Although for an organic chemist, the synthesis of MDMA is reasonably simple, most supplies in the United States are imported and then distributed by organized crime networks. Its price, usually $25 to $40 for a 125-mg tablet--the amount producing the sought-after effect in most intermittent users (Green et al., 1995)--has remained remarkably stable over the past two decades. This high price makes adulteration highly tempting--such adulteration can be either harmless, with the buyer being duped, or harmful, if the substitute is something dangerous.Physiological Effects of MDMA
Ecstasy is almost exclusively available in pill form. Often the pills are stamped with clever images. The usual single dose is 100 mg to 150 mg. The onset of effect begins about 20 minutes to 40 minutes after ingestion and is experienced with immediacy. The plateau stage of drug effects lasts three hours to four hours. The principal desired effect, according to most users, is a profound feeling of relatedness to the rest of the world around them (Liester et al., 1992). Although the desire for sex can increase, the ability to achieve arousal and orgasm is greatly diminished in both men and women (Buffum and Moser, 1986). Thus, MDMA has been termed a sensual, not sexual, drug. Prescription drugs such as sildenafil(Drug information on sildenafil) (Viagra) may be taken in order to counteract this effect and may be sold along with MDMA (Weir, 2000). The array of physical effects and behaviors produced by MDMA is remarkably similar across mammalian species (Green et al., 1995) and includes mild psychomotor restlessness, bruxism, trismus, anorexia, diaphoresis, hot flashes, tremor and piloerection (Peroutka et al., 1988).
After-effects associated with MDMA are common and can be pronounced. People using MDMA once, or on multiple occasions, may experience any number of symptoms including lethargy, anorexia, decreased motivation, sleepiness, depression and fatigue. Severe, immediate effects appear to be rare, but they do occur. Altered mental status, convulsions, hypo- or hyperthermia, severe changes in blood pressure, tachycardia, coagulopathy, acute renal failure, hepatotoxicity, rhabdomyolysis, and death have all occurred (Demirkiran et al., 1996; Kalant, 2001).Mechanism of Action of MDMA
Ecstasy is primarily serotonergic, and its principal mechanism of action is as an indirect serotonergic agonist (Sprague et al., 1998). The drug's effects, and side effects (an arbitrary distinction), including anorexia, psychomotor agitation, difficulty in achieving orgasm and profound feelings of empathy, can be explained as a result of the flooding of the serotonin system (Beck and Rosenbaum, 1994).
Most people who use MDMA on a regular basis tend not to increase their use as time goes on (Cohen, 1998; Peroutka, 1990). Because of its mechanism of action (the drug depletes serotonin stores and inhibits synthesis of new serotonin), subsequent doses produce a diminished high and a worsening of the drug's undesirable effects, such as psychomotor restlessness and teeth gnashing. People who use MDMA most typically become aware of the benefits of periodic, and even rare, use. First-time users are often instant advocates of MDMA, only to have their enthusiasm dampen with time. An adage about Ecstasy captures this succinctly: "Freshmen love it, sophomores like it, juniors are ambivalent, and seniors are afraid of it" (Eisner, 1993).Neurotoxicity of MDMA
The most important individual and public health danger posed by the widespread use of MDMA is its likelihood to cause the permanent destruction of serotonin axons in humans who use it. The ingestion of MDMA in laboratory animals causes a decrease in the serum and spinal fluid levels of 5-HIAA in a dose-dependent fashion (McCann et al., 2000; Shulgin, 1990) and damages brain serotonin neurons (Burgess et al., 2000; McCann and Ricaurte, 1993; Montoya et al., 2002). The dosage necessary to cause permanent damage to most rodent species is many times greater than that normally ingested by humans (Shulgin, 1990); in nonhuman primates, however, the neurotoxic dosage approximates the recreational dosage consumed by humans (McCann and Ricaurte, 1993). To date, MDMA has been found to damage serotonin neurons in all animal species tested (McCann et al., 1996), and the same is likely to occur in humans.
Human studies are, for obvious reasons of safety and ethics, more difficult to execute, and those that are done offer legitimate and ample room for criticism. The bulk of evidence that MDMA is neurotoxic in humans is indirect, but convincing (Burgess et al., 2000; Green et al., 1995). This evidence includes metabolite studies, which quantify the levels of serotonin and metabolites in populations of those people who use Ecstasy. There are an increasing number of investigations demonstrating that metabolite levels of serotonin are much lower in chronic users, even when they remain abstinent for long periods of time. The difficulties of the studies notwithstanding, the available clinical evidence suggests that repeated ingestion of high doses of MDMA produces long-term reductions in serotonergic activity and degeneration of serotonergic terminals in humans (Montoya et al., 2002).Extensive cognitive studies in individuals using MDMA, though rife with methodological problems, show a consistent pattern of cognitive dysfunction seen in the frontal cortex and the hippocampus. This phenomenon is consistent with that found in animals exposed to MDMA (Fox et al., 2001; Montoya et al., 2002). Psychiatric problems, such as depression, anxiety, panic, increased impulsiveness and sleep disturbances, are significantly higher in people who have used MDMA, even while abstinent and when the last use was remote. In a symposium titled "Is MDMA a human neurotoxin?" Turner and Parrott (2000) concluded:
Novel studies … confirmed and extended the range of cognitive, behavioral, [electroencephalographic], and neurological deficits, displayed by drug-free Ecstasy users. Moreover, these deficits often remained when other illicit drug use was statistically controlled. In conclusion: If MDMA neurotoxicity in humans is a myth, then it is a myth with a heavy serotonergic component.