Frontal cortex slices from a squirrel monkey. A = control; B = 2 weeks; C = 6-7 years after MDMA exposure. Slices have been stained with antibodies towards the serotonin transporter, tryptophan hydroxylase and (for some reason) tyrosine hydroxylase.
Interspecies dose scaling based on differences in elimination rate suggests that 5mg MDMA administered to a monkey corresponds to 1,4mg administered to a human. However, since it is the metabolites of MDMA that cause axonal damage, the faster elimination rates of smaller animals may actually increase toxicity. Furthermore, most MDMA studies use intravenous injections. Oral administration results in 50% less immediate serotonin depletion. Differences in the formation of reactive oxygen species between the two routes of administration are not known. If we assume 50% less damage to serotonergic axons with oral consumption, the dosage used in the primate experiments described above correspond to 1680mg MDMA (ca 16 pills) consumed over a period of 4 days in a human weighing 75kg. However, MDMA toxicity is strongly related to MDMA-induced hyperthermia. With with air conditioning and almost no fur, humans may be better suited to avoid hyperthermia than other animals, although MDMA users may compromise this advantage by dancing for hours in crowded clubs. Interspecies differences in neurobiology and metabolism may also affect MDMA toxicity. For instance, MDMA damages dopaminergic rather than serotonergic axons in mice.
Studies on human MDMA users have found a reduction in blood and cerebrospinal fluid concentrations of serotonin and its metabolites. Using PET scans, McCann et al (1998) found significant reductions in serotonin transporter density (60-80% of baseline) in cortical and subcortical regions of heavy MDMA users (n=14, average of 3-4 pills, 6 times per month for 4 years) who had been abstinent for 3-5 weeks or more. The extent of these reductions correlated significantly with the number of times MDMA had been used but not with duration of abstinence. However, Reneman et al (2oo1) (n=23, 50 or more pills total) and Buchert et al (2003) (n=59, average of 793 pills total) found significant reductions in serotonin transporter density in current but not in former users, indicating regenrative capacity in humans. Behavioural studies have yielded highly variable results but tend to report problems with visual and verbal memory, attention and anxiety in heavy users, with varying degrees of persistance following abstinence (see Parrott, 2006 for a review).