Drugs and Human Performance FACT SHEETS - Methylenedioxymethamphetamine (MDMA, Ecstasy)

Synonyms: 3,4-methylenedioxymethamphetamine; ecstasy, ADAM, candy canes, disco biscuit, doves, E, eckie, essence, hug drug, love drug, M&M, rolls, white doves, X, XTC.

Source: MDMA is the methylenedioxy derivative of methamphetamine. Starting materials in its illicit manufacture include isosafrole (Leuckart reaction) and safrole (Merck patent). MDMA is most commonly found in tablet forms of various colors, carrying distinctive markings on one side such as a dove, E, yin/yang symbol, Mitsubishi symbol, etc. MDMA is a Schedule I controlled substance.

Drug Class: Mild CNS stimulant, empathogen, entactogen, mild hallucinogen and psychedelic, appetite suppressant.

Medical and Recreational Uses: Originally patented as an appetite suppressant and used as a possible adjunct to psychotherapy, there is currently no legitimate medical use in the U. S. MDMA is recreationally used as a party, rave or dance drug for its stimulant, mild hallucinogenic, and empathogenic properties.

Potency, Purity and Dose: MDMA exists as a racemic mixture, with the S-(+)-enantiomer having greater CNS potency compared to the R-(-)-enantiomer. Potency of street samples is highly variable, and tablets sold as ‘ecstasy’ may in fact contain little or no MDMA, but may contain caffeine, ephedrine, phenylpropanolamine, paramethoxyamphetamine (PMA), methylenedioxyamphetamine (MDA), dextromethorphan, amphetamine, methamphetamine, and ketamine. Some tablets have been reported to contain LSD or heroin. Typical doses in a series of pills can range between 10–150 mg of MDMA. User surveys report a range of doses between 50-700 mg in a session, with an average of 120 mg. Most common pattern of use is binge consumption at all night rave or dance parties. MDMA is frequently taken with other recreational drugs such as ethanol, marijuana, cocaine, methamphetamine, nitrous oxide, and GHB.

Route of Administration: Primarily oral administration, although MDMA could conceivably be dissolved and injected, or crushed and snorted.

Pharmacodynamics: MDMA is a phenylethylamine that has stimulant as well as psychedelic effects. MDMA is related in structure and effects to methamphetamine, however, it has significantly less CNS stimulant properties than methamphetamine. MDMA has a high affinity for 5-HT 2 receptors. Both S- and R- enantiomers of MDMA cause acute depletion of presynaptic serotonin (5-HT), depression of 5-HT synthesis by tryptophan hydroxylase, and retrograde destruction of 5-HT neurons following high doses. MDMA also increases levels of norepinephrine and dopamine. The MDMA metabolite, S-(+)- MDA, elicits more stereotypic behavior and is an even more potent neurotoxin than the parent drug. MDA destroys serotonin-producing neurons which play a direct role in regulating aggression, mood, sexual activity, sleep, and sensitivity to pain.

Pharmacokinetics: MDMA is rapidly absorbed and t he half-life of MDMA is ~ 7 hours, although non-linear pharmacokinetics have been observed due to stereoselective pharmacokinetics of the enantiomers. MDMA is metabolized to MDA which is the only metabolite reported in blood and plasma. S-(+)- MDA accumulates in blood due to stereoselective metabolism of S-(+)-MDMA. MDA is further metabolized to its 3-hydroxy-4-methoxy and 3,4-dihydroxy derivatives (HMA and HHA). Additional MDMA metabolites include 3-hydroxy-4-methoxymethamphetamine (HMMA) and 3,4-dihydroxymethamphetamine (HHMA). These polar hydroxylated metabolites are conjugated prior to their excretion in urine.

Molecular Interaction / Receptor Chemistry: The majority of MDMA N-demethylation to MDA is via the cytochrome P450 2D6 isoenzyme, with minor contributions by the 1A2 isoform. Potential inhibitors of these isoenzymes could decrease the rate of MDMA elimination if administered concurrently, while potential inducers could increase the rate of elimination. Both extensive and poor MDMA metabolizers have been identified.

Blood to Plasma Concentration Ratio: Data not available.

Interpretation of Blood Concentrations: No clear correlation exists between MDMA blood concentrations and effects. MDMA and MDA are the analytes detected in blood, with MDA concentrations typically only 5-10% of the corresponding MDMA concentrations. Higher MDA:MDMA ratios may indicate co-administration of MDA. Plasma concentrations following single oral doses of 50, 75, 100, 125 and 150 mg of MDMA were 0.02-0.08 mg/L, 0.13 mg/L, 0.19-0.21 mg/L, 0.24 mg/L, and 0.44 mg/L, respectively. Peak concentrations of MDMA and MDA are observed at 1.5-2 hours and 4 hours, respectively.

Interpretation of Urine Test Results: MDMA, MDA, HMMA, HHMA, HMA and HHA are typically found in urine following their hydrolysis. MDA and HMMA concentrations in urine are typically 10-15% of the corresponding MDMA concentrations.

Effects:

Psychological: Low to moderate doses (50-200 mg) produce mild intoxication, relaxation, euphoria, an excited calm or peace, feelings of well-being, increase in physical and emotional energy, increased sociability and closeness, heightened sensitivity, increased responsiveness to touch, changes in perception, and empathy. At higher doses, agitation, panic attacks, and illusory or hallucinatory experiences may occur.

Physiological: Low to moderate doses (50-200 mg) produce mild visual disturbances (blurred or double vision, increased light sensitivity), dilated pupils, dry mouth, sweating, ataxia, muscle tension, and involuntary jaw clenching.

Side Effect Profile: Impairment of cognitive, perception, and mental associations. Psychological difficulties include confusion, depression, sleep problems, drug craving, severe anxiety, and paranoia. Subjects may experience fatigue, uncoordinated gait, decreased fine motor skills, attentional dysfunction (difficulty to maintain attention during complex tasks), preoccupation, hyperthermia, tachycardia, hyperthermia, hyponatremia, convulsions, and catatonic stupor. Prolonged cognitive and behavioral effects may occur including poor memory recall, flashbacks, panic attacks, psychosis, and depersonalization due to serotonergic neuron damage and decreased serotonin production as a result of long-term use.

Duration of Effects: Following oral administration, effects onset in 20-30 minutes and desired effects may last only an hour or more, depending on dose. Other general effects last for approximately 2-3 hours. LSD is sometimes used in combination with MDMA to increase its duration of effects. Residual and unwanted effects are generally gone within 24 hours although confusion, depression and anxiety may last several weeks.

Tolerance, Dependence and Withdrawal Effect: Drug stacking refers to the ingestion of single doses consecutively as effects begin to wane, similar to cocaine or methamphetamine binges. Such extensive or binge use usually occurs over weekends, and can result in exhaustion, apathy, depression, irritability, insomnia and muscle tension early the next week (often referred to as “terrible Tuesdays”). Tolerance does develop, however, the occurrence of physical and/or psychological dependence is unknown. Persistent neurological deficits may occur, including serotonergic neuron damage which leads to less production of serotonin.

Drug Interactions: The dopamine D 2 receptor antagonist, haloperidol, attenuates psychological effects of MDMA but has no effect on physiological effects.

Performance Effects: MDMA can enhance impulsivity and make it difficult for a person to maintain attention during complex tasks (selective attention, divided and sustained attention, and complex attention tasks). Laboratory studies have demonstrated changes in cognitive, perception and mental associations, instability, uncoordinated gait, and poor memory recall. Distortion of perception, thinking, and memory, impaired tracking ability, disorientation to time and place, and slow reactions are also known performance effects. Single oral doses of MDMA causes subjective excitability, anxiety, perceptual changes, and thought disorders 1-3 hours post dose.

Effects on Driving: In an advanced driving simulator study, subjects were given a mean single dose of 56 mg MDMA. Compared to a sober state, moderate effects on vehicle control, acceptance of higher levels of risk, acute changes in cognitive performance, and impaired information processing ability were observed. In six subjects arrested for driving under the influence, MDMA was the only drug detected at blood concentrations ranging from <0.05-0.58 mg/L. The subjects were cooperative and laid back, and experienced muscle twitching, body tremors, perspiring, dilated pupils, slow reaction to light, and poor performance on field sobriety tests. The following concentrations of MDMA have also been measured in other retrospective studies; serum MDMA concentrations ranging from 0.001-0.514 mg/L (mean 0.076 mg/L) in 18 cases of driving impairment; blood MDMA concentrations ranging from 0.04-0.38 mg/L (mean 0.18±0.14 mg/L; median 0.19 mg/L) in 9 impaired driving cases; blood MDMA concentrations of 0.12, 0.08, and 0.14 mg/L in 3 impaired driving cases; and a blood MDMA concentration of 2.14 mg/L and urine 118.8 mg/L in one driving fatality case. Another study reported the occurrence of speeding, jumping red lights, hallucinations/delusions, and a sense of detachment in five impaired driving cases, however, no MDMA concentrations were mentioned.

DEC Category: Hallucinogen; (with many characteristics similar to a CNS stimulant)

DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not present; lack of convergence not present; pupil size dilated; reaction to light slow; pulse rate elevated; blood pressure normal to elevated; body temperature normal to elevated. Other characteristic indicators may include profuse sweating, muscle twitching, body tremors, and poor performance in field sobriety tests. Subjects are usually described as very cooperative and “laid-back”. Note that elevated blood pressure and body temperature are not always observed.

Panel’s Assessment of Driving Risks: Low to moderate single doses of MDMA can cause acute changes in cognitive performance and impair information processing, which in turn would impair driving ability. Basic vehicle control is only moderately affected, however, subjects may accept higher levels of risk.

References and Recommended Reading:

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