Warning against co-administration of 3,4-methylenedioxymethamphetamine (MDMA) with methamphetamine from the perspective of pharmacokinetic and pharmacodynamic evaluations in rat brain.
3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine often cause serious adverse effects (e.g., rhabdomyolysis, and cardiac disease) following hyperthermia triggered by release of brain monoamines such as dopamine and serotonin. Therefore, evaluation of brain monoamine concentrations is useful to predict these drugs risks in human. This study aimed to evaluate risks of co-administration of MDMA and methamphetamine, both of which are abused frequently in Japan, based on drug distribution and monoamine level in the rat brain. Rats were allocated to three groups (1) sole MDMA administration (12 or 25 mgkg, intraperitoneally), (2) sole methamphetamine administration (10 mgkg, intraperitoneally) and (3) co-administration of MDMA (12 mgkg, intraperitoneally) and methamphetamine (10 mgkg, intraperitoneally). We monitored pharmacokinetic and pharmacodynamic variables for drugs and monoamines in the rat brain. Area under the curve for concentration vs. time until 600 min from drug administration (AUC₀₋₆₀₀) increased from 348.0 to 689.8 μgminL for MDMA and from 29.9 to 243.4 μMmin for dopamine in response to co-administration of methamphetamine and MDMA compared to sole MDMA (12 mgkg) administration. After sole methamphetamine or that with MDMA administration, AUC₀₋₆₀₀ of methamphetamine were 401.8 and 671.1 μgminL, and AUC₀₋₆₀₀ of dopamine were 159.9 and 243.4 μMmin. In conclusion, the brain had greater exposure to MDMA, methamphetamine and dopamine after co-administration of MDMA and methamphetamine than when these two drugs were given alone. This suggests co-administration of MDMA with methamphetamine confers greater risk than sole administration, and that adverse events of MDMA ingestion may increase when methamphetamine is co-administered.