α-Methyldopamine (α-Me-DA), also known as 3,4-dihydroxyamphetamine (3,4-DHA), is a neurotoxin and research chemical of the catecholamine and amphetaminechemical classes. The basis of this idea is in the observation that MDA and MDMA may not themselves be responsible for their neurotoxicity, as an intracerebroventricular injection (injection directly into the brain itself) does not appear to cause neurotoxicity. While many studies cite excitotoxicity, or oxidative stress as likely mechanisms, which may be an effect of the chemical itself, this has led to the search for other mechanisms for the observed toxicity of serotonin neurons and subsequent reduction in 5-HT (Serotonin) and 5-HIAA (its major metabolite in the body) in vivo following administration. A common theory follows that a metabolite in the periphery must be responsible, and several have been cited as responsible. Although, alpha-methyldopamine is widely cited as the source of this neurotoxicity in a number of lay sources, McCann, et al. (1991), demonstrated that the major metabolites alpha-methyldopamine (α-Me-DA) and 3-O-methyl-α-methyldopamine (3-O-Me-α-MeDA) did not produce neurotoxicity.
It was first demonstrated, in 1978, by Conway, et al. and possibly others that, while alpha-methyldopamine caused acute decreases in the levels of neuronal dopamine, in some areas of the brain in excess of 75%, levels returned to baseline within 12 hours, indicating that alpha-methyldopamine would not be responsible for the toxic effects observed.
However, the story complicates as alpha-methyldopamine readily oxidizes to the o-quinone and reacts with endogenous antioxidants in the body, such as glutathione (GSH). It was demonstrated by Miller, et al. (1997), that 5-(glutathion-S-yl)-alpha-methyldopamine and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine produced similar effects to the parent compound, but did not induce neurotoxicity. Another related compound however, 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine, did in fact induce neurotoxicity, providing initial evidence that this metabolite may be the source of neuronal toxicity following the administration of MDA and MDMA, and the subsequent reduction in 5-HT (Serotonin) axons.
^McCann, Una D.; Ricaurte, George A. (1991). "Major metabolites of (±)3,4-methylenedioxyamphetamine (MDA) do not mediate its toxic effects on brain serotonin neurons". Brain Research545 (1–2): 279–82. doi:10.1016/0006-8993(91)91297-E. PMID1860050.
^Conway, Elizabeth L.; Louis, William J.; Jarrott, Bevyn (1978). "Acute and chronic administration of α-methyldopa: Regional levels of endogenous and α-methylated catecholamines in rat brain". European Journal of Pharmacology52 (3–4): 271–80. doi:10.1016/0014-2999(78)90279-0. PMID729639.
^Miller, R.Timothy; Lau, Serrine S; Monks, Terrence J (1997). "2,5-bis-(Glutathion-S-yl)-α-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations". European Journal of Pharmacology323 (2–3): 173–80. doi:10.1016/S0014-2999(97)00044-7. PMID9128836.