Many recreational ecstasy/MDMA users display neuropsychobiological deficits, whereas others remain problem free. This review will investigate some of the drug and non-drug factors which influence the occurrence of these deficits. Acute and chronic MDMA usage are both important. Intensive use within a session is often associated with more problems. In term of lifetime usage, novice users generally remain unimpaired, whereas most heavy users report memory or other psychobiological problems which they attribute to ecstasy. These complaints are confirmed by objective deficits in working memory, attention, frontal-executive, and episodic memory tasks. Psychobiological deficits include disturbed sleep, sexual dysfunction, reduced immuno-competence, and increased oxidative stress. Further MDMA-related factors which may contribute to these changes, include acute and chronic tolerance, and drug dependence. Around 90ñ95% of ecstasy/MDMA users also take cannabis, and this can independently contribute to the adverse neuropsychobiological pro.les; although in some situations the acute co-use of these two drugs may be interactive rather than additive, since cannabis has relaxant and hypothermic properties. Alcohol, nicotine, amphetamine, and other drugs, can also affect the psychobiological pro.les of ecstasy polydrug users in complex ways. Pure MDMA users are rare but they have been shown to display significant neurocognitive deficits. Psychiatric aspects are debated in the context of the diathesis-stress model. Here the stressor of ecstasy polydrug drug use, interacts with various predisposition factors (genetic, neurochemical, personality), to determine the psychiatric outcome. Recreational MDMA is typically taken in hot and crowded dances/raves. Prolonged dancing, feeling hot, and raised body temperature, can also be associated with more psychobiological problems. This is consistent with the animal literature, where high ambient temperature and other metabolic stimulants boost the acute effects of MDMA, and cause greater serotonergic neurotoxicity. In conclusion, the neuropsychobiological effects of MDMA are modulated by a wide range of drug and non-drug factors. These multiple influences are integrated within a bioenergetic stress model, where factors which heighten acute metabolic distress lead to more neuropsychobiological problems.