Whole-Body Effects of Psychedelics Part 3 – The Heart

What is known about the divergent roles of the microscopic targets within the cardiovascular system and the cardiac risks versus benefits of psychedelics?

-

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.

José is a biomedical scientist, specialist in Neurorehabilitation, master in Cell Biology, and Assistant Professor of Tissue Biology based in Brazil. He is currently pursuing his PhD in Cellular Biology, investigating the effects of psychedelics on brain organoids at the Federal University of Rio de Janeiro (UFRJ).

Comments

Subscribe
Notify of

1 Comment
Oldest
Newest Most Voted
Inline Feedbacks
View all comments
Mike
2 years ago

Feel like I came in and left with the same knowledge iv had on this subject trying to find info on my own… We def need more studies done

    References
  1. Neumann J, Hofmann B, Gergs U. Production and Function of Serotonin in Cardiac Cells. Serotonin - A Chem Messenger Between All Types Living Cells. Published online July 26, 2017. doi:10.5772/INTECHOPEN.69111
  2. Ayme-Dietrich E, Aubertin-Kirch G, Maroteaux L, Monassier L. Remodelage cardiovasculaire et système sérotoninergique périphérique. Arch Cardiovasc Dis. 2017;110(1):51-59. doi:10.1016/J.ACVD.2016.08.002
  3. Buchborn T, Lyons T, Song C, Feilding A, Knöpfel T. The serotonin 2A receptor agonist 25CN-NBOH increases murine heart rate and neck-arterial blood flow in a temperature-dependent manner. J Psychopharmacol. 2020;34(7):786-794. doi:10.1177/0269881120903465
  4. Fuller RW, Snoddy HD, Perry KW. Tissue distribution, metabolism and effects of bufotenine administered to rats. Neuropharmacology. 1995;34(7):799-804. doi:10.1016/0028-3908(95)00049-C
  5. Kaumann AJ. Do human atrial 5-HT4 receptors mediate arrhythmias? Trends Pharmacol Sci. 1994;15(12):451-455. doi:10.1016/0165-6147(94)90058-2
  6. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003;63(6):1223-1229. doi:10.1124/MOL.63.6.1223
  7. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: A new complication of the ergot derivative dopamine agonists. Mov Disord. 2004;19(6):656-662. doi:10.1002/MDS.20201
  8. McKune C, Watts S. Characterization of the serotonin receptor mediating contraction in the mouse thoracic aorta and signal pathway coupling - PubMed. J Pharmacol Exp Ther . 2001;297(1):88-95. Accessed September 5, 2022. https://pubmed.ncbi.nlm.nih.gov/11259531/
  9. Rothman RB, Baumann MH. Serotonergic drugs and valvular heart disease. Expert Opin Drug Saf. 2009;8(3):317-329. doi:10.1517/14740330902931524
  10. Nagatomo T, Rashid M, Abul Muntasir H, Komiyama T. Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacol Ther. 2004;104(1):59-81. doi:10.1016/J.PHARMTHERA.2004.08.005
  11. Brattelid T, Qvigstad E, Birkeland JAK, et al. Serotonin responsiveness through 5-HT2A and 5-HT4 receptors is differentially regulated in hypertrophic and failing rat cardiac ventricle. J Mol Cell Cardiol. 2007;43(6):767-779. doi:10.1016/J.YJMCC.2007.08.019
  12. Comet MA, Bernard JF, Hamon M, Laguzzi R, Sévoz-Couche C. Activation of nucleus tractus solitarius 5-HT2A but not other 5-HT2 receptor subtypes inhibits the sympathetic activity in rats. Eur J Neurosci. 2007;26(2):345-354. doi:10.1111/J.1460-9568.2007.05673.X
  13. Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD. Serotonin 5-hydroxytryptamine2A receptor activation suppresses tumor necrosis factor-α-induced inflammation with extraordinary potency. J Pharmacol Exp Ther. 2008;327(2):316-323. doi:10.1124/jpet.108.143461
  14. Razzaque Z, Pickard JD, Ma QP, et al. 5-HT1B-receptors and vascular reactivity in human isolated blood vessels: assessment of the potential craniovascular selectivity of sumatriptan. Br J Clin Pharmacol. 2002;53(3):266-274. doi:10.1046/J.0306-5251.2001.01536.X
  15. Nilsson T, Longmore J, Shaw D, Jansen Olesen IJ, Edvinsson L. Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br J Pharmacol. 1999;128(6):1133. doi:10.1038/SJ.BJP.0702773
  16. Ishida T, Kawashima S, Hirata KI, et al. Serotonin-induced hypercontraction through 5-hydroxytryptamine 1B receptors in atherosclerotic rabbit coronary arteries. Circulation. 2001;103(9):1289-1295. doi:10.1161/01.CIR.103.9.1289
  17. Golino P, Piscione F, Willerson JT, et al. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. N Engl J Med. 1991;324(10):641-648. doi:10.1056/NEJM199103073241001
  18. Ghuran A, Nolan J. Topics in Review: The cardiac complications of recreational drug use. West J Med. 2000;173(6):412. doi:10.1136/EWJM.173.6.412
  19. McGrath BP, Xhi Qin W. Dopamine: clinical applications iii. cardiovascular. Aust Prescr. 1994;17(2):44-45. doi:10.18773/AUSTPRESCR.1994.050
  20. Yamaguchi T, Sumida TS, Nomura S, et al. Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure. Nat Commun 2020 111. 2020;11(1):1-8. doi:10.1038/s41467-020-18128-x
  21. Stracina T, Slaninova I, Polanska H, et al. Long-term haloperidol treatment prolongs QT interval and increases expression of sigma 1 and IP3 receptors in guinea pig hearts. Tohoku J Exp Med. 2015;236(3):199-207. doi:10.1620/tjem.236.199
  22. Johannessen M, Ramachandran S, Riemer L, Ramos-Serrano A, Ruoho AE, Jackson MB. Voltage-gated sodium channel modulation by σ-receptors in cardiac myocytes and heterologous systems. Am J Physiol - Cell Physiol. 2009;296(5). doi:10.1152/ajpcell.00431.2008
  23. Shinoda Y, Tagashira H, Bhuiyan MS, Hasegawa H, Kanai H, Fukunaga K. Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction. J Pharmacol Sci. 2016;131(3):172-183. doi:10.1016/j.jphs.2016.05.012
  24. Lewis R, Li J, McCormick PJ, Huang CL-H, Jeevaratnam K. Is the sigma-1 receptor a potential pharmacological target for cardiac pathologies? A systematic review. Int J Cardiol Hear Vasc. 2020;26. doi:10.1016/J.IJCHA.2019.100449
  25. Stracina T, Novakova M. Cardiac sigma receptors - An update. Physiol Res. 2018;67(Suppl 4):S561-S576. doi:10.33549/physiolres.934052
  26. Tagashira H, Fukunaga K. Cardioprotective Effect of Fluvoxamine, Sigma-1 Receptor High Affinity Agonist. YAKUGAKU ZASSHI. 2012;132(2):167-172. doi:10.1248/yakushi.132.167
  27. Tagashira H, Bhuiyan MS, Shioda N, Fukunaga K. Fluvoxamine rescues mitochondrial Ca2 + transport and ATP production through σ1-receptor in hypertrophic cardiomyocytes. Life Sci. 2014;95(2):89-100. doi:10.1016/j.lfs.2013.12.019
  28. Tagashira H, Zhang C, Lu YM, et al. Stimulation of σ1-receptor restores abnormal mitochondrial Ca2 + mobilization and ATP production following cardiac hypertrophy. Biochim Biophys Acta - Gen Subj. 2013;1830(4):3082-3094. doi:10.1016/j.bbagen.2012.12.029
  29. Winstock A. GDS2019 KEY FINDINGS REPORT: ON BEHALF OF GDS CORE RESEARCH TEAM.; 2019. Accessed September 9, 2022. http://www.globaldrugsurvey.com
  30. National Survey on Drug Use and Health. 2017 NSDUH Annual National Report | CBHSQ Data.; 2018. Accessed September 9, 2022. https://www.samhsa.gov/data/report/2017-nsduh-annual-national-report
  31. Ghuran A, Nolan J. Recreational drug misuse: issues for the cardiologist. Heart. 2000;83(6):627-633. doi:10.1136/HEART.83.6.627
  32. Borowiak KS, Ciechanowski K, Waloszczyk P. Psilocybin mushroom (Psilocybe semilanceata) intoxication with myocardial infarction. J Toxicol Clin Toxicol. 1998;36(1-2):47-49. doi:10.3109/15563659809162584
  33. Kotts WJ, Gamble DT, Dawson DK, Connor D. Psilocybin-induced takotsubo cardiomyopathy. BMJ Case Rep. 2022;15(5). doi:10.1136/BCR-2021-245863
  34. Oberli LS, Haegeli LM, Heidecker B. Right coronary anomaly in a patient with myocarditis and cardiac arrest: a case report. Eur Hear J Case Reports. 2018;2(2). doi:10.1093/EHJCR/YTY044
  35. Nepal C, Patel S, Ahmad N, Mirrer B, Cohen R. Out of Hospital Cardiac Arrest Triggered by LSD in a Patient with Suspected Brugada Syndrome. In: CRITICAL CARE CASE REPORTS: DRUG OVERDOSES. American Thoracic Society International Conference ; 2017. Accessed September 4, 2022. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A3773
  36. Strassman RJ, Qualls CR. Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects. Arch Gen Psychiatry. 1994;51(2):85-97. Accessed June 27, 2018. http://www.ncbi.nlm.nih.gov/pubmed/8297216
  37. Isbell H. Comparison of the reactions induced by psilocybin and LSD-25 in man. Psychopharmacologia. 1959;1(1):29-38. doi:10.1007/BF00408109
  38. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006;187(3):268-283. doi:10.1007/s00213-006-0457-5
  39. Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl). 2004;172(2):145-156. doi:10.1007/S00213-003-1640-6
  40. Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ. Human pharmacology of ayahuasca: Subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther. 2003;306(1):73-83. doi:10.1124/jpet.103.049882
  41. Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ. Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. J Psychopharmacol. 2022;36(3):258. doi:10.1177/02698811211069100
  42. Ramaekers JG, Hutten N, Mason NL, et al. A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. J Psychopharmacol. 2021;35(4):398-405. doi:10.1177/0269881120940937
  43. Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-620. doi:10.1177/0269881108093587
  44. Simonsson O, Sexton JD, Hendricks PS. Associations between lifetime classic psychedelic use and markers of physical health. J Psychopharmacol. 2021;35(4):447-452. doi:10.1177/0269881121996863
  45. Simonsson O, Hendricks PS, Carhart-Harris R, Kettner H, Osika W. Association Between Lifetime Classic Psychedelic Use and Hypertension in the Past Year. Hypertension. 2021;77(5):1510-1516. doi:10.1161/hypertensionaha.120.16715
  46. Dahmane E, Hutson PR, Gobburu JVS. Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin. Clin Pharmacol drug Dev. 2021;10(1):78-85. doi:10.1002/CPDD.796
  47. Barnes BJ, Hollands JM. Drug-induced arrhythmias. Crit Care Med. 2010;38(6 Suppl). doi:10.1097/CCM.0B013E3181DE112A
  48. An Evaluation of Psilocybin’s Effect on Cardiac Repolarization - ClinicalTrials.gov identifier NCT05478278. Accessed September 14, 2022. https://clinicaltrials.gov/ct2/show/NCT05478278
  49. Witchel HJ. Drug-induced hERG Block and Long QT Syndrome. Cardiovasc Ther. 2011;29(4):251-259. doi:10.1111/j.1755-5922.2010.00154.x
  50. Hackl B, Todt H, Kubista H, Hilber K, Koenig X. Psilocybin Therapy of Psychiatric Disorders Is Not Hampered by hERG Potassium Channel-Mediated Cardiotoxicity. Int J Neuropsychopharmacol. 2022;25(4):280-282. doi:10.1093/IJNP/PYAB085
  51. Teixeira PJ, Johnson MW, Timmermann C, et al. Psychedelics and health behaviour change. J Psychopharmacol. 2022;36(1):12-19. doi:10.1177/02698811211008554