Effects of psilocin and psilocybin on human 5-HT4 serotonin receptors in atrial preparations of transgenic mice and humans

Psilocybin and psilocin, the hallucinogenic compounds in magic mushrooms, activate cardiac serotonin (5-HT4) receptors, increasing the force and rate of heart contractions. In isolated left and right atrial preparations from transgenic mice overexpressing the human 5-HT4 receptor, both drugs enhanced contraction force and beating rate, though their effects at 10 µM were weaker than those of 1 µM serotonin. No effects were seen in wild-type mice. In human atrial tissue, the positive inotropic effects required inhibition of phosphodiesterase III to become apparent. The effects were blocked by the 5-HT4 receptor antagonists tropisetron and GR125487, confirming that psilocybin and psilocin act as agonists on cardiac 5-HT4 receptors.

Study at a glance

Abstract

Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT4-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT4-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10 µM were smaller than that of 1 µM 5-HT on the left and right atria from 5-HT4-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10 µM psilocybin and psilocin were abrogated by 10 µM tropisetron or by 1 µM GR125487, a more selective 5-HT4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT4 receptors.