Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions

The clinical outcome after MDMA intake ranges from mild entactogenic effects to life-threatening intoxication, and the most relevant mechanisms causing acute adverse effects remain unclear. Genetic factors, such as polymorphisms in CYP2D6 causing poor metabolism, and interactions from polydrug use, like co-exposure with selective serotonin reuptake inhibitors (SSRIs), modulate MDMA pharmacokinetics and dynamics. While SSRIs can increase MDMA plasma levels, they can reduce clinical effects like blood pressure and body temperature, possibly via pharmacodynamic interaction at the serotonin reuptake transporter. Pretreatment with inhibitors of dopamine or norepinephrine transporters, or antagonists like carvedilol, ketanserin, and haloperidol, can reduce multiple MDMA-induced effects. Investigating these drugs for treating MDMA intoxication is worthwhile.

Study at a glance

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.