Metabolism, MDMA

QUESTION Have you done any studies of the metabolism of these compounds As you probably know, there have been reports that MDMA is very quickly metabolized into MDA. Have you looked at MBDB to see if the ethyl group gets cleaved so that you essentially have an MDMA compound after you are through ... 

Recent work shows that, in rodents, MDMA is metabolized, at least in part, to MDA, and that racemic MDMA is preferentially metabolized to 5 (+)MDA (Fitzgerald et al. 1987). The extent to which MDMA metabolites might contribute to the stimulus properties of MDMA is unknown at this time. Because 5 (-b)MDA is capable of producing AMPH-like stimulus effects, involvement of this metabolite might explain some of the different results reported for MDMA (particularly if different animal species and various presession injection intervals were employed). In contrast, certain other potential metabolites of MDMA, such as 3-hydroxy-PMA, 4-hydroxy-MMA, 3,4-dihydroxy-AMPH (a-tnethyldopamine), N-methyl-3-hydroxy-PMA, N-methyl-4-hydroxy-MMA, N-methyl-3,4-dihydroxy-AMPH (N-methyl-a-methyldopamine) do not produce AMPH-like stimulus effects, but may be capable of producing other, distinct types of central activity or may somehow interfere with potential AMPH-like effects. 

COMMENT I was surprised by the results with the N-hydroxy compounds, because a number of years ago N-hydroxy-p-toluylamphetamine was studied, and it was found that it was identical to ptoluylamphetamine in its properties because it was actually rapidly and essentially quantitatively converted to p-toluylamphetamine. You are finding that the N-hydroxy analog of MDMA is not MDMA-like in its properties. These data suggest that they certainly are not metabolized in a similar way, perhaps. 

COMMENT/QUESTION I was not using MDMA-like in the sense that you were using it—as a substitute. I am simply saying it did not have the pharmacologic effect that MDMA had namely, substitution for amphetamine, which obviously must mean that the N-hydroxy compound is not converted to MDMA to the same extent at least as the p-toluylamphetamine analog was. I would like to know if you have any information about the metabolism of those N-hydroxy compounds. 

ANSWER We were measuring radioactivity. So far, we have looked at MDA. We haven t seen much metabolism of MDA to any other metabolite. We haven t looked at those experiments with MDMA yet. 

In light of this, studies of CSF 5-HIAA have been initiated in a cohort of human volunteers with a history of extensive MDMA use. Most participants in the study are individuals who have recently learned of the neurotoxic properties of MDMA and have asked to be evaluated for possible serotonergic damage. To qualify for the study, subjects must (1) have used MDMA on at least 20 to 25 occasions, (2) be drug-free for at least 2 weeks prior to participating in the study, and (3) not have a history of neuropsychiatric illness thought to involve alterations in serotonin metabolism. To date, 34 individuals have participated in the study. The study is now in progress, and completion is anticipated by 1991. At this time, it would be premature to comment on the results. 

Figure 7.6 Metabolism of MDMA in humans. Abbreviations CYP2D6, cytochrome P450 2D6 CYP3A4, cytochrome P450 3A4 COMT, catechol-O-methyltransferase. (Adapted from de la Torre and co-workers.56)...

It is well accepted that MDMA produces 5-HT depletions in rat CNS, but much less attention has been devoted to the effects of MDMA on established markers of neurotoxicity such as cell death, silver-positive staining, and reactive gliosis. Support for the hypothesis of MDMA-induced axotomy relies heavily on immunohistochemical analysis of 5-HT levels, which could produce misleading results if not validated by other methods. For example, MDMA-induced loss of 5-HT could be due to persistent adaptive changes in gene expression or protein function, reflecting a state of metabolic quiescence rather than neurotoxic damage. Table 7.3 summarizes the effects of MDMA on hallmark measures of neurotoxicity. 

A fatal interaction between ritonavir and MDMA (methylenedioxymethamphetamine, ecstasy) has been reported in an HIV-positive man (see Henry et ah, 1998). The patient had allegedly taken MDMA on several occasions without untoward effects. However, several weeks after ritonavir was added to his regular medication with zidovudine and lamivudine, he took some MDMA for recreational purposes and died of a cardiorespiratory arrest within hours. Toxicology showed that the plasma MDMA concentration was about ten times that expected from the ingested dose. Inhibition of CYP2D6, the principal pathway for MDMA metabolism, by ritonavir was thought to be the most likely cause. 

Stimulant drugs commonly abused in the USA include methamphetamine ("crank," "crystal"), methylenedioxymethamphetamine (MDMA, "ecstasy"), and cocaine ("crack") as well as pharmaceuticals such as pseudoephedrine (Sudafed) and ephedrine (as such and in the herbal agent Ma-huang) (see Chapter 32). Caffeine is often added to dietary supplements sold as "metabolic enhancers" or "fat-burners" and is also sometimes combined with pseudoephedrine in underground pills sold as amphetamine substitutes. 

MDMA is metabolized to MDA with 65% of the dose excreted as parent drug within 3 days. Both MDMA and MDA are hydroxylated to mono- and di-hydroxy derivatives and subsequently conjugated before elimination. The plasma half-life has been reported to be 7.6 h.10... 

MDMA is effective in 20-30 min from intake and shows a peak plasma level after about 120 min with continued effects for up to 4-6 h plasma half-life is 6-7 h. Metabolism proceeds by two routes. The principal one involves O-demethylation to 3,4-dihydroxymetamphetamine (HHMA) followed by O-methylation to 4-hydroxy-3-metoxymetamphetamine (HMMA) and 3,4-dihydroxyamphetamine (HHA) and subsequent O-glucuronide and sulfate conjugation. The second pathway involves an N-demethylation to MDA, followed by deamination and oxidation to the corresponding benzoic acid derivative, substantially conjugated with glycine. The MDA is a metabolite of both MDMA and MDEA [19]. 

De la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camt J (2004) Human pharmacology of MDMA pharmacokinetics, metabolism, and disposition. Ther Drug Monit 26 137-144... 

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