Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans.

Andrea E. Steuer; Corina Schmidhauser; Eva H Tingelhoff; Yasmin Schmid; Anna Rickli; Thomas Kræmer; Matthias E. Liechti

doi:10.1371/journal.pone.0150955

Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans.

Andrea E. Steuer, Corina Schmidhauser, Eva H Tingelhoff, Yasmin Schmid, Anna Rickli, Thomas Kræmer, Matthias E. Liechti

PLoS One June 15, 2016 DOI: 10.1371/journal.pone.0150955 (opens in new tab)

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Study at a glance

AI-extracted from the abstract

Characteristics	Double-blind, placebo-controlled, four-period, cross-over design Peer reviewed
Sample size	16
Population	Healthy participants (13 extensive metabolizers and 3 intermediate metabolizers of CYP2D6)
Interventions	Bupropion MDMA
Dose	125 mg MDMA, 1 week placebo or bupropion pretreatment
Duration	24 h after MDMA administration
Topics	MDMA
Citations	18
Key points	Bupropion pretreatment increased the plasma exposure of R-MDMA and S-MDMA and reduced the levels of CYP2D6-dependent metabolites by approximately 40%, with changes in intermediate metabolizers comparable to bupropion-pretreated extensive metabolizers.

Abstract

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs), intermediate metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.

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Study	Year	Design	Participants
MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Patients with severe PTSD, including those with comorbidities such as dissociation,...	2021	Randomized controlled trial	n = 90
The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Patients with chronic post-traumatic stress disorder refractory to both psychotherapy...	2010	Randomized controlled trial	n = 20
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Military veterans and first responders aged 18 or older with chronic PTSD lasting 6...	2018	Randomized, double-blind, dose-response, phase 2 clinical trial	n = 26
A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD) Patients with treatment-resistant PTSD	2012	Randomized controlled trial	n = 12
MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Adults with moderate to severe post-traumatic stress disorder	2023	Randomized controlled trial	n = 104

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