Deciding which measures of serotonergic functioning are good indicators of damage is one important task. I think that one of the more important aspects of this letter is the clarity with which the authors argue this point. There is disappointingly little discussion in the neurotoxicity literature concerning the degree to which different indices of serotonergic functioning are sensitive or selective for neurodegenerative changes. Because serotonin transporter density is a measure of a structural feature on the serotonin axon, it is likely a better indicator of whether the axons are damaged or absent than serotonin levels, which are dependent on diet and enzyme activity and can be depleted by nondamaging drugs. Having argued that serotonin transporter density be used as a marker of neurodegeneration, Vollenweider and colleagues discuss the relationship between dose and toxicity.
Animal studies indicate that neurotoxicity is dose-dependent.
That is, higher doses produce greater damage. The strength of this point is limited as it is not clear how much we need to consider the faster metabolisms of nonhuman animals when comparing doses between species. Because of their higher metabolisms, smaller animals often clear drugs from their bodies faster and therefore frequently experience less toxicity than humans. However, since we do not thoroughly understand the causes of MDMA-induced neurotoxicity, we cannot predict the magnitude of these species differences. The importance of human studies Studies in human users are therefore important.