Review: Cardiovascular Effects and Safety of Classic Psychedelics
Key findings
- The U.S. Food and Drug Administration has awarded its Breakthrough Therapy Designation to several psychedelic drugs to expedite their development and review. But for practical and regulatory reasons, the large prospective safety databases typically accrued during drug development are lacking for psychedelics
- Jeremy N. Ruskin, MD, and colleagues recently reviewed how classic psychedelics affect the cardiovascular system
- This summary presents an overview of the current state of the evidence and the knowledge gaps that require further investigation
The U.S. Food and Drug Administration has awarded its Breakthrough Therapy Designation to several psychedelic drugs to expedite their development and review. However, for practical and regulatory reasons, the large prospective safety databases typically accrued during drug development are lacking for psychedelics.
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Jeremy N. Ruskin, MD, founder and director emeritus of the Telemachus & Irene Demoulas Family Foundation Center for Cardiac Arrhythmias at Massachusetts General Hospital and a cardiologist at Massachusetts General Hospital, and colleagues recently reviewed in Nature Cardiovascular Research how classic psychedelics affect the cardiovascular system. This summary presents an overview of the current state of the evidence and the knowledge gaps that require further investigation.
Classic vs. Nonclassic Psychedelics
Classic psychedelics are a class of psychoactive drugs whose primary effects are mediated by agonism of the serotonin 2A receptor. They are generally categorized as:
- Tryptamines — Psilocybin, psilocybin-containing mushrooms, N,N-dimethyltryptamine (DMT), and the DMT-containing commixture ayahuasca
- Lysergamides — Most prominently lysergic acid diethylamide (LSD)
- Phenethylamines — Mescaline, the mescaline-containing cacti peyote and San Pedro, 4-bromo-2,5-dimethoxyphenethylamine (2C-B), and 2,5-dimethoxy-4-iodoamphetamine (DOI)
Examples of nonclassic psychedelics are cannabinoids, ketamine, 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy or molly), and ibogaine. The psychoactive effects, chemical structures, mechanisms of action, and cardiovascular effects of these drugs differ from those of classic psychedelics.
Cardiovascular Safety in Healthy Individuals at Standard Doses
Clinical studies suggest classic psychedelics are physiologically safe and well tolerated when administered under medical supervision to physically healthy individuals. At standard doses, their acute cardiovascular effects are generally limited to mild, transient elevations in heart rate and blood pressure that rarely require intervention.
In fact, the safety ratio of most classic psychedelics (the extrapolated oral median lethal dose divided by the standard oral recreational dose) is higher than those of ethanol and caffeine. For example, the safety ratio is 310 for mescaline, 600 for psilocybin, and >1,000 for LSD compared to 35–50 for caffeine and 10 for ethanol.
Cardiovascular Safety at High Doses
At high doses of classic psychedelics, serious cardiovascular adverse events have been reported in rare cases:
- High-dose psilocybin has been linked to QT prolongation
- Cardiac arrest, ventricular dysfunction, myocardial infarction, and other cardiovascular toxicities have been reported in rare cases after psilocybin ingestion at high doses or in medically compromised individuals
- Extremely high-dose LSD has been associated in rare instances with severe peripheral vasoconstriction
- In rat aorta, chronic high-dose ayahuasca (DMT + monoamine oxidase inhibitors) was linked to substantial structural changes consistent with hypertensive effects
Knowledge Gap: Valve Disease
Some serotonergic drugs are known to increase the risk of drug-induced cardiac valvulopathy via activity at the 5-HT2B receptor. During the long history of the use of classic psychedelics, valvular heart disease has not been reported, and adverse events related to valve pathology have not been observed in clinical studies. However, no clinical study of classic psychedelics to date has included echocardiographic analysis as an outcome measure.
Knowledge Gap: Safety in Patients With Heart Disease
Safety data on the use of classic psychedelics by individuals with cardiovascular disease are lacking. The need for well-designed clinical trials is substantial because of the high prevalence of serious anxiety and depression in this population, the potential for therapeutic benefit, and the fact that many currently prescribed antidepressant drugs carry substantial cardiac liability.
Other Knowledge Gaps
For now, medical therapy with psychedelics typically involves only one to three doses in anticipation of sustained benefits. Repetitive, long-term exposures (for example, microdosing) will need careful study for cardiac safety.
Data will also be needed on drug–drug interactions. Given the proposed indications for psychedelics, the use of concomitant medications (both psychotropic and other) is inevitable.
As the use of psychedelics expands and as second- and third-generation agents enter preclinical and clinical testing, rigorous collection of safety data must be pursued. Drug development programs should include cardiac ion channel profiling and standard ECG and hemodynamic safety studies and, where indicated based on affinity for the 5-HT2B receptor, clinical echocardiographic studies to evaluate potential liability for cardiac valve pathology.
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