Association between perceived and objective measures of community violence exposure

Abstract

sought to determinewhether sex differences inMDMAmetabolism occur in squirrel monkeys, a species that is frequently employed in studies of MDMA-induced neuro-toxicity, and that metabolizes MDMA similarly to humans. Methods: Squirrel monkeys of both sexes (N=6/group) were given single, clinically relevant doses of oral MDMA (0.8 and 1.6mg/kg). Following treatment, blood was collected at various timepoints, plasma levels ofMDMAand itsmetabolitesweredetermined, andMDMApharmacokineticswere calculated. Potential sex differences inMDMAmetabolismwere explored, and subsequently compared to those previously reported in humans. Results: As recently reported in humans, female monkeys generated significantly higher (∼2.5-fold) peak plasma levels of MDA (p=0.002 and p=0.0002 at 0.8mg/kg and 1.6mg/kg, respectively), and lower levels (∼2-fold) of HMMA (p=0.0004 and p<0.0001 at 0.8mg/kg and 1.6mg/kg, respectively), when compared to males. Further, as occurs in humans, animals of both sexes exhibited non-linear pharmacokinetics indicating inhibition of the CYP2D6 homologue catalyzing MDMA O-demethylenation. Interestingly, female monkeys were more prone to inhibition of MDMA metabolism, as reflected by significantly higher (1.8-fold; p=0.0051) disproportionate increases in peak MDMA levels in females than in males with dose increase. This too is in accordance with reports that state faster clearance of drugs metabolized by CYP2D6 in male human subjects. Conclusions: Squirrel monkeys, like humans, demonstrate sex differences in MDMA pharmacokinetics. These observations provide additional evidence that the squirrel monkey is a useful animal model for predicting (sex specific) outcomes of MDMA exposure in humans. Financial support: This work was supported by NIH grants DA05707 and DA01796401.