Amphetamine abuse is widespread and associated with significant health risk. The most commonly encountered amphetamines are methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), and the ephedra alkaloids. Although each of these harbors unique toxicity, they similarly impact the cardiovascular and neurological systems in overdose. Other serious complications associated with amphetamine abuse include severe hyperpyrexia and hyponatremia. Secondary conditions such as rhabdomyolysis, disseminated intravascular coagulation (DIC), gastrointestinal (GI) bleeding, hepatic necrosis, and renal failure are common, especially in those with hyperthermia. Chronic abuse poses risk of vasculitis, neuropsychiatric abnormalities, and cardiomyopathy. In addition, there is a growing body of evidence that even recreational abuse of methamphetamine and MDMA may produce long-lasting damage to dopaminergic and serotonergic neurons. Management principles include adequate sedation, aggressive cooling, and the use of titratable agents in the management of cardiovascular abnormalities.