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MDMA Neuropharmacology

by Lamont Granquist

MDMA is primarily a seritonergic (5-HTergic) drug. Serotonin (5-hydroxytryptamine, 5-HT) is one of the major neurotransmitters in the brain, and is synthesized from tryptophan through the intermediate 5-hydroxytryptophan. It is synthesized in 5-HT neurons, and stored in synaptic vesicles. These vesicles release their 5-HT into the synaptic cleft in response to the firing of the 5-HT neurons. In the synaptic cleft the 5-HT neurotransmitter excerts its action on both pre- and post- synaptic receptor sites (sites on the 5-HT neuron itself, and on the neuron which it is communicating with.) 5-HT is then taken back into the 5-HT neuron via the synaptic membrane 5-HT transporter (aka "reuptake pump"), where it is again stored in the synaptic vesicles. 5-HT is metabolized primarily by monoamine oxidase (MAO) into 5-hydroxyindileacetic acid (5-HIAA).

Serotonin is thought to be responsible for many psychological (and physiological) states including mood and sleep. It has been particularly associated with major depression and obsessive compulsive disorder, and drugs to treat these disorders tend to effect 5-HT (although things are not quite clear-cut).

MDMA blocks the reuptake of 5-HT, similarly to SSRI (serotonin specific reuptake inhibiting) anti-depressants such as fluoxetine (Prozac), sertraline, and paroxetine. Unlike those drugs, however, MDMA appears to enter the neuron, either through passive diffusion or directly through the reuptake transporter, and causes the release of 5-HT. This release is calcium-independent (i.e. independent of the firing of the 5-HT neuron) and appears to come from cytoplasmic stores rather than from synaptic vesicles. The released 5-HT then enters the synaptic cleft through the 5-HT transporter. MDMA thus acts on 5-HT similarly to the way amphetamines act on dopamine.

It is thought that this efflux of 5-HT into the synaptic cleft, and the subsequent action of this 5-HT on pre- and post- synaptic binding sites is central to MDMA's neuropharmacology. MDMA, however, has micromolar potency for the serotonin 5-HT2, muscarinic M1, alpha-2 adrenergic and histamine H1 receptors. Agonist (stimulation rather than blocking) properties at the 5-HT2 receptor have been found to fairly universally be associated with "classical" psychedelic drugs such as LSD, psilocybin and mescaline. It is possible that some of MDMA's "psychedelic" effect occurs because of interactions with this receptor. The alpha-2 adrenergic receptor may be associated with some of the carciovascular effects of MDMA. MDMA also releases dopamine which may be central to both its psychological action and to its neurotoxicity in animal studies. Pre- treatment of an animal with a drug which blocks dopamine release will also block MDMA neurotoxicity. Also, serotonin specific releasing agents which are non-dopaminergic have been synthesized and been found to be devoid of MDMA's neurotoxicity in animals, they have also been found to be devoid of MDMA's psychological effects. MDMA tends to indirectly *inhibit* the firing and release of dopamine in nigrostriatal dopamine neurons (neurons projecting from the substantia nigra to the striatum) due to local 5-HT release.

MDMA doses of 20 mg/kg in animals can reduce levels of tryptophan hydroxylase, which is the rate-limiting enzyme in 5-HT synthesis. It is thought that this occurs because of oxidative stress which MDMA places on the neuron. This oxidative stress might occur through several possible channels (the metabolism of MDMA into a toxic Quinoid, 5-HT derived toxins, 5-HT mediated cellular events, or temporary inhibition of monoamine oxidase) and the exact mechanism is presently unknown. It is thought that this oxidative stress also leads to the neurodegenerative destruction of 5-HT axons which is observed to occur with large doses of MDMA in animals. Anti-oxidants, anti-dopaminergic agents, agents which block intracellular calcium increases and pre- or post- treatment (up to 6 hours) with fluoxetine all block MDMA's neurotoxicity. Research ontinues on the exact mechanism of MDMA-induced toxicity.

In summary, MDMA effects 5-HT similarly to the way that amphetamines effect dopamine, by inhibiting the reuptake and causing the release of 5-HT. This effect is somewhat similar to the effect that SSRI anti-depressant drugs have. It also effects the 5-HT2 (psychedelic) and alpha-2 adrenergic (cardiovascular) receptor sites. Also, its effects on dopamine appear, at this point, to be involved both with its neurotoxicity and psychological effects. For more information, see:

Rattray-M. "Ecstasy: towards an understanding of the biochemical basis of the actions of MDMA." Essays in Biochemistry. 26:77-87. 1991.

And for general info:

Synder, Solomon H. "Drugs and the Brain." Scientific American Books. 1986. (slightly out of date, but a good introduction).

Cooper-JR, Bloom-FE, Roth-RH. "The Biochemical Basis of Neuro- Pharmacology." Oxford Uniersity Press. 1991 (6th ed). (the bible for grad students)

---------- Lamont Granquist (
"And then the alien anthropologists - Admitted they were still perplexed - But
on eliminating every other reason - For our sad demise - They logged the only
explanation left - This species has amused itself to death" -- Roger Waters