Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms.
Francesco Bavato, Andrea E. Steuer, Anna M. Jacobsen, Amelie Zacher, Josua Zimmermann, David M. Cole, Antje Opitz, Markus R Baumgartner, Ann-Kathrin Stock, Christian Beste, Boris B. Quednow
Translational Psychiatry May 21, 2026 DOI: 10.1038/s41398-026-04069-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Cross-sectional study Peer reviewed |
|---|---|
| Sample size | 140 |
| Population | Chronic MDMA users, chronic METH users, and healthy controls |
| Topics | MDMA |
| Key findings | Chronic METH use was associated with depletion of serum tryptophan and serotonin and general activation of kynurenine pathways, while chronic MDMA use was linked to selective activation of the OH-kynurenine metabolic branch. |
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.
Comparable studies
Other cross-sectional and survey studies on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Recreational MDMA use in Sydney: a profile of ‘Ecstasy’ users and their experiences with the drug Recreational Ecstasy users recruited via snowball peer network | 1992 | Cross-sectional survey | n = 100 |
| Reducedin vivobinding to the serotonin transporter in the cerebral cortex of MDMA (‘ecstasy’) users Male regular ecstasy users and well-matched controls | 1999 | Cross-sectional association study | n = 20 |
| Patterns of simultaneous polysubstance use in drug using university students Drug-using university students | 2006 | Cross-sectional survey | n = 149 |
| Patterns of recreational drug use at dance events in Edinburgh, Scotland Drug users at dance events in Edinburgh, Scotland, UK, aged 16-47, 80% between 18 and... | 2001 | Cross-sectional survey | n = 122 |
| Acute, sub‐acute and long‐term subjective consequences of ‘ecstasy’ (MDMA) consumption in 430 regular users Regular MDMA users | 2003 | Cross-sectional study | n = 466 |
Citations in the library
Cites 10
- Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage? Addiction February 27, 2006
- Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review Journal of Psychopharmacology June 26, 2021
- Neuroimaging of chronic MDMA (“ecstasy”) effects: A meta-analysis Neuroscience & Biobehavioral Reviews November 12, 2018
- Discrete memory impairments in largely pure chronic users of MDMA. European Neuropsychopharmacology October 1, 2017
- White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels NeuroImage: Clinical September 19, 2022
and 5 more in the library