BilZ0r
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Classically available MDMA comes as an equal mix of its two enantiomers (racemic) S(+)MDMA and R(-)MDMA. These two versions of the same drug have subtley different actions, but also many shared actions.
The pharmacokinetics is where these chemicals are the most different. The total Area under the curve (AUC) of the R(-) isomer has been reported to be 2.4 times higher than the S(+) isomer in healthy males given 40mg of racemic MDMA. This is probably a result of the much longer elimination half-life the R(-) isomer was reported to have in the same study 5.6 vs 3.6h (Fallon et al., 1999). In a similar study published from the De La Torre lab, healthy recreational MDMA users were given 100mg of racemic MDMA, the peak plasma level of the R(-) isomer was 30% higher than the S(+) isomer and the elimination half-lives of the R(-) and S(+) isomer were found 14.8 hours vs 4.9 hours respectively(Pizzaro et al., 2004). The large differences in the half lives reported in the study could be explained by the fact that MDMA has non-linear metabolism, and that MDMA metabolism seems to start to saturate at 100mg, as well as the fact that as the Pizzaro study used non-naive users, and MDMA inhibits it own metabolism over a period of days (Farre et al., 2004).
The differences in the potency of these chemicals on neurotransmitter release is going to be hard to deliniate from their pharmacokinetic differences, so these properties need to be considered from an in vitro primarily. Unfortunately, the data here is rather sparse. What is even worse is that the in vivo data is so contradictory it is almost nonsensical. Johnson et al., 1986 showed that the R(-) isomer is about 10% more potent at releasing serotonin, but that the S(+) isomer is about 280% more potent at releasing dopamine, from hippocampal or striatal slices respectively. Conversely, Nichols et al., 1982 showed that the S(+) isomer is ~200% more potent at releasing serotonin from whole brain synaptosomes. Finally Schmidt et al., 1987 showed that the S(+) isomer was more potent at releasing both dopamine and serotonin. Hiramatsu
et al., 1990 using in vivo microdialysis from rat striatum that S(+)MDMA was not only more potent at releasing serotonin and dopamine, but that R(-)MDMA could not release any serotonin or dopamine at all at 10mg/kg I.P. Finally Hiramatu et al., 1991 showed that the S(+)isomer could only release dopamine and had no effect on serotonin release at all as recorded by rat striatal microdialysis. From that collection of largely non-agreeable facts, it seems if one can say that the S(+) isomer is probably the more potent.
They have varying affinities for the 5-HT2 receptor, with the R/- isomer reported as the higher affinity ligand: 3.3µM(Lyon et al., 1986) and 3.1µM(Nash et al., 1994), and the S/+ isomer reporetd as the lower affinity ligand: 15.8µM(Lyon et al., 1986) and 10.3µM(Nash et al., 1994).
Finally, when it comes to potential neurotoxicity, it seems as if the S(+) isomer is the most potent at producing neurotoxicity (Schmidt et al., 1987)
The pharmacokinetics is where these chemicals are the most different. The total Area under the curve (AUC) of the R(-) isomer has been reported to be 2.4 times higher than the S(+) isomer in healthy males given 40mg of racemic MDMA. This is probably a result of the much longer elimination half-life the R(-) isomer was reported to have in the same study 5.6 vs 3.6h (Fallon et al., 1999). In a similar study published from the De La Torre lab, healthy recreational MDMA users were given 100mg of racemic MDMA, the peak plasma level of the R(-) isomer was 30% higher than the S(+) isomer and the elimination half-lives of the R(-) and S(+) isomer were found 14.8 hours vs 4.9 hours respectively(Pizzaro et al., 2004). The large differences in the half lives reported in the study could be explained by the fact that MDMA has non-linear metabolism, and that MDMA metabolism seems to start to saturate at 100mg, as well as the fact that as the Pizzaro study used non-naive users, and MDMA inhibits it own metabolism over a period of days (Farre et al., 2004).
The differences in the potency of these chemicals on neurotransmitter release is going to be hard to deliniate from their pharmacokinetic differences, so these properties need to be considered from an in vitro primarily. Unfortunately, the data here is rather sparse. What is even worse is that the in vivo data is so contradictory it is almost nonsensical. Johnson et al., 1986 showed that the R(-) isomer is about 10% more potent at releasing serotonin, but that the S(+) isomer is about 280% more potent at releasing dopamine, from hippocampal or striatal slices respectively. Conversely, Nichols et al., 1982 showed that the S(+) isomer is ~200% more potent at releasing serotonin from whole brain synaptosomes. Finally Schmidt et al., 1987 showed that the S(+) isomer was more potent at releasing both dopamine and serotonin. Hiramatsu
et al., 1990 using in vivo microdialysis from rat striatum that S(+)MDMA was not only more potent at releasing serotonin and dopamine, but that R(-)MDMA could not release any serotonin or dopamine at all at 10mg/kg I.P. Finally Hiramatu et al., 1991 showed that the S(+)isomer could only release dopamine and had no effect on serotonin release at all as recorded by rat striatal microdialysis. From that collection of largely non-agreeable facts, it seems if one can say that the S(+) isomer is probably the more potent.
They have varying affinities for the 5-HT2 receptor, with the R/- isomer reported as the higher affinity ligand: 3.3µM(Lyon et al., 1986) and 3.1µM(Nash et al., 1994), and the S/+ isomer reporetd as the lower affinity ligand: 15.8µM(Lyon et al., 1986) and 10.3µM(Nash et al., 1994).
Finally, when it comes to potential neurotoxicity, it seems as if the S(+) isomer is the most potent at producing neurotoxicity (Schmidt et al., 1987)
