Ecstasy: Are animal data consistent between species and can they translate to humans?

Abstract

The number of 3,4-methylenedioxymethamphetamine (ecstasy or MDMA) animal research articles is rapidly increasing and yet studies which place emphasis on the clinical significance are limited due to a lack of reliable human data. MDMA produces an acute, rapid release of brain serotonin and dopamine in experimental animals and in the rat this is associated with increased locomotor activity and the serotonin behavioural syndrome in rats. MDMA causes dose-dependent hyperthermia, which is potentially fatal, in humans, primates and rodents. Subsequent serotonergic neurotoxicity has been demonstrated by biochemical and histological studies and is reported to last for months in rats and years in non-human primates. Relating human data to findings in animals is complicated by reports that MDMA exposure in mice produces selective long-term dopaminergic impairment with no effect on serotonin. This review compares data obtained from animal and human studies and examines the acute physiological, behavioural and biochemical effects of MDMA as well as the long-term behavioural effects together with serotonergic and dopaminergic impairments. Consideration is also given to the role of neurotoxic metabolites and the influence of age, sex and user groups on the long-term actions of MDMA.

Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges

“…Collectively, the data suggest that tolerance to neuroendocrine effects of MDMA is due to impairments in SERT-mediated release of 5-HT from nerve terminals in the brain. Our findings could have implications for human MDMA users who often report the development of tolerance to subjective effects after prolonged use (Verheyden et al, 2003, Parrott, 2005.One problem with extrapolating MDMA data from animals to humans is that laboratory animals receive non-contingent doses of drug which are much higher than those taken recreationally by humans (Easton and Marsden, 2006, Baumann et al, 2007). We sought to minimize this obstacle by designing an MDMA dosing regimen in rats based on threshold pharmacological doses.…”

“…The spectrum of MDMA-induced deficits can last for months, prompting general acceptance that the drug is a 5-HT neurotoxin (Ricaurte et al, 2000, Green et al, 2003. Nevertheless, there are unresolved issues surrounding MDMA neurotoxicity in rats (Wang et al, 2005), especially with regard to functional consequences and their potential clinical relevance (Easton and Marsden, 2006, Baumann et al, 2007).Functional correlates of MDMA-induced 5-HT deficits in rats have been examined, but findings are often ambiguous. For example, rats pretreated with high-dose MDMA are reported to exhibit tolerance or reverse tolerance (i.e., sensitization) to locomotor effects of the drug (Kalivas et al, 1998, Brennan andSchenk, 2006).…”

“…The spectrum of MDMA-induced deficits can last for months, prompting general acceptance that the drug is a 5-HT neurotoxin (Ricaurte et al, 2000, Green et al, 2003. Nevertheless, there are unresolved issues surrounding MDMA neurotoxicity in rats (Wang et al, 2005), especially with regard to functional consequences and their potential clinical relevance (Easton andMarsden, 2006, Baumann et al, 2007).…”

Incidental use of ecstasy: no evidence for harmful effects on cognitive brain function in a prospective fMRI study

“…A large body of evidence indicates that MDMA has the potential to damage brain serotonin neurons in various animal species (Easton and Marsden 2006;Green et al 2003). There is still controversy, however, whether similar serotonergic damage does occur in human ecstasy users (Gouzoulis-Mayfrank and Daumann 2006;Kish 2002).…”

“…For example, animal studies indicate that even after a single dose of MDMA, damage can occur in the serotonin system (Adori et al 2006;O'Shea et al 1998;Ricaurte et al 1988). However, whether these animal findings can be extrapolated to humans is still debated (Easton and Marsden 2006). Second, interpretation of human data is hampered by the lack of baseline data (Gouzoulis-Mayfrank and Daumann 2006).…”