The intake of 3,4-methylenedioxymethamphetamine (
MDMA) is known to increase several endogenous substances involved in
steroid and
inflammation pathways. Untargeted metabolomics screening approaches can determine biochemical changes after drug exposure and can reveal new pathways, which might be involved in the pharmacology and toxicology of a drug of abuse. We analyzed plasma samples from a placebo-controlled crossover study of a single intake of
MDMA. Plasma samples from a time point before and three time points after the intake of a single dose of 125 mg
MDMA were screened for changes of endogenous metabolites. An untargeted metabolomics approach on a high-resolution quadrupole time-of-flight mass spectrometer coupled to liquid chromatography with two different chromatographic systems (reversed-phase and hydrophobic interaction liquid chromatography) was applied. Over 10 000 features of the human metabolome were detected. Hence, 28 metabolites were identified, which showed significant changes after administration of
MDMA compared with placebo. The analysis revealed an upregulation of
cortisol and
pregnenolone sulfate 4 h after
MDMA intake, suggesting increased stress and serotonergic activity. Furthermore,
calcitriol levels were decreased after the intake of
MDMA.
Calcitriol is involved in the upregulation of trophic factors, which have protective effects on brain dopamine neurons. The
inflammation mediators hydroxyeicosatetraenoic
acid, dihydroxyeicosatetraenoic
acid, and
octadecadienoic acid were found to be upregulated after the intake of
MDMA compared with placebo, which suggested a stimulation of
inflammation pathways.