Effects of hallucinogenic drugs on the human heart

Neumann and colleagues frame this review around a group of structurally related tryptamine-derived hallucinogenic compounds: bufotenin, psilocin, psilocybin, lysergic acid diethylamide (LSD), ergotamine, ergometrine, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). These molecules resemble serotonin (5-HT) and therefore interact with cardiac serotonin and histamine receptors. Earlier work shows that, in humans, 5-HT increases cardiac force and rate primarily via 5-HT4 receptors rather than the 5-HT2A/3 subtypes that mediate effects in some other species; histamine acts via H2 receptors. Species differences in receptor expression complicate extrapolation from common laboratory animals to human cardiac physiology. This paper aims to consolidate available evidence on the inotropic (force) and chronotropic (rate) effects of the listed hallucinogens on the mammalian, and specifically the human, heart. Neumann and colleagues present mechanistic considerations (receptor binding and intracellular cAMP/PKA signalling), animal and transgenic mouse data, isolated human tissue experiments, clinical pharmacokinetics and small human studies, and case reports to identify potential cardiac risks and therapeutic countermeasures when these agents are used clinically or recreationally.

The extracted text does not present a dedicated Methods section or a clear description of systematic search methods, inclusion/exclusion criteria, databases searched, or formal risk-of-bias assessment. From the content, this review appears to be a narrative synthesis drawing on multiple types of evidence rather than a formal systematic review or meta-analysis. Evidence sources and experimental approaches cited in the review include: in vitro ligand-binding studies to characterise receptor affinities; functional assays in isolated cardiac preparations (human atrial strips, ventricular tissue, and animal hearts); transgenic mouse models that overexpress human 5-HT4 or H2 receptors (5-HT4-TG and H2-TG) to model human cardiac responses; pharmacokinetic and small clinical studies in healthy volunteers; case reports of intoxication; and biochemical studies on metabolism (e.g. CYP2D6 and MAO pathways). Where relevant, the authors integrate reported plasma or tissue concentrations, dose–effect relationships, and interactions with phosphodiesterase (PDE) inhibition or cytochrome/P450 metabolism.

Neumann and colleagues summarise evidence compound by compound, emphasising receptor interactions, functional cardiac effects, pharmacokinetics and clinical observations. Bufotenin: Structurally similar to serotonin, bufotenin binds in vitro to multiple 5-HT subtypes (including 5-HT2A/2C and 5-HT1A/1B/1D) and may also interact with 5-HT2B receptors implicated in drug-induced valvulopathy. Functional data indicate positive chronotropic and inotropic effects in porcine preparations and in transgenic mice overexpressing human 5-HT4 receptors; effects in isolated human atrial strips were antagonised by 5-HT4 antagonists. Bufotenin increases phospholamban phosphorylation in 5-HT4-TG tissue, consistent with cAMP/PKA-mediated augmentation of Ca2+ handling. Peroral bioavailability is low (first-pass effect): hallucinogenic oral doses reported around 100 mg versus parenteral doses of about 10 mg. Endogenous bufotenin has been detected in human plasma and reported levels were elevated in some psychiatric disorders; the clinical relevance is uncertain. The authors note that prolonged 5-HT2B stimulation could, in principle, promote valvular fibroblast proliferation and valvular heart disease. LSD: Binding studies show high affinities for 5-HT1A, 5-HT2A and 5-HT2C receptors, with lower affinity for 5-HT2B and measurable affinity for 5-HT4 and H2 receptors (around 10 µM). Functionally, LSD can act as a partial agonist at cardiac H2 receptors and a partial agonist/antagonist at serotonin receptors; it also shows β-adrenergic antagonism in some assays. Clinical dosing examples: low oral doses (up to 26 µg) raised systolic blood pressure without affecting mean heart rate, whereas 100–200 µg oral increased blood pressure and heart rate, peaking about 1 hour post-dose and resolving within ~12 hours; a 200 µg dose yielded a peak plasma concentration of about 25 ng/mL. Intoxication reports noted plasma concentrations up to 5.9 nM and brain tissue concentrations up to 33 µM. Cardiac observations during LSD use include sinus tachycardia and hypertension. The authors suggest H2 antagonists (e.g. cimetidine, ranitidine) for management of LSD-induced tachycardia. Ergotamine: Shares the lysergic acid core with LSD and binds 5-HT2A and 5-HT2B receptors; it also has partial α1-adrenoceptor agonism producing vasoconstriction. Ergotamine exposure has been linked historically to valvular heart disease, plausibly via chronic 5-HT2B stimulation. High plasma concentrations reported in intoxications (for example 0.015 µM) could be pharmacologically active on cardiac receptors. In isolated human right atrial preparations ergotamine increased force via H2 receptors; species differences limit extrapolation from some animal data. Ergometrine (ergonovine): An ergoline used clinically in obstetrics, ergometrine interacts with multiple receptor classes (α1/α2 adrenoceptors, 5-HT1, 5-HT2A, H2 and 5-HT4). It induces peripheral vasoconstriction and coronary constriction in susceptible patients and has been associated with provoking atrial fibrillation postpartum in case reports. In transgenic atrial tissues (H2-TG, 5-HT4-TG) ergometrine increased force and rate, more effectively via H2 receptors. Therapeutic peak plasma concentrations when used in gynaecology are reported as about 4 nM, below concentrations expected to affect contractility in many assays; higher levels in intoxication could have cardiac effects. Like LSD and ergotamine, ergometrine can show a time- and concentration-dependent negative inotropic effect in the absence of PDE inhibition, attributed partly to β-adrenoceptor antagonism. N,N-dimethyltryptamine (DMT): DMT binds multiple 5-HT receptors (notably 5-HT1A with highest affinity, followed by 5-HT2A/2C and 5-HT2B at ~3.4 µM). Functional effects include positive chronotropy in rabbit hearts, though mechanisms in rabbits differ from humans (noradrenaline release rather than 5-HT4 mediation). Intravenous DMT (0.3 mg/kg) produced peak plasma levels of ~70 ng/mL (~0.38 µM) and increased heart rate and blood pressure in a placebo-controlled human study. Oral DMT is inactivated by gut MAO-A unless administered with MAO inhibitors as in ayahuasca; ayahuasca pharmacokinetics show a DMT half-life reported as about 260 minutes and a large reported volume of distribution. Binding to 5-HT2B raises a theoretical concern about valvular effects with prolonged exposure, though clinical proof is lacking. 5-MeO-DMT: Found in plants and toads, 5-MeO-DMT is metabolised by CYP2D6 to bufotenin. Typical reported hallucinogenic doses are around 10 mg (≈0.14 mg/kg) by various administration routes. In isolated human atrial tissue, 5-MeO-DMT was more potent than DMT at increasing contractile force; these effects were reduced by tropisetron, implicating 5-HT4 receptors. The metabolism by CYP2D6 implies interindividual variability and the potential for drug interactions with CYP2D6 inhibitors. Psilocin and psilocybin: Psilocin binds strongly to 5-HT2A/2C receptors and shows little affinity for 5-HT2B (Ki >20 µM), suggesting a low valvulopathy risk from 5-HT2B. Functional experiments reported positive inotropic and chronotropic effects in isolated human atrial preparations, and these effects were antagonised by tropisetron, indicating mediation via 5-HT4 receptors and cAMP signalling. Psilocybin is a prodrug converted to psilocin; peroral psilocybin doses (for example 30 mg) produced peak plasma psilocin around 0.1 µM and about 50% brain 5-HT2A receptor occupancy. Clinical reports describe tachycardia and increased blood pressure after therapeutic doses; small clinical trials reported mixed findings on ECG intervals and arrhythmias, with sample sizes typically small. The authors note that phosphodiesterase inhibitors (e.g. milrinone, theophylline, caffeine) can potentiate cardiac effects of serotonergic agonists and thus may amplify psilocin’s cardiac actions in susceptible patients. Cross-cutting findings: Several hallucinogens can increase atrial force and rate via human 5-HT4 or H2 receptors in isolated human tissue or in transgenic mouse models engineered to express human cardiac receptors. Many of the cardiac effects are mediated through cAMP–PKA signalling, increasing L-type Ca2+ current and phospholamban phosphorylation, thereby enhancing Ca2+ handling. The authors repeatedly stress species differences and the modulation of effects by co-administered drugs (PDE inhibitors, MAO inhibitors, CYP2D6 inhibitors) and by genetic polymorphisms (CYP2D6). Therapeutic or emergency countermeasures proposed include H2 antagonists (cimetidine/ranitidine) and 5-HT4 antagonists such as tropisetron or piboserod, although availability and CNS penetration differ between agents. Finally, several agents have the theoretical or observed potential to contribute to vasoconstriction (via 5-HT2A/1B) or to valvular pathology (via prolonged 5-HT2B stimulation), but clinical evidence for valvulopathy is strongest for some ergot derivatives and remains limited or absent for others.

Neumann and colleagues interpret the assembled evidence as indicating that tryptamine-derived hallucinogens can exert meaningful cardiac actions in humans through direct receptor interactions rather than solely via indirect sympathomimetic mechanisms. They emphasise that 5-HT4 and H2 receptor activation in atrial tissue explains many positive inotropic and chronotropic effects observed in isolated human preparations and in humanised transgenic mouse models, while 5-HT2A/1B receptor activation in vascular beds may provoke vasoconstriction with potential ischaemic consequences. The authors position these findings relative to prior literature by noting substantial species differences that complicate extrapolation from standard laboratory animals to humans; to address this, they highlight transgenic mouse models expressing human cardiac receptors as useful tools. They also reconcile apparently paradoxical findings (for example concentration-dependent negative inotropy) by pointing to partial agonism or antagonism at different receptor classes, and to interaction with β-adrenergic signalling. Key limitations acknowledged include the narrative (non-systematic) nature of the review and reliance on heterogeneous evidence: in vitro binding, isolated tissue experiments, transgenic animals, small human pharmacokinetic and physiological studies, and case reports. The authors note that many clinical studies are small, that concentrations measured in intoxications vary widely, and that for several compounds there is limited or no longitudinal clinical data on outcomes such as valvular disease. They explicitly state that proof of valvular damage in humans is lacking for several agents despite mechanistic plausibility. Regarding implications, the authors recommend clinical vigilance for proarrhythmic and haemodynamic side effects when these agents are used therapeutically or recreationally. Practical suggestions include readiness to treat tachycardia or arrhythmias with H2 or 5-HT4 antagonists (tropisetron, piboserod), consideration of β-blockers to blunt heart-rate increases during therapeutic use of psilocybin, and caution when patients are taking PDE inhibitors, MAO inhibitors, or drugs that inhibit CYP2D6. Finally, they call for controlled clinical trials and prospective cardiac monitoring to better define safety profiles and to make therapeutic use safer.