The popular illicit drug 3,4-methylendioxymethamphetamine, better known as MDMA or ecstasy, is abused because of its psychodelic effects. Adverse MDMA-effects often include muscle fasciculations, rapidly progressing hyperthermia or even rhabdomyolysis. These features are not fully explained by ecstasy-mediated neurotransmitter release in the central nervous system. Hence, we tested the hypothesis of a direct MDMA action on human skeletal muscle. Additionally, we addressed the question whether muscle from malignant hyperthermia-susceptible (MHS) individuals may be predisposed to adverse ecstasy reactions. We used surgically dissected muscle strips, cultivated myotubes and isolated sarcoplasmic reticulum (SR) vesicles. Mechanographic registrations showed that MDMA enhanced the sensitivity to the Ca2+-releasing agents halothane and caffeine. MDMA increased cytosolic [Ca2+] and cellular metabolism from myotubes but did not release Ca2+ from the SR. Alpha-bungarotoxin, a specific antagonist of the nicotinic acetylcholine receptor (nAChR) abolished the MDMA effects. The nAChR agonistic action of MDMA was confirmed by current measurements on HEK-cells expressing nAChR. We were surprised that MDMA did not affect EC-coupling and we conclude that an activation of the nAChR contributes to the muscle related symptoms of MDMA.