Effects of MDMA On The Human Body - Long-term Adverse Effects - Serotonergic Changes

Serotonergic Changes

Experiments indicate that both moderate and high dose or rapidly repeated MDMA exposure may lead to long-lasting changes in neurons that make serotonin. Serotonergic changes have been demonstrated experimentally in the brains of all mammalian species studied, with most studies involving rats. In these studies, the brains of animals who are given high or repeated doses of MDMA show long-term decreases in all measures of serotonergic functioning, including concentrations of serotonin, tryptophan hydroxylase, and binding of the serotonin transporter protein. Although measures of serotonin are decreased, there are no decreases in the number of cells in the dorsal raphe, which indicates that the serotonin neurons have not died. Limited studies attempting to stain and photograph serotonergic axons shortly after high-dose MDMA exposure have reported that axons appear swollen and misshapen, as if they might be degenerating. However, few studies have attempted to stain and examine axons and with the measures commonly used in MDMA studies it is difficult or impossible to distinguish axon loss from decreases in production of markers of serotonin.

Animal studies show that there is recovery of serotonergic markers. However, if axons are actually regrowing, there is no assurance that they will reform their original connections. While rats show extensive recovery that sometimes appears complete, some primate studies show evidence of lasting alterations in serotonergic measures. Human studies, discussed below, show recovery, but these studies use indirect measures that may lack sensitivity for detecting subtle changes.

It is not known what dose(s) of MDMA would produce similar toxic effects in humans. This is because there are some difficulties in translating animal MDMA toxicity studies to humans. Firstly, it is difficult to equate rat doses to human doses, because rats metabolize MDMA twice as fast as humans and often larger doses or multiple doses are administered to simulate human plasma levels. Second, if the neurotoxicity of MDMA depends on its metabolites (Jones 2004;), it may be difficult or impossible to translate an MDMA dose between species since different species metabolize MDMA to different extents. Therefore, it is difficult to say what dose in humans would produce the effects seen in animals.

Keeping these limitations in mind, comparisons of MDMA exposures can be made between animal neurotoxicity studies and human clinical studies. One (uncertain) estimate suggests that the neurotoxic dose may be only moderately higher than amounts given in clinical studies (1.5 or 1.7 mg/kg, about 100 or 120 mg). That published comparison was made based on data from rats.

Further comparisons can be made using monkey data. In a recent study by Mechan et al. (2006), the lowest repeated dose regimen that produced serotonergic effects, detectable after 2 weeks, in squirrel monkeys was 2.4 mg/kg given orally three times in a row (every 3 hours). The peak plasma MDMA concentrations seen after that dose was 787 ± 129 ng/ml (mean ± SEM, range: 654 to 1046 ng/ml) and the Area Under the Concentration vs. Time-Curve (AUC, a measure of overall drug exposure) was 3451 ± 103 hr*ng/ml. In comparison, 1.6 mg/kg oral (112 mg in a 70 kg / person) in humans produces peak MDMA concentrations of 291.8 ± 76.5 ng/ml (range: 190 - 465 ng/ml) and an AUC of 3485.3 ± 760.1 hr*ng/ml (Kolbrich et al. 2008). Thus, a typical human dose produces peak MDMA concentrations that are about 37% of a known neurotoxic dose and has a very similar AUC. Because MDMA has nonlinear kinetics, it is likely that fewer than three of these doses would be needed to produce an exposure in humans greater than the dose schedule that produced decreased brain serotonin and decreased serotonin transporter binding in monkeys.