title: Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.
abstract: Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.
authors.affiliation: University Medical Center Utrecht, Division of Anesthesiology, Intensive Care and Emergency Medicine, National Poisons Information Center (NVIC), P.O. box 85500, 3508 GA, Utrecht, The Netherlands. S.Rietjens@umcutrecht.nl
authors.forename: Saskia J
authors.initials: SJ
authors.lastname: Rietjens
authors.forename: Laura
authors.initials: L
authors.lastname: Hondebrink
authors.forename: Remco H S
authors.initials: RH
authors.lastname: Westerink
authors.forename: Jan
authors.initials: J
authors.lastname: Meulenbelt
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004347:Drug Interactions; D005982:Glutathione Transferase / Q000235:genetics; D006220:Haloperidol / Q000493:pharmacokinetics / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007650:Ketanserin / Q000493:pharmacokinetics / Q000494:pharmacology; D023421:Models, Animal; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D050479:Neurotransmitter Transport Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000493:pharmacokinetics / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6; D005982:Glutathione Transferase; D006220:Haloperidol; D007650:Ketanserin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D050479:Neurotransmitter Transport Proteins; D011412:Propanolamines; D017981:Receptors, Neurotransmitter; D017367:Selective Serotonin Reuptake Inhibitors