[32] Short-term adverse effects include grinding of the teeth, blurred vision, sweating, and a rapid heartbeat,[26] and extended use can also lead to addiction, memory problems, paranoia, and difficulty sleeping.

[75][76] Partly due to the global supply shortage of sassafras oil—a problem largely assuaged by use of improved or alternative modern methods of synthesis—the purity of substances sold as molly have been found to vary widely.

[84] Even at the very low doses that are comparable to those self-administered by humans, MDMA causes oxidative stress and both single and double-strand breaks in the DNA of the hippocampus region of the mouse brain.

[88] Long-term exposure to MDMA in humans has been shown to produce marked neurodegeneration in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.

[15][86] Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users.

[91] Impairments in multiple aspects of cognition, including attention, learning, memory, visual processing, and sleep, have been found in regular MDMA users.

[8] At high doses, MDMA induces a neuroimmune response that, through several mechanisms, increases the permeability of the blood–brain barrier, thereby making the brain more susceptible to environmental toxins and pathogens.

[103][104] Therefore, chronic use of MDMA at high doses can result in altered brain structure and drug addiction that occur as a consequence of ΔFosB overexpression in the nucleus accumbens.

[116] A scheme for management of acute MDMA toxicity has been published focusing on treatment of hyperthermia, hyponatraemia, serotonin syndrome, and multiple organ failure.

[8][77] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors (MAOIs),[8][77] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).

[126] Serotonin reuptake inhibitors (SRIs) such as citalopram (Celexa), duloxetine (Cymbalta), fluoxetine (Prozac), and paroxetine (Paxil) have been shown to block most of the subjective effects of MDMA.

[127] Norepinephrine reuptake inhibitors (NRIs) such as reboxetine (Edronax) have been found to reduce emotional excitation and feelings of stimulation with MDMA but do not appear to influence its entactogenic or mood-elevating effects.

[124][128] SRIs like citalopram and paroxetine, as well as the serotonin 5-HT2A receptor antagonist ketanserin, have been found to partially block the increases in heart rate and blood pressure with MDMA.

[124][139] Due to the theoretical risk of "unopposed α-stimulation" and possible consequences like coronary vasospasm, it has been suggested that dual α1- and β-adrenergic receptor antagonists like carvedilol and labetalol, rather than selective beta blockers, should be used in the management of stimulant-induced sympathomimetic toxicity, for instance in the context of overdose.

[17][153][154] MDMA enters monoaminergic neurons via the MATs and then, via poorly understood mechanisms, reverses the direction of these transporters to produce efflux of the monoamine neurotransmitters rather than the usual reuptake.

[17][153][171][172] The entactogenic effects of MDMA, including increased sociability, empathy, feelings of closeness, and reduced aggression, are thought to be mainly due to induction of serotonin release.

[181][179][180] Repeated activation of serotonin 5-HT2B receptors by MDMA is thought to result in risk of valvular heart disease (VHD) and primary pulmonary hypertension (PPH).

[223] MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death.

Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances.

In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals injected with mescaline and several analogues, including MDMA.

[234][237] MDMA likely emerged as a substitute for MDA,[238] a drug at the time popular among users of psychedelics[239] which was made a Schedule 1 controlled substance in the United States in 1970.

[226] They described MDMA as inducing "an easily controlled altered state of consciousness with emotional and sensual overtones" comparable "to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA".

[246] According to one participant in an ethnographic study, the Texas Group produced more MDMA in eighteen months than all other distribution networks combined across their entire histories.

The agency cited increased distribution in Texas, escalating street use, and new evidence of MDA (an analog of MDMA) neurotoxicity as reasons for the emergency measure.

[261] In 1985, the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 United Nations Convention on Psychotropic Substances.

Unwitting substitution with other drugs, such as mephedrone and methamphetamine,[278] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.

[248] MDMA is legally controlled in most of the world under the UN Convention on Psychotropic Substances and other international agreements, although exceptions exist for research and limited medical use.

[289][290] An editorial he wrote in the Journal of Psychopharmacology, where he compared the risk of harm for horse riding (1 adverse event in 350) to that of ecstasy (1 in 10,000) resulted in his dismissal as well as the resignation of his colleagues from the ACMD.

[305] A new research area named Drug Intelligence aims to automatically monitor distribution networks based on image processing and machine learning techniques, in which an Ecstasy pill picture is analyzed to detect correlations among different production batches.

As of October 2015[update], most of the MDMA in the United States is produced in British Columbia, Canada and imported by Canada-based Asian transnational criminal organizations.