Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine

Abstract

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as 'bath salts' that have gained popularity among drug abusers.

Keywords: 3-4-Methylenedioxymethamphetamine; Excitotoxicity; Methamphetamine; Neurotoxicity; Oxidative stress; Psychosis.

Figure 1. Mechanisms of Meth and MDMA Neurotoxicity

Meth and MDMA produce persistent monoaminergic terminal damage that is associated with neuropsychiatric symptoms as well as increased vulnerability to psychosis. Acutely, drug exposure contributes to increases in DA and/or 5HT, and glutamate. These substituted amphetamines also produce acute hyperthermia and can contribute to liver damage. Downstream of these short-term effects, numerous interacting and feed-forward mechanisms have been identified as contributors to the neurotoxicity of these drugs of abuse. These mechanisms include excitotoxicity, metabolic compromise, oxidative stress, and more recently, inflammation and altered endocannbinoid system function.