Clinical Textbook of Addictive Disorders 3rd ed - R. Frances, S. Miller, A. Mack (Guilford, 2005) WW

166 III. SUBSTANCES OF ABUSEin serotonin and 5-HIAA after initial recovery, persistently depressed TPHactivity, and a decrease in serotonin terminal density (Demirkiran et al., 1996;Ricaurte, McCann, Szabo, & Scheffel, 2000). 5-HIAA levels most typicallyrecover to baseline levels within 24 hours.NeurotoxicityThe most important individual and public health danger posed by the widespreaduse of MDMA is the likelihood that it causes the permanent destructionof serotonin axons in humans who use it. The ingestion of MDMA in laboratoryanimals causes a decrease in the serum and spinal fluid levels of 5-HIAA ina dose-dependent fashion (McCann et al., 2000; Shulgin, 1990) and damagesbrain serotonin neurons (Burgess, McDonoghoe, & Gill, 2000; McCann &Ricaurte, 1993; Montoya, Sorrentino, Lucas, & Price, 2002). The dosage necessaryto cause permanent damage to most rodent species is many times greaterthan that normally ingested by humans (Shulgin, 1990). In nonhuman primates,the neurotoxic dosage approximates the recreational dosage taken byhumans (McCann & Ricaurte, 1993). A recent study by Ricaurte and McCann(2001), which reported an alarmingly small dose necessary for the neurotoxicityto occur, has subsequently been retracted due to a human error in the laboratory(Walgate, 2003). Nevertheless, like its close structural relative methylenedioxyamphetamine(MDA, or “Eve”), MDMA has been found to damageserotonin neurons in all animal species tested to date (McCann, Slate, &Ricaurte, 1996), and the same is likely to occur in humans.MDMA produces a 30–35% drop in serotonin metabolism in humans(McCann et al., 1994). Even one dose of MDMA may cause lasting damage tothe serotonin system. There are many reports of individuals with lasting neuropsychiatricdisturbances after MDMA use (Cohen, 1998; Creighton, Black, &Hyde, 1991; McCann & Ricaurte, 1991; Schifano, 1991). Such damage mightbecome apparent only with time or under conditions of stress. Users with noinitial complications may manifest problems over time (McCann et al., 1996).For obvious reasons of safety and ethics, human studies are more difficultto 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 butconvincing (Burgess et al., 2000; Green et al., 1995). This evidence includesmetabolite studies, which quantify the levels of serotonin and metabolites inpopulations of Ecstasy users. An increasing number of investigations demonstratethat metabolite levels of serotonin are much lower in chronic users, evenwhen abstinent for long periods of time. The difficulties of the studies notwithstanding,the available clinical evidence suggests that repeated ingestion ofhigh doses of MDMA produces long-term reductions in serotonergic activityand degeneration of serotonergic terminals in humans (Montoya et al., 2002).