Key interindividual determinants in MDMA pharmacodynamics

ABSTRACT

Introduction: MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use.

Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use.

Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.

KEYWORDS:

• MDMA
• 3,4-methylenedioxymethamphetamine
• pharmacodynamics
• pharmacokinetics
• sex-gender
• race-ethnicity
• genetic polymorphisms

Article highlights

• Acute MDMA effects are more pronounced in women than in men. Psychosocial and biological differences, or a combination of factors, have been identified as a source of the variability. Nevertheless, a significant knowledge gap remains in understanding the role sex-gender plays in mediating MDMA effects in women.

• MDMA research regarding race-ethnicity is scarce, and studies considering this factor are needed.

• MDMA metabolism plays a key role in the potential risk of acute MDMA effects and toxicity. The genetic polymorphism of metabolic CYP450 isoenzymes is a relevant factor for MDMA concentrations and acute effects.

• Preliminary/pilot-controlled clinical trials suggest that MDMA holds considerable promise in the treatment of PTSD, but further research is needed to ensure that MDMA-assisted psychotherapy is of use.

• In recreational and poly-drug consumption, repeated administrations of MDMA are relevant to its pharmacokinetics and effects that should be assessed to minimize potential acute toxicity.

• More systematic investigation in humans is warranted, focused on interindividual determinants in MDMA pharmacokinetics-pharmacodynamics to better understand its acute pharmacological effects and toxicity.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was supported in part by grants from Ministerio de Sanidad, Servicios Sociales e Igualdad (Plan Nacional sobre Drogas-PNSD, 2015I054 and 2016I024), Instituto de Salud Carlos III (ISCIII, FIS-FEDER, PI14/00715, PI17/01962), ISCIII-Red de Trastornos Adictivos (RTA-FEDER RD12/0028/0009 RD16/0017/0003 and RD16/0017/0010). Esther Papaseit is a Juan Rodes fellow (ISC-III, JR16/00020).