Lysergic acid diethylamide (LSD) increases the force and rate of heart contractions by activating two types of receptors: 5-HT4 serotonin receptors and H2 histamine receptors. In transgenic mouse hearts overexpressing human 5-HT4 or H2 receptors, LSD (up to 10 µM) increased contraction force and beating rate, effects blocked by specific antagonists (tropisetron for 5-HT4, cimetidine and GR 125487 for H2). In human atrial muscle strips from bypass surgery patients, LSD (10 µM) also increased contraction force after cilostamide pre-stimulation. These findings indicate LSD directly stimulates cardiac function through both receptor pathways.
Bufotenin, a hallucinogenic drug, can stimulate human cardiac serotonin 5-HT4 receptors, increasing the force of contraction and beating rate. In transgenic mice expressing only the human 5-HT4 receptor in heart cells, bufotenin enhanced left atrial contraction and right atrial beating rate, with effects potentiated by a monoamine oxidase inhibitor. In isolated human atrial muscle strips, bufotenin concentration-dependently increased contraction force, reversed by the 5-HT4 antagonist tropisetron. Bufotenin also increased phosphorylation of phospholamban, a protein regulating heart muscle relaxation, in transgenic mouse and human atrial tissue. These findings indicate bufotenin acts as a positive inotropic and chronotropic agent through human 5-HT4 receptors.
LSD increases the force and rate of heart muscle contraction by activating H2-histamine receptors in humans, and also acts as a partial agonist at 5-HT4 serotonin receptors in mice. In human atrial tissue from heart surgery patients, LSD's contractile effects were blocked by cimetidine, an H2-receptor antagonist. These findings clarify the cardiac effects of LSD, which is being studied again for psychiatric uses.