Sami Ben Hamida

MDMA: Interactions with other psychoactive drugs

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most widely abused illegal drugs. Some users self-report euphoria and an increased perception and feeling of closeness to others. When taken in warm environments, MDMA users may develop acute complications with potential fatal consequences. In rodents, MDMA increases locomotor activity and, depending on ambient temperature, may produce a dose-dependent, potentially lethal hyperthermia. Like most other recreational drugs, MDMA is frequently taken in combination with other substances including tobacco, EtOH, marijuana, amphetamines, cocaine and, caffeine. Although polydrug use is very common, the understanding of the effects of this multiple substance use, as well as the analysis of consequences of different drug-drug associations, received rather little attention. The purpose of this review is to summarize our current knowledge about the changes on MDMA-related behavior, pharmacology, and neurotoxicity associated with co-consumption of other drugs of abuse and psychoactive agents.

Interactions between ethanol and cocaine, amphetamine, or MDMA in the rat: Thermoregulatory and locomotor effects

Rationale(±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia.ObjectiveExperiment 1 compared the interactions between EtOH (1.5xa0g/kg) and MDMA (6.6xa0mg/kg) with EtOH + cocaine (COCA; 10xa0mg/kg) and EtOH + amphetamine (AMPH; 1xa0mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3xa0mg/kg) and larger doses of COCA (20xa0mg/kg) and AMPH (2xa0mg/kg).Materials and methodsDrug treatments were administered on four occasions (2, 5, and 2xa0days apart, respectively; experiment 1) or two (2xa0days apart; experiment 2).ResultsAll psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5°C). Co-treatment with EtOH and AMPH (1xa0mg/kg) or COCA (10xa0mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA.ConclusionBecause of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.

MDMA (ecstasy) effects in pubescent rats : Males are more sensitive than females

In Experiment 1, we assessed the effects of 3,4-methylenedioxymethamphetamine (MDMA) on locomotor activity in pubescent male and female Long-Evans rats. Thirty-nine day old rats were injected ip with 10 mg/kg of MDMA (ambient temperature 25 degrees C) three times at 2 h intervals. Initially, females showed greater locomotor activation by the drug than males, however after the second injection, males showed greater hyperlocomotion. After the third injection, 3 of 10 females and all of the males died. In the surviving females, we observed serotonin depletion in cortex and hippocampus, but catecholaminergic markers were unaltered. In Experiment 2, male and female rats were repeatedly injected with saline or 2, 5 or 10 mg/kg MDMA and body temperature was measured (ambient temperature 21.5 degrees C). After the third injection of 10 mg/kg MDMA, the MDMA-induced hyperthermia was greater in males than in females (about +0.8 degrees C); at the lower dose, no difference was observed. Probably because of the lower ambient temperature, only 1 female and 2 males succumbed to the MDMA treatment, and MDMA induced less serotonin depletion than in the first experiment, with no difference between females and males. Thus, pubescent males appear to be more sensitive than females to locomotor and hyperpyretic effects of MDMA. This sex-dependent effect, which is at variance with previously reported dimorphisms in psychostimulant effects, is discussed in terms of possible differences in dopamine D1 and D2 receptors at pubescence, or other factors related to drug metabolism.

Ethanol increases the distribution of MDMA to the rat brain: Possible implications in the ethanol-induced potentiation of the psychostimulant effects of MDMA

Ecstasy (3,4-methylenedioxymethylamphetamine; MDMA) is a popular club drug often taken with ethanol (EtOH). We recently found EtOH potentiated the psychomotor effects of MDMA in rats. This potentiation could reflect pharmacodynamic or/and pharmacokinetic processes. To test the latter hypothesis, rats were injected i.p. with 6.6 or 10 mg/kg MDMA with or without 1.5 g/kg EtOH, and were killed at 5, 15 or 60 min after injection. MDMA, its primary metabolite, 3,4-methylenedioxyamphetamine (MDA), and EtOH concentrations were determined in the plasma and the hippocampus, frontal cortex and striatum at each time-point. EtOH potentiated MDMA-induced hyperactivity mainly during the first 60 min post-administration. Fifteen and 60 min after treatment with MDMA and EtOH, MDMA concentrations were greater than after MDMA alone in the blood and the three brain regions examined. EtOH, however, did not increase the fraction of MDMA converted to MDA, as shown by unaltered MDA/MDMA ratios at either MDMA dose. Interestingly, when combined with EtOH, the distribution of MDMA and MDA in the brain was not homogeneous. Concentrations of both were much higher in the striatum and cortex, than in the hippocampus. Thus, at least part of the potentiation of the MDMA-induced hyperlocomotion by EtOH might be the result of a higher concentration of MDMA and metabolites in the blood and brain. Our results present clear evidence that EtOH increases brain and blood concentrations of MDMA and leads to the possibility of both enhanced MDMA-based neurotoxicity and increased liability for abuse.

Ethanol-MDMA interactions in rats: the importance of interval between repeated treatments in biobehavioral tolerance and sensitization to the combination.

RationaleIn our previous work, we showed that ethanol (EtOH) potentiates 3,4-methylenedioxymethamphetamine (MDMA)-induced hyperlocomotion while protecting against its hyperthermic effects. Whereas the effect on activity were found on all days (although declining over the three first days), the protection against hyperthermia completely disappeared on the second day. The latter effect was previously thought to reflect tolerance to ethanol or the combination, per se.ObjectiveIn the present study, we changed the treatment regimen to irregular and longer intervals between treatments (48, 120, and again 48xa0h) to check if tolerance was still observed.ResultsWe found progressive sensitization of locomotor activity to EtOH (1.5xa0g/kg, i.p.)+MDMA (6.6xa0mg/kg, i.p.), and a partial EtOH protection against MDMA-induced hyperthermia that persisted after the first drug challenge day. When the monoamine neurotransmitters, dopamine, and serotonin were assessed 2xa0weeks after treatment, we found no consistent effect on the concentration of any of these neurotransmitters, whatever the treatment. Similarly, we found that regional brain concentrations of MDMA were not significantly affected by EtOH at a 45-min post-treatment delay; however, the overall ratio of the metabolite 3,4-methylenedioxyamphetamine (MDA) to MDMA was lower (overall, −16%) in animals treated with the combination compared to MDMA alone, indicating possible contribution of pharmacokinetic factors. This difference was especially marked in the striatum (−25%).ConclusionsThese findings shed new light on the consequences of EtOH–MDMA, taken together at a nearly normal ambient temperature, both in terms of motivation and potential risks for recreational drug users.

Ethanol-ecstasy (MDMA) interactions in rats: preserved attenuation of hyperthermia and potentiation of hyperactivity by ethanol despite prior ethanol treatment.

Recreational use of ecstasy, or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), is often associated with other drugs, among which ethanol is one of the most common. Little is known, however, about the interaction between these two drugs. Using a daily ethanol and/or MDMA administration regimen, we recently showed that ethanol potentiated the hyperactivity (in the home cage), but attenuated the hyperthermia induced by MDMA. The prevention of hyperthermia occurred only on the first of four daily ethanol-MDMA treatments, indicating possible tolerance to ethanol. In order to test the tolerance hypothesis, we treated Long-Evans adult male rats with ethanol on 4 consecutive days prior to their first treatment with MDMA-ethanol. Our results first confirmed that ethanol (1.5 g/kg, i.p.) potentiates the psychomotor effects of MDMA (10 mg/kg, i.p.), while attenuating its pyretic effects (6.6 mg/kg, i.p.). The results also showed that both the potentiation of locomotor activity and the attenuation of hyperthermia by ethanol are not at all altered by prior ethanol treatment. This indicates that tolerance to ethanol per se does not account for what appears to be tolerance to the ethanol-MDMA combination, thus indicating that ethanol-MDMA combination likely has unique pharmacological effects.

Interactions between 3,4-methylenedioxymethamphetamine and ethanol in humans and rodents.

Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely used recreational drug, often associated with dance parties. Users self-report euphoria, a sense of well-being and increased feelings of affiliation. In experimental animals, MDMA produces an acute, rapid release of serotonin and, to a lesser extent, dopamine and norepinephrine in the brain. It can also produce a dose-dependent, life-threatening hyperthermia in rodents, primates and humans. Moreover, there is evidence of long-term neurological and psychological effects in heavy users. In rats, MDMA increases the locomotor activity. When used recreationally, MDMA is often taken with other drugs including amphetamine, cannabis, cocaine or ethanol (EtOH). Epidemiological data suggest that MDMA-EtOH is one of the most common combinations. In rats, EtOH potentiates MDMA-induced hyperactivity but may attenuate its hyperthermic effect, depending on the ambient temperature. The possibility that EtOH may modify the pharmacokinetics and pharmadynamics of MDMA is of concern in terms of liability for misuse abuse. In this short review, we focus on the known interactions between MDMA and EtOH in humans and rodents.

Contents Vol. 60, 2009

N. Brunello, Modena G. Erdmann, Berlin S. Galderisi, Naples U. Hegerl, Leipzig K. Hirata, Mibu Y. Koga, Tokyo J. Kornhuber, Erlangen P.T. Loosen, Nashville, Tenn. D. Lehmann, Zürich K.P. Lesch, Würzburg G.N. Papadimitriou, Athens M. Reuter, Bonn F. Rösler, Marburg G. Ruigt, Oss J.K. Rybakowski, Poznan F. Schneider, Aachen R. Schwarting, Marburg D. Souery, Brussels P. Willner, Swansea H. Yoneda, Osaka Associate Editors