Posts Tagged ‘ stereochemistry

The Mirrored Magic of MDMA

MDMA is one of the most popular illicit drugs in the world, and is unique relative to other stimulating drugs of abuse in that it possesses significant therapeutic potential and is less behaviorally reinforcing. Effects can be described as similar to both stimulants and classical psychedelics. This appears to be more than a simple qualitative description however, as the very geometry of the MDMA molecule seems to produce two distinct drugs.

It is easy to forget when looking at flat diagrams of molecules on paper, but these compounds exist in a three dimensional world. One of the consequences of this is the concept of chirality, or “handedness”. Both your left and right hand contain fingers, a palm, and a thumb which appear to be assembled in the same way - but they are not the same. We can put both of our palms downward - but our thumbs point in different directions. If we point our thumbs in the same direction, one palm faces up and the other down. No matter how hard we try, we cannot wave our hands around and make them line up together perfectly.

Something similar can happen to sufficiently complex molecules, and MDMA is one of these. There are two geometrically distinct enantiomers of MDMA.

R(-)-MDMA Rectus (Latin for right) rotates polarized light counterclockwise (-) in a pure sample
S(+)-MDMA Sinister (Latin for left) rotates polarized light clockwise (+) in a pure sample

Racemic MDMA is “normal” MDMA, a mixture of both.

In the late 1970s, Alexander Shulgin began to collect data about the subjective effects of these stereoisomers of MDMA. Various doses of R(-)-MDMA, S(+)-MDMA, and racemic MDMA were given to volunteers in doses from 40 to 200mg and the relative intensity of their reported experience rated zero to three on the Shulgin scale.

It soon became clear that a subjective difference in potency could be observed between the two stereoisomers. R(-)-MDMA was least potent, with only threshold effects observed between 100 and 200mg. Racemic MDMA caused full effects between 140 and 160mg, while S(+)-MDMA was most potent with full effects observed at 120mg. But was this difference in apparent potency the only distinction between the two?

Shulgin plotted the effects of racemic MDMA (red above) versus a simple average of the regressions he found earlier for R(-)-MDMA and S(+)-MDMA (black above). If the different stereoisomers differed only in apparent potency, these plots should be identical. Interestingly, they were not - with racemic MDMA quite literally reporting effects more than the sum of its parts. This was borne out by user reports as well. The S(+)-MDMA may have been more potent by weight at first glance, but alone it was more stimulating and lacked the indescribable “magic” of the full racemic MDMA experience.

Further investigation was undertaken by researchers including Kevin Murnane, who conducted experiments designed to further delineate the effects of each stereoisomer.


2C-T-7, a psychedelic phenethylamine, fully substituted for R(-)-MDMA in trained mice. DPT, a psychedelic tryptamine, acted as a partial substitute. S(+)-amphetamine substituted for S(+)-MDMA in trained mice. Cocaine acted as a partial substitute.
In rhesus monkeys, R(-)-MDMA significantly increased prolactin levels. S(+)-MDMA significantly increased both dopamine and serotonin levels.

In general, R(-)-MDMA appears to produce psychedelic effects and has a longer duration relative to the more stimulating effects of S(+)-MDMA. MDMA is an incredibly unique compound, where each stereoisomer has a distinct and centrally active mode of action. Unlike other compounds where one stereoisomer is more potent or responsible for the majority of effects, each stereoisomer of MDMA contributes to produce a full and complex experience.

Phenethylamines may be classified as stimulants (such as amphetamine where the S(+) entianomer is most active) or psychedelics (such as DOC where the R(-) entianomer is most active). MDMA appears to uniquely straddle this divide.

Shulgin, A.T. Personal Lab Notes (Book 2), page 238.

Murnane KS, Murai N, Howell LL, Fantegrossi WE. Discriminative stimulus effects of psychostimulants and hallucinogens in S(+)-3,4-methylenedioxymethamphetamine (MDMA) and R(-)-MDMA trained mice. J Pharmacol Exp Ther. 2009 Nov;331(2):717-23. Epub 2009 Aug 14.

Murnane KS, Fantegrossi WE, Godfrey JR, Banks ML, Howell LL. Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys. J Pharmacol Exp Ther. 2010 Aug;334(2):642-50. Epub 2010 May 13.