Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy

Abstract

This review of chronic tolerance to MDMA (3,4-methylenedioxymetamphetamine) covers the empirical data on dosage escalation, reduced subjective efficacy and bingeing in recreational Ecstasy users. Novice users generally take a single Ecstasy tablet, regular users typically take 2-3 tablets, whereas the most experienced users may take 10-25 tablets in a single session. Reduced subjective efficacy following repeated usage is typically described, with many users subjectively reporting the development of tolerance. Intensive self-administration or bingeing is often noted by experienced users. This can comprise 'stacking' on several tablets together, and 'boosting' on successive doses over an extended period. Some experienced users snort Ecstasy powder nasally, whereas a small minority inject MDMA. Chronic tolerance and bingeing are statistically linked to higher rates of drug-related psychobiological problems. In terms of underlying mechanisms, neuroadaptive processes are certainly involved, but there is a paucity of evidence on hepatic and behavioural mechanisms. Further studies specifically designed to investigate chronic tolerance, involving low intermittent dose regimens, are required. Most animal research has involved intensive MDMA dosing regimens designed to engender serotonergic neurotoxicity, and this may comprise another underlying mechanism. If distal serotonin axon terminal loss was also developing in recreational users, it may help to explain why reducing subjective efficacy, dosage escalation and increasing psychobiological problems often develop in parallel. In conclusion, there is extensive evidence for chronic pharmacodynamic tolerance to recreational Ecstasy/MDMA, but the underlying mechanisms are currently unclear. Several traditional processes are probably involved, but one of the possible causes is a novel mechanism largely unique to the ring substituted amphetamine derivatives, namely serotonergic neurotoxicity.

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

“…Third, as described in this review, self-administration of MDMA and its analogs is a reasonably robust phenomenon, particularly in the rhesus monkey (but see De La Garza's review in this issue for a discussion of the challenges in maintaining rodent self-administration of MDMA). Finally, the progressive loss of MDMA selfadministration behavior previously noted in rhesus monkeys replicates the similar phenomenon of spontaneous abstinence in human users (von Sydow et al 2002;Parrot 2005), and may be a novel and sensitive behavioral model for the persistent neurochemical effects of the drug. In approximately 20 years of MDMA research, only a handful of studies have employed self-administration techniques to study the effects of this compound.…”

“…It has been suggested that these data may indicate the development of chronic tolerance to the effects of MDMA (Parrot 2005); however, it may be more difficult to assert that tolerance has developed to the reinforcing effects of a drug than is commonly appreciated. In the case of complete tolerance to the reinforcing effects of a drug, it seems reasonable to assume that the drug would lose its capacity to engender self-administration (as no amount of drug could be taken that could serve the function of maintaining the behavior) and extinction would thus ensue.…”

“…Subsequent self-administration experiments with MDMA were conducted over an approximately 18-month period to assess the persistence of these reinforcing effects (Fantegrossi et al 2004a) because diminished subjective effects over repeated uses have often been reported by human ecstasy users (see, for example, the recent review of chronic tolerance to MDMA in Parrot 2005). In these studies, monkeys were given the opportunity to selfadminister one of several MDMA doses about twice per week under the single-dose FR10 schedule described above, and dose-effect curves were repeatedly determined in this manner over the duration of the experiment.…”

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

“…The present study utilized large MDMA challenge doses, and so a robust effect on locomotor stimulation might have offset diminished serotonin stores, although the latter were not quantitated at 4 days. Since the duration of treatment was so brief, this finding is not necessarily relevant to reports of gradual tolerance to the subjective effects of MDMA nor to reports of supersensitivity which occurs after longer treatment durations (Parrot 2005). Females but not males showed sensitized responding when tested 2 weeks after the last treatment.…”

Plasma Drug Concentrations and Physiological Measures in ‘Dance Party’ Participants

“…There have been several studies in which MDMA was administered to humans in a controlled laboratory setting and in which plasma pharmacokinetics of MDMA were measured (Helmlin et al, 1996;de la Torre et al, 2000de la Torre et al, , 2004Pacifici et al, 2001Pacifici et al, , 2002. However, these studies necessarily involved a limited dose range that was well below that reported by some MDMA users (Parrott, 2005). Further, it is possible that factors associated with MDMA use in dance settings (eg increased temperature, crowding, activity, ingestion of other psychoactive substances) may influence the pharmacokinetics, pharmacodynamics, and/or neurotoxic potential of MDMA.…”