of this complex topic. For a broader sense of the range of views on MDMA neurotoxicity, thereader is therefore advised to consult other review articles (Boot, 2000; Burgess, 2000; Green,1995; Hegadoren, 1999; McKenna , 1990; Morgan 2000; O'Callaghan, 2001; Seiden, 1996;Sprague, 1998; Steele, 1994), and the issue of Neuropsychobiology (Vol. 42, 2000) dedicated toMDMA neurotoxicity.
MDMA Can Induce Long-term Serotonergic Changes
Before discussing MDMA-induced changes and their meaning, it is necessary to define a fewterms. In this chapter, drug doses and dosing patterns used in research that produce these long-term serotonergic changes will be referred to as "neurotoxic regimens." Neurotoxic regimensoften consist of four to eight injections of MDMA given over the course of one to four days;however, a single injection of MDMA can also produce these changes. In this chapter, anychanges noted at 7 or more days after drug administration will be considered "long-term." Manystudies examining the brains of animals at longer time periods (often at 2, 4, or 8 weeks) haveestablished that the MDMA-induced changes at 7 days are primarily long-term in nature.The term "neurotoxicity" is more difficult to define. Though no universal definition exists, mostdefinitions are broad enough to encompass both short-term alcohol-induced headaches and thepermanent nerve cell loss caused by the drug MPTP. A more useful approach to the question of whether MDMA is neurotoxic is to describe the nature and mechanisms of the long-term changesit can cause. In this way, it is evident that some neurotoxic MDMA regimens produce bothchanges in the serotonergic system and acute damage to the brain by free radicals, and therebycause a loss of nerve cell axons. This suggests that MDMA neurotoxicity is a type of drug-induced damage, even though the consequences of this damage are unknown.MDMA does produce long-lasting changes to the serotonergic system at some doses. Theselong-term changes include decreases in brain concentrations of the neurotransmitter serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Levels of tryptophan hydroxylase(TPH), the enzyme that begins the synthesis of 5-HT within the serotonergic nerve cell aredecreased. There are also decreases in the density of the serotonin reuptake transporter (SERT),the protein on the membrane of serotonergic neurons that recycles released 5-HT by pulling itback into the cell. Most studies suggest that MDMA primarily causes long-term changes inserotonergic axons that have their cell bodies in an area of the brainstem called the dorsal raphenucleus.Long-lasting decreases in these serotonergic markers suggest that either (a) some type of "downregulation" has occurred, meaning the nerve cell is making and maintaining less of the markers,or (b) that serotonergic axons are permanently lost. The question of whether MDMA is trulyneurotoxic stems from this issue. Down regulation suggests an active adaptation to drug effects,while axonal loss suggests true damage may have occurred. Determining which actually happenscan be difficult. SERT density may change in response to drugs, but this has been difficult toconsistently demonstrate (Le Poul, 2000; Ramamoorthy, 1998). Similarly, 5-HT levels can beinfluenced by diet and other factors. Because MDMA has been shown to rapidly inactivate theenzyme TPH, decreased 5-HT levels would be expected until TPH activity returns to normal.