MDMA (3,4 - methylenedioxymethamphetamine), or more commonly known as Molly or Ecstasy, is a synthetic substance first developed in 1912 as a precursor to the synthesis of hemostatic agents (not as an appetite suppressant as incorrectly reported). Due to its effects on promoting empathy and facilitating communication, the drug became popular in the early 1970s among psychiatrists for its therapeutic potential. The drug would later find heavy use in dance parties and festivals as it became prominently associated with rave culture due to its heightened euphoric effects. The DEA subsequently classified it as a schedule 1 drug in 1985 as the potential for harm and abuse was recognized. To this day, ecstasy continues to be used by millions. Its effects on the cardiovascular, neurologic, renal, and hepatic systems can be devastating, and recognition of its toxicity is essential to medical providers.
The potential for MDMA toxicity exists with every ingestion. MDMA is commonly ingested orally through tablet form; however, the powder itself can be snorted. Recreational doses of the drug can vary significantly. During the 1990s and early 2000s, doses ranged between 73 mg to 103 mg while doses have also been reported to be as low as 50 mg to as high as 150 mg per tablet. Analysis of compounds sold as Ecstasy/Molly has also revealed variability of composition with other substances aside from MDMA which include MDEA, MDA, ephedrine, ketamine, paracetamol, and other substitutes - some of which are inactive and others which may have profound hemodynamic effects. As a result, significant adverse effects and toxicity can occur with a one time or first-time ingestion due to the random dosage and composition of the drug.
Ecstasy is also often taken with other illicit drugs which can potentially lead to a compounding of each drug’s individual effects on the neurologic and cardiovascular system. This compounding effect in combination with physical activity in a hot, humid environment such as a rave can lead to significant hyperthermia and dehydration.
Trends in MDMA use have been well documented throughout the years with user age ranging from the 8th grade all the way to the college level and adulthood. Review of epidemiological data revealed a significant increase in usage between the 1990s to early 2000s. For example, lifetime ecstasy use on one college campus was found to increase from 16% to 24% between the years 1986 to 1990 while a national sample of college students saw a 69% increase between the years 1997 to 1999. From 1999 to 2000, lifetime use among 8th graders increased from 2.7% to 4.3% while this increase was significantly more in 12th graders (8% to 11%). Also, emergency room visits in the United States were also found to increase from 253 to 4511 between 1994 and 2000. A 2002 “Monitoring the Future” study, found 12.7% of United States college students having used ecstasy once in their lifetime. The 2002 National Survey of Drug Use and Health found a greater than 200% increase in ecstasy use by 18 to 25-year-olds from 1996 to 2002.
While the number of users increased significantly from the early 1990s and 2000s, the number of new users was variable from the period of 2002 to 2007. Surveys found a decrease in users from 1.2 million in 2002 down to 642000 in 2003 then up to 860000 from 2006 to 2007. 2011 data from the National Survey on Drug Use and Health estimated about 14.5 million users aged 12 or older had used ecstasy at least once in their lifetime with approximately 900000 using it for the first time in 2011. This number increased to 17 million in 2013 with the highest use among individuals aged 18 to 25 years. Though MDMA still falls behind cannabis, opioids, and other amphetamine use in the United States and worldwide, it remains a significant public health concern due to its adverse effect profile.
MDMA differs from other amphetamines due to the attachment of the methylenedioxy group which is structurally similar to the psychedelic hallucinogen mescaline. Because of this, MDMA is a chemical compound that shares properties of both amphetamines and hallucinogens. It primarily acts to increase the overall concentration of norepinephrine, dopamine, and serotonin within the synaptic cleft. MDMA inhibits the re-uptake of the neurotransmitter, serotonin, thereby stimulating its carrier-mediated release. This action, in addition to depletion of serotonin-containing vesicles, results in increased synaptic levels of serotonin. Like other amphetamine analogs, MDMA also inhibits the activity of monoamine oxidase which further contributes to increased levels of serotonin (in addition to dopamine and norepinephrine). Like serotonin, MDMA affects dopamine transporters promoting their release and inhibiting their re-uptake. The binding of noradrenergic, histaminergic, and muscarinic receptors contribute to the noradrenaline, histamine, GABA, and acetylcholine affects of the drug. The result is a surge of activity upon post-synaptic receptors that play a role in mood, thermoregulation, and autonomic nervous system activity.
Desired effects of the drug include sympathomimetic arousal, sensual enhancement, feelings of euphoria, and emotional closeness to others. Other effects include nausea, trismus, and bruxism. These effects are attributable to the increase in circulation of the neurotransmitters mentioned above dopamine and serotonin. Blood pressure and heart rate elevations are secondary to the adrenergic effects of an increase in circulating norepinephrine acting on alpha, beta-1, and beta-2 receptors.
In addition to its effects on neurotransmitters, MDMA has also been found to increase the blood levels of arginine vasopressin (antidiuretic hormone) leading to the retention of fluid. This effect, coupled with excessive intake of water, have been implicated in the development of life-threatening hyponatremia and coma.
MDMA is absorbed via the GI tract with an onset of effect between 20 minutes and 1 hour after consumption. Peak concentrations occur 2 hours after oral ingestion, and it is broken down in the liver by the enzyme CYP2D6. MDMA has a half-life of about 8 hours taking approximately 40 hours to clear 95% of the drug from the body. Thus, continued effects of the drug will continue to linger for several hours after ingestion.
Presentation of MDMA toxicity is variable due to the common practice of co-ingestion with other illicit substances. Even self-reported mono-ingestion of Ecstasy/Molly is not reliable due to the varying composition of the synthesized drug. Patients may present tachycardic, hypertensive, hyperthermic, and agitated. Adverse effects, even at minor recreational doses, include increased muscle activity (such as bruxism, restless legs, and jaw clenching), hyperactivity, insomnia, difficulty concentrating and feelings of restlessness. The sympathomimetic properties in MDMA overdose can lead to severe toxicity manifesting as cardiovascular, neurologic, hepatic, and electrolyte disturbances. Significant elevations in both heart rate and blood pressure have led to reports of life-threatening cardiac dysrhythmias, myocardial infarction, aortic dissection, and intracranial hemorrhages. Because MDMA undergoes hepatic metabolism via cytochrome P450, severe hepatoxicity can occur leading to fulminant liver failure. CNS hyperactivity can lead to delirium and seizures. Elevated levels of serotonin can result in serotonin syndrome, and patients may present with hyperpyrexia and myoclonus.
Because Ecstasy is a popular rave drug, the dangerous combination of intense physical activity (such as dancing) along with the heightened sympathomimetic effects of the drug lead to an increase in body temperature that resembles heat stroke and resulting in rhabdomyolysis. Significant increases in fluid consumption by users in such a setting coupled with elevated levels of vasopressin have potentially contributed to the development of cerebral edema, seizures, and death.
Emphasis should be on maintaining airway along with stabilization of breathing and circulation. Patients may present obtunded due to hyponatremia requiring endotracheal intubation. Though no formal contraindication to specific RSI agents exists, caution can be taken with ketamine which could potentiate the hyperadrenergic state of the already hypertensive and tachycardic patient. If rhabdomyolysis is a consideration, avoiding succinylcholine due to hyperkalemia should be considered in favor of rocuronium or vecuronium. Patients who present in severe toxicity within one hour of ingestion can receive activated charcoal PO or via an NG tube. Agitation should be controlled with benzodiazepines such as lorazepam or diazepam. For the hyperthermic patient, evaporative cooling along with ice packs to the groin and axilla are beneficial. More invasive measures may be necessary in extreme cases. If treatment fails, dantrolene is a consideration. Antipyretics, such as acetaminophen, have no role and can worsen an already compromised liver.
Patients in MDMA toxicity can present with seizures and hyponatremia. Those with seizures should receive benzodiazepines. If hyponatremia is the cause, patients should be free water restricted and treated with hypertonic saline. Urine output should be closely monitored with a foley. Caution is necessary with the judicious administration of IV fluids.
The undifferentiated tachycardic, hypertensive, hyperthermic, and altered patient, necessitates a broad approach to treatment and evaluation since this constellation of findings is not specific to MDMA toxicity. Hence, patients may require a head CT, LP, and coverage with broad-spectrum antibiotics.
The two most frequently reported causes of death include hyperthermia and hyponatremia. While toxicity can be severe, review of the literature reveals deaths related to MDMA toxicity to be rare. Confounding factors in some reports are that other drugs were co-ingested thus making it difficult to find MDMA as the sole cause of death. One study found that in the 10 years to 2006, ecstasy-related deaths numbered approximately 50 per year though were not purely ecstasy-related. When it was the sole drug implicated, this number dropped to 10 per year. A retrospective case review of ED admissions related to ecstasy revealed a death rate of 0 to 2%.  It is worth noting that these conclusions were level III evidence-based.
Though deaths are rare, the potential for long term side effects has been demonstrated through animal and radiological studies. Serotonin plays a role in emotion, memory, and high order cognitive processes. Previous animal studies revealed a loss of serotonin axon terminal markers. These losses were found to be extremely long lasting in MDMA-treated monkeys. PET scans in baboons showed significant decreases in radioactivity levels in variable areas of the brain. Human volunteers with a history of MDMA use underwent PET scanning and were found to have a global dose-related reduction in a structural element of serotonin. Further studies of PET scans in volunteers with a history of MDMA abuse yielded similar findings however with additional alterations to the amygdala and areas of the neocortex. Deficits in short term memory, visual memory, and verbal memory and reasoning seem to be associated. Cerebrovascular systems may also be affected which may manifest down the line as a decline in cognitive potential akin to dementia.
Neurologic complications include delirium, seizures.
GI complications include severe hepatotoxicity which can lead to fulminant liver failure.
Renal complications include rhabdomyolysis and acute renal failure.
Minor complications include increased muscle activity (such as bruxism, restless legs, and jaw clenching), hyperactivity, insomnia, difficulty concentrating and feelings of restlessness.
MDMA toxicity can be life-threatening and involve multiple organ system dysfunctions necessitating the need for a multidisciplinary approach. It is important, thus, for providers to be aware of the potential toxicities that may arise and be ready to treat aggressively as treatment is mainly supportive.
Ultimately, the primary remedy to the problem is prevention. Peters and Kok performed a literature review to identify reasons for ecstasy use and found reasons varied widely from curiosity, to achieve the same level of intoxication as friends, availability/pricing, enhance mood and social interaction, and social influence. The myth that Molly is safer because it is pure MDMA also does not aid in preventing its use. Further education among youth and young adolescents to the toxic potential of MDMA is essential to blunting its continued use.
|||Freudenmann RW,Oxler F,Bernschneider-Reif S, The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction (Abingdon, England). 2006 Sep; [PubMed PMID: 16911722]|
|||Passie T,Benzenhöfer U, The History of MDMA as an Underground Drug in the United States, 1960-1979. Journal of psychoactive drugs. 2016 Apr-Jun; [PubMed PMID: 26940772]|
|||Hysek CM,Simmler LD,Schillinger N,Meyer N,Schmid Y,Donzelli M,Grouzmann E,Liechti ME, Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination. The international journal of neuropsychopharmacology. 2014 Mar; [PubMed PMID: 24103254]|
|||Parrott AC, MDMA in humans: factors which affect the neuropsychobiological profiles of recreational ecstasy users, the integrative role of bioenergetic stress. Journal of psychopharmacology (Oxford, England). 2006 Mar; [PubMed PMID: 16510474]|
|||Parrott AC, Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy. Journal of psychopharmacology (Oxford, England). 2005 Jan; [PubMed PMID: 15671132]|
|||García-Repetto R,Moreno E,Soriano T,Jurado C,Giménez MP,Menéndez M, Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose. Forensic science international. 2003 Aug 12; [PubMed PMID: 12927411]|
|||Traub SJ,Hoffman RS,Nelson LS, The [PubMed PMID: 12468674]|
|||Meyer JS, 3,4-methylenedioxymethamphetamine (MDMA): current perspectives. Substance abuse and rehabilitation. 2013; [PubMed PMID: 24648791]|
|||Kiyatkin EA,Ren S, Clubbing with ecstasy. Temperature (Austin, Tex.). 2014 Oct-Dec; [PubMed PMID: 27627800]|
|||Wish ED,Fitzelle DB,O'Grady KE,Hsu MH,Arria AM, Evidence for significant polydrug use among ecstasy-using college students. Journal of American college health : J of ACH. 2006 Sep-Oct; [PubMed PMID: 17017306]|
|||Leshner AI, Ecstasy abuse and control: hearing before the Senate Subcommittee on Governmental Affairs--July 30, 2001. Statement for the record. Journal of psychoactive drugs. 2002 Apr-Jun; [PubMed PMID: 12691202]|
|||Wu LT,Parrott AC,Ringwalt CL,Yang C,Blazer DG, The variety of ecstasy/MDMA users: results from the National Epidemiologic Survey on alcohol and related conditions. The American journal on addictions. 2009 Nov-Dec; [PubMed PMID: 19874166]|
|||Passie T,Benzenhöfer U, MDA, MDMA, and other [PubMed PMID: 28851034]|
|||Vollenweider FX,Gamma A,Liechti M,Huber T, Psychological and cardiovascular effects and short-term sequelae of MDMA ( [PubMed PMID: 9718588]|
|||Parrott AC, Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity. Psychopharmacology. 2004 May; [PubMed PMID: 15007594]|
|||Moritz ML,Kalantar-Zadeh K,Ayus JC, Ecstacy-associated hyponatremia: why are women at risk? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013 Sep; [PubMed PMID: 23804804]|
|||Mas M,Farré M,de la Torre R,Roset PN,Ortuño J,Segura J,Camí J, Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans. The Journal of pharmacology and experimental therapeutics. 1999 Jul; [PubMed PMID: 10381769]|
|||Wu D,Otton SV,Inaba T,Kalow W,Sellers EM, Interactions of amphetamine analogs with human liver CYP2D6. Biochemical pharmacology. 1997 Jun 1; [PubMed PMID: 9264312]|
|||Lai TI,Hwang JJ,Fang CC,Chen WJ, Methylene 3, 4 dioxymethamphetamine-induced acute myocardial infarction. Annals of emergency medicine. 2003 Dec; [PubMed PMID: 14634599]|
|||Duflou J,Mark A, Aortic dissection after ingestion of [PubMed PMID: 10990289]|
|||Lange-Brock N,Berg T,Müller AR,Fliege H,Neuhaus P,Wiedenmann B,Klapp BF,Mönnikes H, [Acute liver failure following the use of ecstasy (MDMA)]. Zeitschrift fur Gastroenterologie. 2002 Aug; [PubMed PMID: 12297982]|
|||Theune M,Esser W,Druschky KF,Interschick E,Patscheke H, [Grand mal series after Ecstasy abuse]. Der Nervenarzt. 1999 Dec; [PubMed PMID: 10637815]|
|||Tao R,Shokry IM,Callanan JJ, Environment Influencing Serotonin Syndrome Induced by Ecstasy Abuse. Annals of forensic research and analysis. 2017; [PubMed PMID: 29732414]|
|||Ginsberg MD,Hertzman M,Schmidt-Nowara WW, Amphetamine intoxication with coagulopathy, hyperthermia, and reversible renal failure. A syndrome resembling heatstroke. Annals of internal medicine. 1970 Jul; [PubMed PMID: 5433281]|
|||Matthai SM,Davidson DC,Sills JA,Alexandrou D, Cerebral oedema after ingestion of MDMA ( [PubMed PMID: 8646063]|
|||O'Connor A,Cluroe A,Couch R,Galler L,Lawrence J,Synek B, Death from hyponatraemia-induced cerebral oedema associated with MDMA ( [PubMed PMID: 10448984]|
|||Davies N,English W,Grundlingh J, MDMA toxicity: management of acute and life-threatening presentations. British journal of nursing (Mark Allen Publishing). 2018 Jun 14; [PubMed PMID: 29894255]|
|||Rogers G,Elston J,Garside R,Roome C,Taylor R,Younger P,Zawada A,Somerville M, The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Health technology assessment (Winchester, England). 2009 Jan; [PubMed PMID: 19195429]|
|||Kelly PA, Does recreational ecstasy use cause long-term cognitive problems? The Western journal of medicine. 2000 Aug; [PubMed PMID: 10924441]|
|||Ricaurte GA,McCann UD,Szabo Z,Scheffel U, Toxicodynamics and long-term toxicity of the recreational drug, 3, 4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'). Toxicology letters. 2000 Mar 15; [PubMed PMID: 10720723]|
|||Peters GJ,Kok G, A structured review of reasons for ecstasy use and related behaviours: pointers for future research. BMC public health. 2009 Jul 13; [PubMed PMID: 19594926]|