Two amphetamine derivatives, MDA and MDMA, cause lasting damage to serotonin-producing nerve fibers in the rat brain. Two weeks after repeated high doses, serotonin axons throughout the forebrain are profoundly lost, while dopamine and norepinephrine axons remain intact. The damage is selective to fine axon terminals; thicker fibers and the cell bodies in the raphe nuclei survive. Some brain regions, such as the hippocampus and parts of the neocortex, show partial sparing. Swollen and fragmented axons observed shortly after treatment confirm ongoing degeneration. MDA produces greater loss of serotonin axons than MDMA at the same dose. The findings establish that these drugs are toxic to serotonin axon terminals and cause long-term denervation of the forebrain.
Methylenedioxy-substituted amphetamine derivatives, including MDMA, cause widespread and long-lasting degeneration of serotonin neurons in the brain after administration in animals, without consistently affecting dopamine or other catecholamine neurons. The severity of damage depends on dose and frequency, occurs across species including primates, and can be prevented by a serotonin uptake blocker, implicating active uptake of MDMA, a toxic metabolite, or an endogenous neurotoxin. Neuronal recovery may take up to a year, while functional recovery may be permanently impaired. Neurochemical and autoradiographic data show predominant reductions in serotonin uptake sites in terminal regions, with relative sparing of axons of passage and cell bodies.