Ecstasy is a recreational drug containing 3,4-methylenedioxymethamphetamine (MDMA). In the U.S., there are several millions of lifetime users, and millions each year added to the list as new users. Only several thousand every year show signs of severe toxicity and require emergency intervention. The illness is known as serotonin (5-HT) syndrome, which can be mild, moderate or severe. The relationship between mild, moderate and severe syndromes appears to be interchangeable, but the severe syndrome is life-threatening. The serotonergic mechanisms of how the mild or moderate syndrome becomes severe and life-threatening have attracted considerable attention in the last few years as an effort to explore new treatments potentially to manage illness and prevent death of patients. High levels of extracellular 5-HT in the brain produced by large doses of MDMA are not always necessary to cause a severe serotonin syndrome. Additional mechanisms may be more important. Recent research has demonstrated that environmental conditions (i.e., non-drug factors) are more critical in determining the severity of MDMA-induced serotonin syndrome than the drug dose. The purpose of the current article was to review available evidence regarding the effect of non-drug factors on serotonergic extrasynaptic receptor responsivity and the severity of MDMA-induced serotonin syndrome.
Keywords: 5-HT1A; 5-HT2A; Ecstasy; Extrasynaptic receptor; Hyperthermia; MDMA toxicity; Serotonin syndrome.