How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy?

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Abstract

Understanding the diverse functions of serotonin in the human brain can be obtained through examination of subjects having a lower than normal number of brain serotonin neurons. Behavioral abnormalities consistent with brain serotonergic damage have been reported in some polydrug users who also use the neurotoxin ecstasy (methylenedioxymethamphetamine, MDMA). This review evaluates the evidence from neuroimaging studies that brain serotonergic damage is a feature of human users of ecstasy. To date, neuroimaging studies designed to establish whether levels of brain serotonin neurons are lower than normal in ecstasy users have employed radioligands that bind to one component of the serotonin neuron, the serotonin transporter (SERT). Because these studies are methodologically flawed in terms of reliability or validity of the SERT measurement and appear to have employed polydrug users, no definitive information is yet available on the question of ecstasy toxicity to human brain serotonin neurons. Until these issues are resolved, it cannot be assumed that ecstasy exposure represents a chronic serotonin deficiency condition.

Introduction

Experimental animal studies of the role of monoamine neurotransmitters in brain function typically assess the influence of experimental surgical and pharmacologic manipulation of the activity or concentrations of brain monoamine neurons on behavior. In the human, such information can also be obtained through pharmacological investigation of drugs that reversibly or irreversibly alter neurotransmitter function and, for some neurotransmitter systems, study of behavior in humans chronically deficient in number of brain monoamine neurons due either to a neurodegenerative condition of unknown etiology or to damage by a selective neurotoxin. In the case of the brain dopamine neurotransmitter system, the results of human investigations showing that degeneration of brain dopamine neurons is the fundamental characteristic of both idiopathic Parkinson's disease (Ehringer and Hornykiewicz, 1960) and parkinsonism caused by a dopaminergic neurotoxin, MPTP (Vingerhoets et al., 1994), and that human parkinsonism can be reversed by dopaminergic agents Sano, 1960, Birkmayer and Hornykiewicz, 1961 have established the role of nigrostriatal dopamine in the control of movement.

Serotonin neurons originate, in the human, in the lower brain stem raphe nuclei, including the dorsal and median, and project to all regions of the brain (Tork, 1990). In humans, the results of a variety of pharmacological studies have suggested a role for the brain serotonin system in regulation of such biological processes as mood and appetite (cf. Staley et al., 1998). However, to date, no human behavioral disorder has been described for which the etiological involvement of the brain serotonin system has been clearly established. As in the case of the dopamine neurotransmitter system, further information on the function of serotonin in human brain could be obtained through behavioral examination of subjects deficient in number of serotonin neurons due either to a neurodegenerative disorder or to damage caused by a neurotoxin. The objective of this review is to assess the strength of the evidence, involving examination of the brain, that chronic exposure to the serotonergic neurotoxin ecstasy (methylenedioxymethamphetamine, MDMA) represents a state of decreased brain serotonin neuron concentration in human users of the drug.

Section snippets

Some behavioral abnormalities reported in chronic users of ecstasy could be explained by ecstasy-induced damage to brain serotonin neurons

Animal data indicate that ecstasy causes elevation of extracellular levels of brain serotonin and, to a lesser extent, dopamine Nichols et al., 1982, Kankaapaa et al., 1998. Since this action is blocked by selective serotonin reuptake inhibitors (SSRIs), the elevation of serotonin is generally considered to involve serotonin transporter (SERT)-mediated release Hekmatpanah and Peroutka, 1990, Rudnick and Wall, 1992, Gudelsky and Nash, 1996, although inhibition of serotonin reuptake might also be

Why have so few brain studies of ecstasy users been conducted?

Ecstasy use is now recognized as a major public health issue worldwide. However, to date (October 2001), only three investigations (two neuroimaging, one postmortem) have been conducted in which components of serotonin neurons have been measured in the brain of human ecstasy users. The lack of autopsied human brain investigations is probably due to the low number of ecstasy users who are autopsied each year as compared to the number of users of other neuroactive drugs such as cocaine,

Assessment of strength of neuroimaging data on ecstasy and brain SERT in human brain

SERT has been measured by neuroimaging in a PET investigation (McCann et al., 1998a) and in a SPECT study (Semple et al., 1999) of polydrug users of ecstasy. The major difficulty with both investigations is the uncertainty that SERT was ever reliably measured.

Recommendations

It can be expected that many of the important issues affecting the interpretation of studies of serotonin neuronal markers in living brain of ecstasy users will be satisfactorily addressed in future studies, in part by the use of more selective radioligands for SERT measurement by SPECT or PET, appropriate quantitation of the data, confirmation of drug use by forensic drug analysis, and, if at all possible, selection of a group of “pure ecstasy users” for study. Furthermore, as neuroimaging

Conclusions

1. It is likely, on the basis of animal data, that ecstasy, at some dose, will damage serotonin neurons in human brain. However, because of methodological problems in the limited number of studies conducted in the human, no conclusions can yet be established on ecstasy toxicity in human brain or whether ecstasy exposure represents a chronic serotonin deficiency syndrome.

2. The theoretical limitation of studies relying on neurochemical markers of the integrity of serotonin neurons, which can be

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