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			{{Short description|Chemical compound}}
	{{lowercase}}
			{{lowercasetitle}}
	{{Drugbox		{{Drugbox
	| verifiedrevid = 413313180		| verifiedrevid = 413314944
			| drug_name = α-Methyldopamine
⚫	| IUPAC_name = 4-(2-aminopropyl)benzene-1,2-diol
	| image = Methyldopamine.svg		| image = Methyldopamine.svg
			| width =
	| alt =
			<!-- Clinical data -->
			| tradename =
			<!-- Identifiers -->
			| CAS_number_Ref = {{cascite|correct|CAS}}
		⚫	| CAS_number = 555-64-6
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = XQ9A7WCY2L
			| ATC_prefix = None
		⚫	| PubChem = 17005
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 16110		| ChemSpiderID = 16110
			| ChEBI = 193722
	| InChI = 1/C9H13NO2/c1-6(10)4-7-2-3-8(11)9(12)5-7/h2-3,5-6,11-12H,4,10H2,1H3
	| InChIKey = KSRGADMGIRTXAF-UHFFFAOYAD
⚫	| smiles = Oc1ccc(cc1O)CC(N)C
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 28278		| ChEMBL = 28278
			| synonyms = α-Me-DA; 3,4-Dihydroxyamphetamine; 3,4-DHA; HHA; 3,4-Dihydroxy-α-methylphenethylamine; 3,4-Dihydroxy-α-methyl-β-phenylethylamine; Methyldopamine; Catecholamphetamine
			<!-- Chemical data -->
		⚫	| IUPAC_name = 4-(2-aminopropyl)benzene-1,2-diol
		⚫	| C=9 | H=13 | N=1 | O=2
		⚫	| SMILES = Oc1ccc(cc1O)CC(N)C
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C9H13NO2/c1-6(10)4-7-2-3-8(11)9(12)5-7/h2-3,5-6,11-12H,4,10H2,1H3		| StdInChI = 1S/C9H13NO2/c1-6(10)4-7-2-3-8(11)9(12)5-7/h2-3,5-6,11-12H,4,10H2,1H3
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = KSRGADMGIRTXAF-UHFFFAOYSA-N		| StdInChIKey = KSRGADMGIRTXAF-UHFFFAOYSA-N
⚫	| CAS_number = 555-64-6
	| ATCvet =
	| ATC_prefix = <!-- 'none' if uncategorised -->
	| ATC_suffix =
⚫	| PubChem = 17005
	| DrugBank =
⚫	| C=9 |H=13 |N=1 |O=2
	| molecular_weight = 167,21 g/mol
	| bioavailability =
	| protein_bound =
	| metabolism =
	| elimination_half-life =
	| excretion =
	| pregnancy_category=
	| legal_status =
	| routes_of_administration =
	}}		}}
			'''α-Methyldopamine''' ('''α-Me-DA'''), also known as '''3,4-dihydroxyamphetamine''' ('''3,4-DHA''' or '''HHA''') or as '''catecholamphetamine''', is a ] of the ] and ] families. It is a ]<ref name="Blough2008">{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref> and a ] of ] and ].<ref name="MonksJonesBai2004">{{cite journal | vauthors = Monks TJ, Jones DC, Bai F, Lau SS | title = The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity | journal = Ther Drug Monit | volume = 26 | issue = 2 | pages = 132–136 | date = April 2004 | pmid = 15228153 | doi = 10.1097/00007691-200404000-00008 | url = }}</ref> The ''bis''-] ] of α-methyldopamine is slightly ] when directly ].<ref name="MonksJonesBai2004" />
	'''α-Methyldopamine''' ('''α-Me-DA'''), also known as '''3,4-dihydroxyamphetamine''' ('''3,4-DHA'''), is a ] and ] of the ] and ] ]es. It is a ] of various amphetamine ]s such as ] itself, ], and ] ("Ecstasy"), ] and has been suggested to play significant role in their ] effects on ]rgic ]s. {{citation needed|date=August 2010}} Further study has suggested that, alpha-methyldopamine itself is not directly responsible for the damaging effects, but a specific reaction between alpha-methyldopamine and one of the bodies endogenous antioxidants -], may produce 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, which has been demonstrated in laboratory animals to cause the same neurotoxic effects seen by related stimulants and empathogens.
			==Role in MDMA-induced serotonergic neurotoxicity==
	The basis of this idea is in the observation that ] and ] 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 ], or ] 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 ] neurons and subsequent reduction in ] (Serotonin) and ] (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-MeDA) and 3-O-methyl-α-methyldopamine (3-O-Me-α-MeDA) did not produce neurotoxicity.<ref>{{Citation | last = McCann | first = Una D. | last2 = Ricaurte | first2 = George A. | title = Major metabolites of(±)3,4-methylenedioxyamphetamine (MDA) do not mediate its toxic effects on brain serotonin neurons. | journal = Brain Research | volume = Volume 545 | issue = Issue 1-2. | pages = Pages 279–282. | date = 5 April 1991. | url = http://www.sciencedirect.com/science/article/B6SYR-4834MB0-1MH/2/ee635e5177d434a20613e6941e9ab37f | doi = doi:10.1016/0006-8993(91)91297-E }}</ref>		Interest in α-methyldopamine lies in the fact that ] (MDA) and ] (MDMA) may not themselves be responsible for their ] ], as an ] does not appear to cause neurotoxicity. While many studies suggest ] or ] as likely mechanisms, which may be an effect of MDMA itself, this has led to the search for other mechanisms for the observed toxicity of ] axons and subsequent reduction in ] (5-HT) and ] (its major metabolite in the body) '']'' following administration. A common theory follows that a ] of MDA and MDMA in the periphery must be responsible, and several have been cited as responsible. Although α-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 α-methyldopamine and 3-''O''-methyl-α-methyldopamine (3-O-Me-α-MeDA or HMA) did not produce neurotoxicity.<ref name="McCannRicaurte1991">{{cite journal | vauthors = McCann UD, Ricaurte GA | title = Major metabolites of (+/-)3,4-methylenedioxyamphetamine (MDA) do not mediate its toxic effects on brain serotonin neurons | journal = Brain Research | volume = 545 | issue = 1–2 | pages = 279–282 | date = April 1991 | pmid = 1860050 | doi = 10.1016/0006-8993(91)91297-E | s2cid = 2574803 | doi-access = free }}</ref>
	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.<ref>{{Citation | last = Conway | first = EL | last2 = Louis | first2 = WJ |last3 = Jarrot |first3 = B. | title = Acute and chronic administration of alpha-methyldopa: regional levels of endogenous and alpha-methylated catecholamines in rat brain. | journal = Eur J Pharmacol. | volume = Volume 52. | issue = Issue 3-4. | pages = 271–80. | date = 1 Dec. 1978 | url = http://www.ncbi.nlm.nih.gov/pubmed/729639 | id = PMID 729639}}</ref>		It was first demonstrated, in 1978, by Conway ''et al.'' and possibly others that, while α-methyldopamine caused acute decreases in the levels of ]al ], in some areas of the brain in excess of 75%, levels returned to baseline within 12{{nbsp}}hours, indicating that α-methyldopamine could not be responsible for the toxic effects observed.<ref name="ConwayLouisJarrott1978">{{cite journal | vauthors = Conway EL, Louis WJ, Jarrott B | title = Acute and chronic administration of alpha-methyldopa: regional levels of endogenous and alpha-methylated catecholamines in rat brain | journal = European Journal of Pharmacology | volume = 52 | issue = 3–4 | pages = 271–280 | date = December 1978 | pmid = 729639 | doi = 10.1016/0014-2999(78)90279-0 }}</ref>
	However, the story complicates as alpha-methyldopamine readily oxidizes to the o-]and reacts with endogenous antioxidants in the body, such as ] (GSH). The mechanism of action behind amphetamines and their related compounds, causes the normally encapsulated neurotransmitters to be released from their oxidative vesicle within the neuron into the reductive environment of the cell cystol. This sudden release of oxidative molecules into the cell puts it under oxidative stress. As Glutathione is the major endogenous anti-oxidant produced in the body to protect against ] and ] (foreign compounds), it likely plays at least some role in the neutralization of the suddenly released ] (Dopamine and Norepinephrine), and Serotonin, as well as the break down of ], ], ], ], and other ] compounds. 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.<ref>{{Citation | last = Miller | first = RT | last2 = Lau | first2 = SS | last3= Monks | first3= TJ | title = 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations. | journal = Eur J Pharmacol. | volume = Volume 323. |issue = Issue 2-3. | pages = 173–80 | date = 1997 Apr 4. | url = http://www.ncbi.nlm.nih.gov/pubmed/9128836 | id = PMID: 9128836 }}</ref>.		However, the story complicates as α-methyldopamine readily ] to the ''o''-] and reacts with ] ]s in the body, such as ] (GSH). It was demonstrated by Miller ''et al.'' (1997), that 5-(glutathion-''S''-yl)-α-methyldopamine and 5-(''N''-acetylcystein-''S''-yl)-α-methyldopamine produced similar effects to the parent compound, but did not induce neurotoxicity when injected intracerebroventricularly. However, the derivative metabolite 2,5-''bis''-(glutathion-''S''-yl)-α-methyldopamine (injected at ~1.5{{nbsp}}times the usual per-kg MDMA dose) 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 serotonergic ]s.<ref name="MillerLauMonks1997">{{cite journal | vauthors = Miller RT, Lau SS, Monks TJ | title = 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations | journal = European Journal of Pharmacology | volume = 323 | issue = 2–3 | pages = 173–180 | date = April 1997 | pmid = 9128836 | doi = 10.1016/S0014-2999(97)00044-7 }}</ref>
			In spite of the above, there is also evidence that metabolites may not be involved in the neurotoxicity of MDMA or related drugs and that the neurotoxicity is intrinsic to their ], specifically simultaneous induction of serotonin and dopamine release.<ref name="BaggottMendelson2001">{{cite book | author1-last=Baggott | author1-first=Matthew | author2-last= Mendelson | author2-first=John | chapter=Does MDMA Cause Brain Damage? | pages=110–145,396–404 | editor1-last=Holland | editor1-first=J. | title=Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA | publisher=Inner Traditions/Bear | year=2001 | isbn=978-0-89281-857-0 | chapter-url=https://www.erowid.org/chemicals/mdma/mdma_neurotoxicity1.shtml | url=https://books.google.com/books?id=CUCcyklcO00C | access-date=24 November 2024 | quote = While a single injection of MDMA into the brain (intracerebroventricularly) had no effect on TPH activity, slow infusion of 1 mg/kg MDMA into the brain over 1 hr produced enough oxidative stress to acutely reduce TPH activity (Schmidt and Taylor 1988). The acute decrease in TPH activity is an early effect of MDMA and can be measured at post 15 min (Stone et al. 1989b). TPH inactivation can also be produced by non-neurotoxic MDMA doses (Schmidt and Taylor 1988; Stone et al. 1989a; Stone et al. 1989b). It therefore appears that MDMA rapidly induces oxidative stress but only produces neurotoxicity when endogenous free radical scavenging systems are overwhelmed.}}</ref><ref name="SpragueEvermanNichols1998">{{cite journal | vauthors = Sprague JE, Everman SL, Nichols DE | title = An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine | journal = Neurotoxicology | volume = 19 | issue = 3 | pages = 427–441 | date = June 1998 | pmid = 9621349 | doi = | url = https://www.researchgate.net/profile/Jon-Sprague/publication/13663847_An_integrated_hypothesis_for_the_serotonergic_axonal_loss_induced_by_34-methylenedioxymethamphetamine/links/5c49bd7192851c22a38d1be2/An-integrated-hypothesis-for-the-serotonergic-axonal-loss-induced-by-3-4-methylenedioxymethamphetamine.pdf}}</ref> Accordingly, while single injections of MDMA directly into the brain have not been found to produce neurotoxicity, slow infusions of MDMA into the brain over 1{{nbsp}}hour do result in signs of neurotoxicity.<ref name="BaggottMendelson2001" />
⚫	== See also ==
	* ]
	* ]
	== References ==		==Chemistry==
			α-Methyldopamine, also known as 3,4-dihydroxy-α-methylphenethylamine or as 3,4-dihydroxyamphetamine, is a ], ], and ] ]. It is the α-] or amphetamine ] of ] (3,4-dihydroxyphenethylamine).
⚫	{{Reflist|2}}
			Analogues of α-methyldopamine include ] (levonordefrin; α-methylnorepinephrine; 3,4,β-trihydroxyamphetamine), ] (α-methylepinephrine; 3,4,β-trihydroxy-''N''-methylamphetamine), and ] (norpholedrine; α-methyltyramine; 4-hydroxyamphetamine)
	{{Stimulants}}
	{{Adrenergics}}
		⚫	==See also==
	{{Dopaminergics}}
			* ] (HHMA; α-methylepinine)
			* ] (HMA)
			* ] (HMMA)
			* ] (THA)
			* ] (THMA)
			==References==
		⚫	{{Reflist}}
			{{Monoamine neurotoxins}}
			{{Adrenergic receptor modulators}}
			{{Dopamine receptor modulators}}
			{{Monoamine releasing agents}}
	{{Phenethylamines}}		{{Phenethylamines}}
			{{DEFAULTSORT:Methyldopamine, alpha-}}
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