Genetic Factors in Human MDMA Toxicity: A PET Study

The aims of this exploratory/developmental proposal are to use the serotonin (5-HT) receptor ligand [18F] setoperone positron emission tomography (PET) to examine the chronic effects of MDMA (Ecstasy) use on serotonin 2A (5-HT2A) receptors in cerebral cortex of abstinent MDMA users characterized according to genetic variations potentially influencing 5-HT2A receptor expression.

MDMA has been used by millions of people worldwide and is toxic to serotonin (5-HT) axons in some animal models of MDMA administration. 5-HT influences mood, memory, sleep-wake cycle, anxiety, appetite, body image, aggression, suicidality, and sexual function. Therefore, alterations in 5-HT function have potentially broad consequences for the individual.

The post-synaptic 5-HT2A receptor mediates acute MDMA effects and activity at the 5-HT2A receptor and is necessary to produce MDMA-induced axonal toxicity. In addition, preliminary evidence from other researchers suggests that the 5-HT2A receptor may show compensatory changes in the face of altered pre-synaptic 5-HT signaling associated with axotomy or other MDMA effects on 5-HT neurotransmission. Therefore, the status of this receptor in MDMA users is of great importance in understanding the mechanisms of MDMA's effects.

Levels of the 5-HT2A receptor may be influenced by genetic variations that could confound the interpretation of 5-HT2A ligand binding assays. The T102C single nucleotide polymorphism (SNP) is a silent SNP in near complete linkage disequilibrium with another common polymorphism, 1438G/A. The T102C SNP has been associated with numerous clinical conditions and with altered levels of 5-HT2A expression. To control for the potential effects of this SNP on 5-HT2A receptor levels, we will enroll MDMA users homozygous for the C/C or T/T alleles of the T102C. To control for various additional factors affecting 5-HT2A expression we will enroll Caucasian females ages 18-25 who do not use hormonal contraception and who are non-smokers. Twenty MDMA users abstinent from MDMA at least 90 days (as verified by hair sample analysis) will be compared to 20 controls (matched by age, sex, and genotype) that have never used MDMA to compare 5-HT2A levels in cerebral cortex as assayed by [18F] setoperone PET.

We hypothesize that abstinent MDMA users will have increased 5-HT2A receptor expression consistent with (but not proof of) reduced pre-synaptic 5-HT release. Because 5-HT may affect brain volume, we will also examine regional brain volume using structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM). Exploratory analyses will examine for potential interactions of 5-HT2A receptor and 5-HT transporter genotype with the degree of MDMA exposure and outcome measures of 5-HT2A levels and brain volume.