"We had been looking for drugs that cause the release of neuronal serotonin,with the expectation that they might have therapeutic value similar to the SSRIs. We had noted that selectivity for the 5-HT uptake carrier seemed to be increased when amphetamine structures had large, hydrophobic groups in the 4-position. A methylthio group falls into this category.

Methylthioamphetamine was readily synthesised and when tested was a very potent releaser of 5-HT. We also then discovered that MTA is a fairly potent inhibitor of MAO-A, which no doubt contributes to the toxic effect. I suspect that the toxicity of MTA is similar to the "serotonin syndrome" observed in humans who have been on MAO inhibitors and are placed on SSRIs too quickly.

MTA may ultimately prove to be the starting material for a reagent we are trying to develop to map out the residues that line the channel in the 5-HT uptake carrier and I am sad to see it being used on the streets. I can't imagine what pleasure it might produce in users because our tests with similar compounds in rats showed the substances to have aversive or unpleasant effects.

The effect of MTA therefore must be similar to that of giving an MAO inhibitor along with Prozac, a combination that is known to be very toxic and has also led to deaths. With other amphetamines you apparently get hypertensive crises from peripheral NE release, and often malignant hyperthermia. It seems unlikely that serotonin release would do the same things, and in animal studies MTA had little direct effect on DA or NE."