MDMA (3,4-METHYLENE-DIOXY-METHAMPHETAMINE)


Common street names:


  • Ecstasy
  • E
  • XTC
  • Adam

OVERVIEW


“Ecstasy” is the common street name for MDMA, but many other related substances (e.g. 3,4-methylenedioxyamphetamine (MDA), 3,4-ethylenedioxyethamphetamine (MDEA (MDE)), paramethoxyamphetamine (PMA)) have similar pharmacological effects and are often found in “ecstasy” tablets. Other common adulterants include methamphetamine, caffeine, dextromethorphan and pseudoephedrine (Tanner-Smith, 2006).

The drug is a serotonergic-amphetamine and toxicity is predominantly due to CNS stimulant effects. Generally, it is of low acute toxicity and those with adverse effects can simply be managed with reassurance, sedation and supportive care. However, there are a number of potentially fatal complications including severe hyperthermia, hyponatremia with cerebral edema, hepatotoxicity, rhabdomyolysis, seizures, CVA, myocardial infarction and arrhythmias.

MECHANISM OF TOXIC EFFECTS

The primary effect of MDMA is (like amphetamines) to alter the release, uptake, and metabolism of neurotransmitters (serotonin, dopamine, norepinephrine). MDMA has the highest affinity for the serotonin transporter, in contrast to most amphetamines which are more selective for dopamine. Binding to the transporter both inhibits reuptake and increases movement of serotonin into the synapse. In animal studies, a rise and then fall in extracellular serotonin is observed. Other secondary effects include a marked irreversible inhibition of tryptophan hydroxylase (a rate–limiting enzyme involved in serotonin production). This begins several hours after peak CNS concentrations but then lasts for many days until new enzymes are synthesised. This effect is likely due to a metabolite.

TOXICOKINETICS


ABSORPTION

MDMA is rapidly absorbed with peak concentrations and effects occurring within 1 to 3 hours.

DISTRIBUTION

There is low plasma protein binding and the volume of distribution is around 6L/kg.

METABOLISM - ELIMINATION

Between 10 and 20% of a typical dose of MDMA is excreted unchanged in urine. The rest is metabolised by multiple pathways which produce active metabolites that are likely to be relevant to acute and chronic toxicity.

MDMA has non-linear pharmacokinetics. With increasing doses, the bioavailability is much higher, the half-life longer and total and hepatic clearance lower. MDMA also inhibits its own metabolism leading to increased bioavailability and decreased clearance with repeated doses. This effect is probably mediated by irreversible CYP2D6 inhibition by both MDMA and MDA.

Metabolism of MDMA.


MDMA metabolism.jpg
From : de la Torre R, Farré M. Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends Pharmacol Sci. 2004 Oct;25(10):505-8.




CLINICAL EFFECTS

The adverse effects of MDMA most commonly are simply excessive stimulation on the cardiovascular and central nervous systems beyond the desired effects. Complaints are most common in first-time users and usually consist of agitation, anxiety, and confusion. More serious psychoactive effects such as delusions, hallucinations, acute psychosis and suicidal ideation are rare.

The most common serious complications of acute MDMA toxicity are
• severe hyperthermia leading to multi-organ failure (usually with severe disseminated intravascular coagulation)

• severe electrolyte disturbance (hyponatremia, hypernatremia, hyperkalemia)
• cerebral oedema
• rhabdomyolysis and renal failure
• seizures
• ischemic complications
• arrhythmias

Serious adverse effects often indicate ingestion of tablets adulterated with PMA (Ling et al., 2001) or other substances.

The dose ingested does not predict severe toxicity which is largely unpredictable and idiosyncratic. Ingestion of fifty tablets has led to only moderate toxicity while death has followed a single tablet. High ambient temperatures, excessive exercise and under or over-hydration are the most important known risk-factors for severe complications.

INVESTIGATIONS


When severe toxicity is suspected the following investigations may be useful:
• Full blood count,
• Serum glucose, electrolytes, creatinine, urea
• Troponin, calcium, phosphorus, creatine phosphokinase, urinanalysis.
• Hepatic transaminases, coagulation studies
• ECG
• Neuro-imaging (in anyone with impaired consciousness)

Urine & Blood drug screens

Many rapid urine screens (immunoassays) will detect ‘amphetamines’ in someone who has ingested MDMA. Specific assays with HPLC are required to determine specific amphetamines.

TREATMENT

Supportive care, mild sedation and reassurance is usually all that is required. Benzodiazepines are the most appropriate first-line treatment for agitation not responding to simple reassurance. The use of physical restraints in agitated patients should be minimized, as sudden death has been reported in restrained agitated patients with drug-induced delirium. Core temperatures should also be frequently measured in any agitated patient, as the temperature may rise rapidly in response to physical activity. However, hyperthermia can occur without any increased activity or restraint.

Patients with any serious complications require very close monitoring of temperature and electrolytes, and intravenous access. The complications of severe MDMA toxicity (e.g. multi-organ failure, hyperkalemia, hyponatremia, hepatitis, acute renal failure, rhabdomyolysis, cerebrovascular accident, myocardial infarction, arrhythmias) should be managed conventionally. The only specific management consideration is the relative contraindication against beta-blockers in the treatment of arrhythmia, myocardial infarction and hypertension.

Patients may be discharged after they become asymptomatic as long as at least 3 to 4 hours have elapsed since ingestion and investigations are normal.

GI DECONTAMINATION

No GI decontamination is warranted due to the rapid absorption, good prognosis and rapid recovery with supportive care alone in most cases.

ANTIDOTES

There is no specific antidote for MDMA intoxication. Benzodiazepines provide adequate treatment for most patients.

Beta blockers are contraindicated as they may increase hypertension and increase ischemia (due to unopposed alpha agonist adrenergic effects).

Serotonin antagonists (e.g. cyproheptadine 4 to 8 mg po TDS PRN and chlorpromazine 25-50 mg IM PRN) could be considered where the clinical syndrome resembles severe serotonin toxicity (i.e. severe hyperthermia, muscle rigidity, and marked hyperreflexia with clonus (see also serotonin syndrome monograph).

ELIMINATION ENHANCEMENT

Is not indicated due to the relatively short half-life.

LATE COMPLICATIONS, PROGNOSIS & FOLLOW UP

An uneventful recovery is the usual course and no routine follow up is required.


References and Further reading:


Ecstasydata.org. http://www.ecstasydata.org/results.php . 2006. Erowid and Dance safe.

Psychostimulant Users - Clinical Guidelines for Assessment and Management – NSW Health
http://www.health.nsw.gov.au/policies/gl/2006/pdf/GL2006_001.pdf

Tanner-Smith EE. Pharmacological content of tablets sold as "ecstasy": results from an online testing service. Drug Alcohol Depend. 2006;83(3):247-54.

Green AR, Mechan AO, Elliott JM, O'Shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). Pharmacol.Rev. 2003;55(3):463-508.

Johnson M, Elayan I, Hanson GR, Foltz RL, Gibb JW, Lim HK. Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems. J.Pharmacol.Exp.Ther. 1992;261(2):447-53.

Farre M, de la TR, Mathuna BO, Roset PN, Peiro AM, Torrens M et al. Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology (Berl). 2004;173(3-4):364-75.

de la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura M et al. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther.Drug Monit. 2004;26(2):137-44.

Liechti ME, Kunz I, Kupferschmidt H. Acute medical problems due to Ecstasy use. Case-series of emergency department visits. Swiss.Med.Wkly. 2005;135(43-44):652-7.

Ling LH, Marchant C, Buckley NA, Prior M, Irvine RJ. Poisoning with the recreational drug paramethoxyamphetamine ("death"). Med J Aust 2001;174(9):453-5.

Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007;187(6):361-5.