Do Psychedelic Compounds Affect the Heart?
Part II of this article series discussed the abundance of psychedelic target receptors within the circulatory system. The heart, which is the muscular pump of this system, also expresses these receptors.1 It is reasonable to assume that classical psychedelics would change how the heart works by directly targeting it, as is true for other drugs targeting serotonergic (5-HT) receptors.2
In fact, heart rate changes after psychedelic intake may not be merely related to the emotional response to the experience itself. Animal studies performed under anesthesia to minimize changes attributed to emotional arousal report intrinsic cardiovascular effects of psychedelics.3 Moreover, for some compounds such as bufotenin, the highest concentration after administration in rodents is found in the heart rather than in the brain.4
Interestingly, research investigating psychedelics in the human brain is often based on cerebral blood flow because areas with increased functioning require increased blood perfusion to deliver oxygen and glucose as fuel for cells to work in a region-specific, demand-driven fashion. However, the activation of 5-HT2A by the psychedelic 25CN-NBOH directly modulates the pulse of carotid arteries, the vessels that take the blood through the neck to the brain.3 This observation may highlight that the heart and associated structures are in fact directly modulated by psychedelics.
The Psychedelic Target Receptors’ Puzzle in the Heart
Very few studies have been conducted with psychedelics in heart or vascular cells, which calls for inferences based on the receptors’ biology with endogenous serotonin. More critical than for other systems within the human body, the outcomes of drug exposure in the cardiovascular system largely depend on which subtype of serotonin receptor might be switched on or off. Serotonin exerts several described effects on the heart, such as increases in heart rate and force of contraction.1 On the other hand, serotonin was already shown to be involved in pathological processes such as the thickening of cardiac valves and irregular heart rhythms, known as arrhythmias.1 It seems that the wide variety of serotonin receptors ends up configuring a complex puzzle that requires further investigating to determine the molecular effects of psychedelics on the heart.
Upon binding at 5-HT4 receptors, for example, serotonin makes heart muscle contractions stronger, increasing the amount of blood the heart can pump out, a mechanism associated with arrhythmias.5 The selective activation of 5-HT2B receptors is a molecular event detrimental to cardiac valves, causing excessive thickening and potentially fatal consequences.6,7 This mechanism raises concerns regarding the risks associated with repeated activation of this receptor as part of a microdosing regimen, particularly for molecules with high affinity for 5-HT2B receptors such as LSD and psilocin.
Although psychedelic compounds have different affinity profiles for serotonin receptors, a closer look into the signaling pathway through the 5-HT2A subtype, which is their main target for subjective effects, may help to narrow the possibilities. First, 5-HT2A activation was shown to be part of the primary mechanism by which the aorta – the body’s biggest artery – contracts to pump blood.8,9 In fact, 5-HT2A is expressed in vascular smooth muscle cells and endothelial cells of blood vessels where they mediate vasoconstriction, which is thought to be the mechanism by which psychedelics transiently increase blood pressure.8,10,11 However, activation of 5-HT2A receptors in the central nervous system was shown to lower blood pressure and heart rate.12
In addition to constrictive mechanisms, 5-HT2A has also been studied regarding its anti-inflammatory signaling. The agonistic activity by DOI and LSD at these receptors in primary aortic smooth muscle cells inhibits inflammation.13 Since inflammation coincides with the hardening and narrowing of the arteries during gradual fatty plaque buildup, 5-HT2A agonists could be considered a potential therapeutic avenue to treat atherosclerosis.
The distribution of serotonin receptors can also lead to divergent outcomes. Although in peripheral tissues 5-HT2A receptors were shown to mediate acute vascular constriction, in arteries around the brain, the 5-HT1B subtype seems to play a more prominent role.14,15 A similar profile is observed for coronary arteries, the vessels that supply blood to the heart walls, where only 5-HT1B receptors appear to be involved in coronary spasms.16 Intriguingly, even opposite contractile responses in separate segments of the very same coronary artery were reported upon serotonin signaling.17
To further complicate this issue, some psychedelics target not only serotonin receptors but also adrenaline, dopamine, and sigma receptors, among others. When present, these molecules’ adrenergic effects are usually mild and can give rise to general arousal due to increased sympathetic nervous system function.18 This mimics adrenaline to cause pupil dilation and increased heart rate and blood pressure, but cardiovascular complications are rarely severe. For dopamine receptors, despite the association of the D1 subtype in cardiac muscle with heart failure, dopamine infusions are still used in the clinic to manage congestive heart failure acutely. This makes it hard to theorize the final outcome after exposure to psychedelics that also binds to these receptors.19,20
At sigma-1 receptors, widely studied in the heart, its activation is reasonably well accepted as a cardioprotective mechanism against excessive cardiac muscle growth, arrhythmias, and heart failure.21–28 Unfortunately, no study has yet assessed the role of any psychedelics on sigma-1-mediated cardioprotection. However, given the affinity of DMT for this receptor, it is reasonable to hypothesize about a beneficial impact on heart health. Whether this presumed beneficial effect would be counteracted by detrimental 5HT2B activation, also a DMT target, remains unexplored.
The cardiac effects of psychedelics result from this complex polypharmacology with different affinities for various receptors, which is why their precise molecular mechanism on the heart remains largely unknown. Since the consequences of psychedelic binding in the heart are controversial when studying basic receptor biology, assessing the final cardiovascular outcomes after psychedelic administration in humans may be the best route to gain insights into this complex microscopic puzzle.
Clinical Studies on Cardiovascular Function Under Psychedelics
There are few reports on adverse cardiovascular effects associated with psychedelic use in the medical scientific literature. The lack of case reports is partly a result of the safety of these drugs, reflected by consistently low emergency visits in the US (0.1% of hospital admissions), with less than 1% of users reporting seeking medical assistance.29,30 Nevertheless, given that the mechanisms of action of psychedelics are complex with various agonist, partial agonist, and antagonist effects at the widely distributed target receptors, a justifiable caution should be maintained by cardiologists.31
Unfortunately, the few pieces of evidence of cardiac risks come from the first wave of research between the ‘50s and ‘60s, which wouldn’t meet the scientific scrutiny of the present day. A case report dating back to the ‘90s describes a heart attack presumably associated with chronic consumption of a psilocybin-containing mushroom.32 However, whether the mushroom intake was a confounding variable was unclear. Recent studies in humans evaluating cardiovascular parameters are still scarce but can help to draw a more realistic landscape of the risks of psychedelics to the heart.
A recent case report correlated the ingestion of the same species of mushroom (Psilocybe semilanceata) reported in the ‘90s case report with a reversible type of cardiomyopathy popularly known as the “broken-heart syndrome” where the patient responded to standard medical care.33 LSD may have accounted for two cases of cardiac arrest in young adults with previous heart conditions, namely, Brugada syndrome and malignant coronary anomaly.34,35 In healthy subjects under a controlled setting, however, even at high doses, psychedelics, such as psilocybin and DMT, only elicit minor transient increases in heart rate and blood pressure.36–40 As nicely reviewed by Schlag and colleagues,41 psychedelics indeed induce short-term sympathomimetic effects (i.e., adrenergic, as mentioned above) in healthy subjects, including increased body temperature, blood pressure, and heart rate while the substance is active, with no later medical assistance required.42 Noteworthy safety guidelines for human psychedelic research published in 2008 stated that there were no reports of patients who experienced a medically dangerous rise in blood pressure.43 In fact more recently, a national survey showed lower odds of hypertension associated with those who report lifetime use of a classic psychedelic.44,45
A recent study evaluated the effects of psilocybin on electrocardiogram QT interval, which roughly corresponds to the time it takes for the heart muscle to contract and recover for the next contraction. The study reported a consistent but shallow prolongation of 2.1 milliseconds (msec) following a 25 mg oral psilocybin dose; however, only prolongations greater than 60 msec are considered a risk value for arrhythmias.46,47 Similar results were obtained with 2.5-fold higher doses, and no serious adverse effects were reported.46 However, the effects of higher doses of psilocybin on this parameter are being further investigated in an ongoing clinical trial by the Usona Institute.48 Since the most common reason for drug-induced QT prolongation is blockage of the human ether-a-go-go-related gene (hERG) potassium channels in the heart, further experimental research was performed on that issue.49 Scientists found that a 500-fold higher psilocin concentration than that actually reached in human plasma after a 25 mg psilocybin dose is needed to cause relevant hERG channel inhibition.50
Recently, it has also come to attention that even the subjective effects of a psychedelic experience may contribute to lifestyle changes that could minimize cardiometabolic risk factors such as improved dietary habits and diminished alcohol and tobacco use.51 This giant puzzle is only starting to be put together, and the hope is that multidisciplinary studies will soon help the scientific community to establish a balanced map of the cardiovascular risks and benefits of psychedelics.