| dc.description.abstract | 3,4-methylenedioxymethamphetamine (MDMA) is a psychostimulant drug that causes feelings of increased euphoria and love, increased sociability and increased energy. MDMA acts on the serotonin transporter (SERT), dopamine transporter (DAT), monoamine oxidase B, serotonin 2A and 2B receptor and tryptophan hydroxylase. The actions of MDMA on these proteins cause the desired effects of the drug by increasing the serotonin concentration in the synaptic cleft. Furthermore, MDMA increases the dopaminergic concentration in the synaptic cleft, which causes increased energy. MDMA is believed to cause neurotoxicity in a number of ways. During the metabolism of MDMA highly reactive ortho-quinones are formed, these can undergo redox cycling which may lead to the formation of free radicals. These free radicals promote alkylation of crucial proteins and/ or DNA, resulting in neuronal damage. Moreover, free radicals also interfere with the mitochondrial electron transport chain and cause a state of energy crisis in the neuron in this way. This mitochondrial dysfunction can cause serious problems in the functioning of the neuron, which may eventually lead to apoptosis. Besides the ortho-quinone metabolites of MDMA, monoamine metabolism and dopamine oxidation also contribute to oxidative stress that can lead to serotonergic terminal loss and apoptosis. Animal research has shown that MDMA is able to reduce SERT expression and protein levels, as well as decrease the availability of serotonin by its actions on the SERT and tryptophan hydroxylase. In addition, it has been found that MDMA-induced neurotoxicity is highly dependent on the serotonin 2A receptor activation. In human ecstasy users it was found that MDMA use leads to reduced SERT and 5HT2A receptor densities throughout the brain. There are indications that these changes in SERT and 5HT2A receptor densities may be reversible when MDMA use is stopped. However, results are not conclusive since conflicting results have been found. It has been found that MDMA use leads to impairments in verbal memory and prospective memory performance. Furthermore, cessation of ecstasy use may cause depression symptoms.
MDMA use is often combined with nicotine, cannabis or alcohol. It was found that when nicotine is combined MDMA, nicotine does not alter the neurotoxic effect of MDMA. Moreover, ∆9-tetrahydrocannabiol (THC) seems to be able to protect neurons from the toxic effect of MDMA. It is thought that this neuroprotective effect of THC is due to its antioxidant properties. Results and conclusions of studies investigating the neurotoxic effects of MDMA should be interpreted with care, since most of them have important limitations. Animal studies often have limitations to their translational value. Whereas human studies often use polydrug users instead of MDMA alone users. Future research to the neurotoxicity of MDMA is needed to address issues as why there are differences between men and women in susceptibility to neurotoxity of MDMA. Furthermore, it should be investigated whether the MDMA-induced changes in the serotonin system are reversible or not. | |
