Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms.

Summary

Chronic users of methamphetamine (METH) and MDMA (Ecstasy) show distinct alterations in blood levels of tryptophan-related metabolites, which may help explain their different clinical effects. In a study of 36 chronic MDMA users, 33 chronic METH users, and 71 healthy controls, METH use was linked to depleted serum tryptophan and serotonin and broad activation of kynurenine pathways, whereas MDMA use was associated with selective activation of the OH-kynurenine branch. These metabolite changes correlated with the severity of depression and psychosis symptoms. The findings suggest that persistent changes in peripheral tryptophan metabolism may contribute to the substances' contrasting addiction and psychiatric profiles.

Study at a glance

Abstract

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are two types of substituted amphetamines that share structural-chemical similarities but exhibit contrasting acute and chronic effects including addictive liability. Tryptophan (TRY) pathways are involved in pleiotropic physiological functions at the interface of brain-body connections. Preclinical evidence suggests that amphetamines may modulate these pathways and, thus, indirectly influence brain functions via persistent alterations of peripheral metabolites. However, little is known about alterations of TRY-related metabolites in the blood and their clinical implications in chronic users of MDMA and METH. Hence, we characterized serum levels of TRY-related metabolites in a comparative cross-sectional study including n = 36 chronic MDMA users, n = 33 chronic METH users, and n = 71 sex-matched, healthy controls. An ultra-high performance liquid chromatography-mass spectrometry method was used to determine TRY metabolites. Combining metabolite levels, metabolic ratios, and network analysis we found robust evidence of divergent pathway alterations between METH and MDMA users. Chronic METH use was particularly associated with a depletion of serum TRY and serotonin levels, and a general activation of kynurenine pathways, while chronic MDMA use was linked to a selective activation of the OH-kynurenine metabolic branch. Metabolite changes were associated with the severity of psychopathology in the depression and psychosis domains across groups. Altogether, our findings demonstrate differential changes of serum TRY pathways in chronic MDMA and METH users. Persistent alterations of these pathways might contribute to the contrasting clinical profile of the substances and constitute a peripheral dimension of neurochemical plasticity with relevant implications for therapeutic targets.