk. They caution that some 5‑HT2B agonists (for example, ropinirole and lorcaserin) have not produced VHD, underscoring that affinity alone is not a perfect predictor and that functional potency across multiple assays appears important. The reviewers therefore present their conclusions as cautious and hypothesis‑generating rather than definitive: existing data support plausible biological mechanisms and pharmacological similarities, but direct clinical evidence linking microdosing regimens to VHD is lacking. Several limitations and uncertainties are acknowledged in the extract. The authors note the paucity of long‑term microdosing studies, the mixed and small‑sample nature of available trials, and the absence of systematic data on TGF‑β or other molecular fibrotic markers after psychedelic microdoses. They also recognise that the review itself is not presented with a clear systematic methodology in the available text, limiting the transparency of study selection. For future research and clinical monitoring, the authors recommend designing longer microdosing trials with features intended to minimise fibrotic risk (for example, incorporating drug‑free breaks), routine screening for vascular and valvular abnormalities (echocardiography), measurement of pro‑fibrotic biomarkers such as TGF‑β, cross‑sectional echocardiographic investigations of chronic microdoser cohorts, application of in silico models to estimate valvulopathy risk, and use of large survey datasets to monitor self‑reported cardiac symptoms—while emphasising that surveys cannot substitute for controlled clinical or imaging studies.

The extract concludes that chronic microdosing of serotonergic psychedelics may carry a credible risk of cardiac fibrosis and valvulopathy, given the mechanistic role of 5‑HT2B stimulation, the high 5‑HT2B affinity of LSD and psilocin, and pharmacokinetic comparisons indicating that microdose exposures could be biologically relevant. Because the available human data directly addressing long‑term microdosing and VHD are absent or inadequate, the authors call for targeted clinical studies and surveillance approaches that include echocardiographic screening, biomarker assessments, protocolised dosing breaks, in silico risk modelling, and cross‑sectional assessments of existing microdoser populations to determine whether the theoretical risk translates into measurable harm.