Psilocybin therapy of psychiatric disorders is not hampered by hERG potassium channel-mediated cardiotoxicity

This brief report details that a high dose of psilocin (the active metabolite of psilocybin) doesn’t cause adverse heart-related issues (e.g. QT interval prolongation). The route, via hERG channel blockage, is not activated by psilocin.

Abstract

“Psilocybin, a hallucinogen contained in magic mushrooms, holds great promise for the treatment of various psychiatric disorders, and early clinical trials are encouraging. Adverse cardiac events after intake of high doses of psilocybin, and a trial reporting QT interval prolongation in the electrocardiogram, attributed to the drugs main metabolite psilocin, gave rise to safety concerns. Here we show that clinical concentrations of psilocin do not cause significant hERG potassium channel inhibition, a major risk factor for adverse cardiac events. We conclude that hERG channel blockage by psilocin is not liable for psilocybin- associated cardiotoxic effects.”

Authors: Benjamin Hackl, Hannes Todt, Helmut Kubista, Karlheinz Hilber & Xaver Koening

Summary

CINP is an open access journal published by Oxford University Press. This article is distributed under the Creative Commons Attribution-NonCommercial License.

High doses of psilocybin were associated with QT interval prolongation, but clinical concentrations of psilocin do not cause significant hERG potassium channel inhibition. Psilocybin is an indole alkaloid found in mushrooms commonly named “magic mushrooms”. It has been shown to have significant therapeutic potential in treating anxiety, depression, end of life distress, and various forms of addiction, but its cardiotoxic effects have not yet been sufficiently studied.

Psilocin prolongs the QTc interval in the ECG, but not significantly at a dose of 25 mg. Higher doses have the potential to prolong QTc above the threshold of regulatory concern. Psilocybin, a psychedelic drug, may block human ERG potassium channels, which are crucial determinants of the repolarization phase of the cardiac action potential. Psilocin’s metabolite 4-HIAA, which is uncharged, may thus reach the channel’s canonical binding site and induce QT prolongation.

Psilocin is not a hERG blocker and its cardiotoxic effects cannot be explained by hERG channel inhibition. However, low in vitro hERG affinity does not entirely rule out association of a drug with torsade de pointes arrhythmias. In a 68-year-old woman, psilocybin poisoning may have led to arrhythmia generation. However, hERG channel blockage by psilocin in clinical settings is not liable for psilocybin-associated cardiotoxic effects.

Potassium currents through hERG channels were recorded in tsA-201 cells with the whole-cell patch clamp technique as previously described (Koenig et al., 2013). The effect of psilocin, 4-HIAA, and E4031 on hERG channels was tested. Psilocin inhibited hERG current at -50 mV (+10 mV) by a concentration-response curve, and a relative hERG current level was displayed upon application of 4-HIAA or 1 m E4031.