3,4‑Methylenedioxymethamphetamine (MDMA)

MDMA is a ring‑substituted amphetamine that promotes presynaptic release of serotonin, norepinephrine and dopamine, and inhibits their re‑uptake. Additional direct agonist actions at 5‑HT_2A, α₁, and other receptors have been demonstrated Drevin 2024. Peak plasma concentrations occur 1–3 h after oral dosing, and elimination is nonlinear because the parent drug inactivates CYP2D6.

Recreational use is common under the street name "ecstasy". In controlled settings, MDMA‑assisted psychotherapy for post‑traumatic stress disorder is under late‑phase investigation Mitchell 2023. Reported harms include acute hyperthermia, hyponatraemia, serotonergic toxicity and longer‑term neurocognitive impairment.

The primary metabolic route is CYP2D6‑mediated O‑demethylenation to HHMA followed by COMT‑catalysed methylation; an N‑dealkylation pathway leading to MDA is secondary de la Torre 2005. Both pathways generate active metabolites, and CYP2D6 becomes functionally inhibited after a single recreational dose, further accentuating inter‑individual variability.

CYP2D6: Highly polymorphic cytochrome P450 isoform responsible for the initial O‑demethylenation step. Activity ranges from absent (poor metaboliser, PM) to duplicated gene copies (ultrarapid metaboliser, UM) Schmid 2016.

COMT: Catechol‑O‑methyltransferase clears catechol metabolites of dopamine and norepinephrine. The common Val158Met (rs4680) variant reduces enzyme activity by roughly 3‑ to 4‑fold in Met/Met carriers, altering dopaminergic tone in prefrontal cortex Colzato 2017.

Alterations in these genes are plausible determinants of both pharmacokinetic exposure (CYP2D6) and pharmacodynamic sensitivity (COMT). Evidence is limited and not entirely consistent, therefore genotype‑guided advice remains provisional.

CYP2D6. Controlled studies show that PMs have 2‑ to 3.5‑fold higher MDMA area‑under‑the‑curve values than normal metabolisers, with faster rise in blood pressure and subjective effects; UMs show only marginally lower exposure de la Torre 2005, Schmid 2016. The clinical relevance is debated because CYP2D6 autoinhibition diminishes phenotype differences after the first hour Schmid 2016.

COMT. Observational work links the high‑activity Val/Val genotype to greater acute cardiovascular stimulation and larger post‑dose deficits in working memory, whereas Met/Met has been associated with dizziness and prolonged tachycardia in recreational users Pardo‑Lozano 2012, Aitchison 2012. Effect sizes are small and confounded by poly‑substance use.

CYP2D6 categories

• Ultrarapid metaboliser: Possible subtherapeutic peak and shorter duration; evidence insufficient to recommend higher doses.
• Normal metaboliser: Reference exposure; typical therapeutic and adverse effect profile.
• Intermediate metaboliser: Approximately 2.5‑fold higher exposure; increased risk of hyperthermia and neurotoxicity.
• Poor metaboliser: Up to 3.5‑fold higher exposure; well‑documented cases of severe hyperthermia and hyponatraemia.

COMT functional groups

• High activity (Val/Val): Faster dopamine clearance; studies report larger decrements in attention and memory plus stronger haemodynamic response.
• Intermediate (Val/Met): Average pharmacodynamic sensitivity.
• Low activity (Met/Met): Prolonged dopaminergic stimulation; risk of dizziness, hyponatraemia and tachycardia.

Indeterminate / Not Available

• Effect: Unknown
• Implication: No specific guidance; follow standard dosing with careful monitoring.

CYP2D6 dosing guideline

COMT functional guideline

CYP2D6 poor metaboliser genotypes occur in approximately 5–10 % of individuals of European ancestry, 1 % of East Asians and 2 % of sub‑Saharan Africans. Ultrarapid metaboliser genotypes exceed 20 % in north‑eastern Africa but are below 3 % in most European and Asian groups Gaedigk 2018.

COMT Met allele frequency ranges from 0.45 in European cohorts to 0.25 in East Asian cohorts, implying that low‑activity phenotypes are common but not universal Palmatier 1999.

Consequently, clinically important variation in MDMA exposure and effect is expected worldwide, supporting the rationale for pre‑treatment genotyping in therapeutic protocols.

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• de la Torre R et al. Eur J Clin Pharmacol. 2005.
• Schmid Y et al. Pharmacogenet Genomics. 2016.
• Pardo‑Lozano R et al. PLoS ONE. 2012.
• Aitchison K et al. J Psychopharmacol. 2012.
• Gaedigk A et al. Front Pharmacol. 2018.
• Palmatier M et al. Anthropol Sci. 1999.
• Studerus E et al. J Psychopharmacol. 2021.