ChemistryMDMA is structurally related to amphetamines. One important difference between MDMA and amphetamines is the presence of the methylenedioxy group (-O-CH2-O-) attached to the aromatic ring. This attachment makes it also resemble the structure of the hallucinogen mescaline. Like amphetamines, MDMA is a synthetic substance that does not exist in nature.
Similarly to amphetamines and cocaine, MDMA can exist as a free base or as salts of various acids. Unlike these drugs, however, MDMA tends not to be inhaled in its free base form. This is because the methylenedioxy group raises the boiling point of the free base so high that it becomes too difficult to use in such a manner (Shulgin, 1986).
The salts are not volatile, but are quite soluble in water and thus can be administered intravenously, orally or intranasally. 'Ecstasy' tablets sold on the street do not always contain MDMA, but may contain methylenedioxyethylamphetamine (MDEA), methylenedioxyamphetamine (MDA), paramethoxyamphetamine (PMA), ephedrine, ketamine or a range of other compounds (Becker, Neis, Rohrich & Zorntlein, in press; Byard, Gilbert, James & Lokan, 1998; Holden & Jackson, 1996).
MDMA is a chiral molecule, meaning that it exists in two forms, which are denoted as S(+) MDMA and R(-) MDMA. S(+) MDMA is thought to possess greater central pharmacological effects (Steele, Nichols & Yim, 1987).
PharmacokineticsMDMA is readily absorbed from the gastrointestinal tract. Onset of action is within 30 minutes and peak serum levels occur after one to three hours (Mas, Farre, de la Torre, Roset et al., 1999). The elimination half-life is approximately seven hours (Mas et al., 1999). Like amphetamines, alkaline urine can increase the half-life of MDMA to 16-31 hours.
MDMA is metabolised in the liver to an active metabolite (methydioxyamphetamine), which has a longer half-life (16–38 hours). Whilst the enzyme cytochrome P450 2D6 is mainly responsible for the metabolism, other enzymes are also involved (Lin, Di Stefano, Schmitz, Hsu et al., 1997; Ramamoorthy,Yu, Suh, Haining et al., 2002; Tucker, Lennard, Ellis,Woods et al., 1994). Some of these are saturable, which means that once the enzymes are saturated, as the dose increases, disproportionately large increases in blood and brain concentrations occur, increasing risk of toxicity (de la Torre, Farre, Ortuno, Mas et al., 2000).Top of page
PharmacodynamicsThe primary mode of action of MDMA is as an indirect serotonergic agonist, increasing the amount of serotonin released into the synapse (Kalant, 2001). MDMA acts on the serotonin transporter and is transported into the nerve terminal. This promotes release of serotonin through the serotonin transporter by a process of transporter-mediated exchange. Whilst within the terminal, MDMA interferes with the storage of serotonin within the vesicles and thus increases the amount of serotonin available to be released (Rothman & Baumann, 2002). This process can lead to significant increases in serotonin available in the synapse.
MDMA is also able to enhance release of dopamine (Gold, Hubner & Koob, 1989; Lyles & Cadet, 2003) and noradrenaline (Frei, Gamma, Pascual-Marqui, Lehmann et al., 2001). It is presumed that MDMA's effects on dopamine and noradrenaline release are mediated in a similar manner to the serotonin release. MDMA can also inhibit monoamine reuptake and delay metabolism by inhibition of monoamine oxidase (Leonardi & Azmitia, 1994).
In addition to increasing extracellular levels of monoamines (Kalant, 2001), there is some evidence to suggest that MDMA might also have a range of other receptor effects, acting on 5HT2 receptors, a2-adrenergic receptors and M1 muscarinic cholinergic receptors (Battaglia, Brooks, Kulsakdinun & De Souza, 1988; McDaid & Docherty, 2001). It has relatively low affinity for D1 and D2 dopamine receptors (Battaglia et al., 1988).
Effects on the user
Sought-after effectsThe sought-after effects for which MDMA is used are similar to those of amphetamines (Tancer & Johanson, 2001). Psychological effects include a sense of euphoria and wellbeing (Vollenweider, Gamma, Liechti & Huber, 1998), but unlike amphetamines, MDMA users particularly report a sense of closeness to others, greater sociability, sharpened sensory perception, extraversion and greater tolerance of others' views and feelings (Greer & Tolbert, 1986; Peroutka, Newman & Harris, 1988; Siegel, 1986). 'Positive mood state' has been cited as an important desired outcome of MDMA use (Solowij et al., 1992). Users have reported the sensation of 'an expanded mental perspective' and 'improved self-examination'. Hallucinations are sometimes reported (Peroutka et al., 1988).
Although MDMA can also produce wakefulness, increased energy and alleviation of fatigue (Tancer & Johanson, 2001), these effects need not be present at doses required to enhance mood (Vollenweider et al., 1998).
Repeated use of MDMA over a short time frame may lead to reduced drug effects, or tolerance. This has been observed in animal (Frederick, Ali, Slikker, Gillam et al., 1995) and human studies (Peroutka et al., 1988). Although the mechanisms of tolerance to MDMA are not well established, they may include short-term inhibition of serotonin synthesis or depletion of serotonin (Lyles & Cadet, 2003).Top of page
Other behavioural effectsOther psychological effects occurring during or after use of MDMA may include hyperactivity, racing thoughts, insomnia, mild hallucinations, depersonalisation, anxiety, agitation and bizarre or reckless behaviour (Cohen, 1995; Siegel, 1986). Occasionally, this may lead to panic attacks, delirium, or brief psychotic episodes. Although increases in sexual arousal are reported (Cohen, 1995), impairments in sexual functioning may also occur (Zemishlany, Aizenberg & Weizman, 2001). In the few days following drug use, reduced appetite, depression, anxiety, difficulty concentrating, muscle aches and fatigue have been reported (Cohen, 1995; Peroutka et al., 1988; Vollenweider et al., 1998). Chronic use may also be associated with depression, anxiety or cognitive impairments (Krystal, Price, Opsahl, Ricaurte & Heninger, 1992; Parrott, Buchanan, Scholey, Heffernan et al., 2002).
Physiological effectsCommon adverse effects reported during the drug experience and shortly afterwards include dry mouth, ataxia, stiffness and pain in the back and limbs, headache, nausea, loss of appetite, blurred vision, insomnia and increased muscle tension, experienced as jaw clenching, tooth grinding and restless leg movements (Cohen, 1995; Downing, 1986; Greer & Tolbert, 1986; Vollenweider et al., 1998). Other physical symptoms may include reduced appetite and pupil dilation (Cohen, 1995; Greer & Tolbert, 1986; Mas et al., 1999). Increased body temperature stems from the drug's effects on the thermoregulatory system in the brain, but is not always observed in experimental conditions (Mas et al., 1999; Vollenweider et al., 1998).
As with amphetamines (O'Cain, Hletko, Ogden & Varner, 2000), acute cardiovascular effects of MDMA include dose-dependent increases in heart rate, blood pressure and cardiac output (Lester, Baggott, Welm, Schiller et al., 2000; Mas et al., 1999; Peroutka et al., 1988; Vollenweider et al., 1998), although animal studies suggest that these effects may be influenced by other factors such as ambient temperature (Irvine, Toop, Phillis & Lewanowitsch, 2001).
In an examination of responses during MDMA 'binge' administration in rats (Badon, Hicks, Lord, Ogden et al., 2002), the first binge led to an increase in mean arterial pressure and a biphasic effect on heart rate (decrease then increase). In subsequent binges, the reduction in heart rate was more pronounced and was accompanied by hypotension, suggesting that binge administration may produce a different profile of cardiovascular effects than that observed from alternative dosing regimes. Increases in heart rate and blood pressure or myocardial oxygen consumption may be clinically relevant in producing adverse reactions.Top of page
ToxicitySevere MDMA overdoses are associated with intense sympathomimetic responses and active hallucinations as well as thermoregulatory, neurologic, cardiovascular, hepatic and electrolyte disturbances (Gowing, Henry-Edwards et al., 2002; Kalant, 2001). Neurological symptoms include agitation, hallucinations, seizures, coma and acute and chronic psychiatric symptoms (Kalant, 2001;Vaiva, Boss, Bailly, Thomas et al., 2001). Serotonin toxicity may occur in combination with antidepressants (Kaskey, 1992; Vuori, Henry, Ojanpera, Nieminen et al., 2003) or after MDMA alone (Brown & Osterloh, 1987; Henry, Jeffreys & Dawling, 1992; Screaton, Singer, Cairns, Thrasher et al., 1992). It has been suggested that jaw clenching commonly experienced by MDMA users may be a result of serotonergic overactivity (Parrott, 2002).
Cerebrovascular crises may also occur. One case study describes right-sided subarachnoid haemorrhage and middle cerebral artery aneurysm occurring after MDMA ingestion (Auer, Berent, Weber, Lassnig & Eber, 2002). MDMA-induced hyperthermia is modulated by serotonergic and dopaminergic systems. Severe hyperthermia can be associated with rhabdomyolysis, renal failure, disseminated intravascular coagulation, multiorgan failure and death (Kalant, 2001; Screaton et al., 1992). There is a strong correlation between hyperthermia and poor survival rates in patients who have ingested ecstasy (Kalant, 2001).
Cardiovascular effects include hypertension, which results from the enhanced vasoconstrictive effects of monoamines. Hypotension resulting from depletion of these chemicals may also occur. Supraventricular and ventricular tachyarrhythmias with or without haemodynamic instability may also be present (Kalant, 2001). Unlike other amphetamine derivatives, MDMA has not been reported to result in acute myocardial infarction.
Use of MDMA may lead to various electrolyte disturbances. These include hypoglycaemia, hypernatraemia (related to reduction in body water) and hyponatraemia (may be related to the syndrome of inappropriate secretion of vasopressin or to hypervolaemia resulting from excess water ingestion) (Holden & Jackson, 1996; Traub, Hoffman & Nelson, 2002). Fatal hyponatraemia and cerebral oedema after MDMA use has been reported (Milroy, Clark & Forrest, 1996; Parr, Low & Botterill, 1997). In healthy volunteers, a single ingestion (47.5 mg) of MDMA led to increased vasopressin secretion and reduced sodium concentrations. There are isolated case reports of inappropriate vasopressin levels in MDMA users presenting with severe hyponatraemia.
Growing evidence suggests that MDMA may be hepatotoxic (Jones & Simpson, 1999). Liver damage may occur via a range of mechanisms (Beitia, Cobreros, Sainz & Cenarruzabeitia, 2000), but may be secondary to hyperthermia (Brauer, Heidecke, Nathrath, Beckurts et al., 1997; Carvalho, Carvalho & Bastos, 2001).
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Ring substituted amphetamine derivatives, such as MDA, MDEA or PMA, may confer a riskier toxicity profile than MDMA. In particular, PMA is considered responsible for a number of ecstasy-associated deaths (Becker et al., in press; Felgate, Felgate, James, Sims & Vozzo, 1998), producing life threatening hypertension or hyperthermia. Fatalities have also occurred after MDEA ingestion (Weinmann & Bohnert, 1998).
A considerable amount of research examining psychostimulants and neurotoxicity has focused on MDMA. In animal studies, administration of high dose MDMA leads to long-term depletion of serotonin, accompanied by reductions in other markers of serotonergic function including serotonin metabolites, transporters and serotonin-specific enzymes, degeneration of serotonergic axons and axon terminals and increased numbers of glial cells (Commins, Vosmer, Virus, Woolverton et al., 1987; Ricaurte, DeLanney, Irwin & Langston, 1988; Rothman & Baumann, 2002; Schmidt & Taylor, 1987; Sprague, Everman & Nichols, 1998). Although some animal studies have been criticised for utilising doses that are not representative of doses consumed by humans, other research in primates has demonstrated serotonergic alterations using doses similar to those used by humans (Ricaurte et al., 1988; Ricaurte, Yuan, Hatzidimitriou, Cord & McCann, 2002).
A range of human studies suggest that MDMA users demonstrate reduced levels of serotonin metabolites, blunted neuroendocrine responses to serotonergic drugs, reduced density of serotonin reuptake sites, reduced glucose metabolism in certain brain regions and EEG patterns resembling those of ageing and dementia (Boot, McGregor & Hall, 2000). Challenges in this area include the difficulty in establishing causality in cross-sectional research and establishing the clinical significance of observed neurological changes (Kish, 2002; Lyles & Cadet, 2003). Nonetheless, it has been suggested that MDMA users at high risk for neurotoxic effects are those who use two or more street doses of MDMA at a time, those who use the drug fortnightly or more frequently, those who inject MDMA and those who use it for 24 hours or more (Boot et al., 2000).
The exact mechanisms of MDMA induced neurotoxicity are not known. Factors that may be involved in development of neurotoxicity include hyperthermia, formation of toxic metabolites, inhibition of serotonin synthesis, oxidative stress and free-radical formation, dopamine release and glutamate and nitric oxide pathways (Lyles & Cadet, 2003; Rothman & Baumann, 2002; Sprague et al., 1998).