MDMA (Ecstasy) Inhibition of MAO Type A and Type B: Comparisons with Fenfluramine and Fluoxetine (Prozac)

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Abstract
3,4-Methylenedioxymethamphetamine (MDMA), a serotonin (5-HT) neurotoxin, has been shown to promote the release of serotonin (5-HT) and block its reuptake. The increased buildup of extracellular 5-HT should normally be degraded by monoamine oxidase (MAO). The effects of both enantiomers of MDMA were examined on MAO-A and monoamine oxidase-B (MAO-B) activity in rat brain homogenates. Both enantiomers competitively inhibited 5-HT catabolism by rat brain MAO-A. The Ki of MDMA for MAO-A was 22 µmol/L. A mixed type of inhibition by MDMA was observed for phenethylamine catabolism by MAO-B for both optical antipodes. Logistical analysis of concentration response curves for MDMA inhibition of MAO-A and MAO-B show an IC50 of 44 µmol/L for inhibition of MAO-A by MDMA. The IC50 value of MDMA inhibition of MAO-B was 370 µmol/L, showing a selective potency for MAO-A inhibition. The MAO inhibitory properties of fenfluramine (FEN) and fluoxetine (FLUOX) were compared to those of MDMA. The rank order potency of these drugs for MAO-A inhibition was MDMA>FLUOX>FEN, whereas for MAO-B inhibition, FLUOX>MDMA>FEN. A combination of FLUOX and MDMA at their respective IC50 did not inhibit MAO activity more than either drug alone at equivalent concentrations. These results indicate that the actions of FEN do not appear to involve MAO inhibition. MDMA (ecstasy) produced a preferential inhibition of MAO-A (IC50 = 44 µmol/L), which should increase extracellular 5-HT. This may explain its high toxicity potential. Finally, FLUOX (Prozac) showed an inhibition of MAO-B (IC50 = 80 µmol/L, which may increase the intracellular content of 5-HT. This may contribute to its therapeutic potential. In contrast, FEN appears to be a poor inhibitor of both MAO-A and MAO-B.

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