Substituted amphetamine

{{Short description|Class of compounds based upon the amphetamine structure}} {{Redirect|Amphetamines|the chemical|Amphetamine||Amphetamine (disambiguation)}} {{Use dmy dates|date=March 2014}} {{Infobox drug class | Image = Racemic amphetamine.svg | ImageClass = skin-invert-image | Alt = Racemic amphetamine skeleton | Caption = Racemic amphetamine skeleton | Chemical_class = Substituted derivatives of amphetamine | Synonyms = Amphetamines; α-Methylphenethylamines; α-Methylphenylethylamines; Phenylisopropylamines }} {{Multiple image | perrow=2 | | header = Optical isomers of amphetamine | image1 = Levoamphetamine.svg |width1=120 | <!-- class1 = skin-invert-image --> | image2 = Dextroamphetamine.svg |width2=120 | <!-- class2 = skin-invert-image --> | image3 = L-amphetamine-3D-vdW.png |width3=120 | class3 = bg-transparent | image4 = D-amphetamine-3D-vdW.png |width4=120 | class4 = bg-transparent | caption3 = <small>L</small>-amphetamine | caption4 = <small>D</small>-amphetamine }}

'''Substituted amphetamines''', or simply '''amphetamines''', are a class of compounds based upon the amphetamine structure;<ref name="Amphetamine - a substituted amphetamine" /> it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents.<ref name="Amphetamine - a substituted amphetamine">{{cite journal | vauthors = Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ | title = Biosynthesis of amphetamine analogs in plants | journal = Trends Plant Sci. | volume = 17 | issue = 7 | pages = 404–412 | date = 2012 | pmid = 22502775 | doi = 10.1016/j.tplants.2012.03.004 | bibcode = 2012TPS....17..404H | quote = Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3].&nbsp;... Beyond (1''R'',2''S'')-ephedrine and (1''S'',2''S'')-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (''S'')-enantiomers being more potent. For example, (''S'')-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (''R'')-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (''S'')-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79].&nbsp;... <br />[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.}}</ref><ref name="Substituted amphetamines">{{cite book | author = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | title=Foye's principles of medicinal chemistry | date=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20amphetamine%20substitution&pg=PA646 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quote = The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).}}</ref><ref name="pmid1855720">{{cite journal | vauthors = Lillsunde P, Korte T | title = Determination of ring- and N-substituted amphetamines as heptafluorobutyryl derivatives | journal = Forensic Sci. Int. | volume = 49 | issue = 2 | pages = 205–213 | date = March 1991 | pmid = 1855720 | doi=10.1016/0379-0738(91)90081-s}}</ref><ref>{{Cite journal|last1=Custodio|first1=Raly James Perez|last2=Botanas|first2=Chrislean Jun|last3=Yoon|first3=Seong Shoon|last4=Peña|first4=June Bryan de la|last5=Peña|first5=Irene Joy dela|last6=Kim|first6=Mikyung|last7=Woo|first7=Taeseon|last8=Seo|first8=Joung-Wook|last9=Jang|first9=Choon-Gon|last10=Kwon|first10=Yong Ho|last11=Kim|first11=Nam Yong|date=2017-11-01|title=Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites|journal=Biomolecules & Therapeutics|language=en|volume=25|issue=6|pages=578–585|doi=10.4062/biomolther.2017.141|issn=2005-4483|pmc=5685426|pmid=29081089}}</ref> The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others.<ref name="Substituted amphetamines" /> Examples of substituted amphetamines are amphetamine (itself),<ref name="Amphetamine - a substituted amphetamine" /><ref name="Substituted amphetamines" /> methamphetamine,<ref name="Amphetamine - a substituted amphetamine" /> ephedrine,<ref name="Amphetamine - a substituted amphetamine" /> cathinone,<ref name="Amphetamine - a substituted amphetamine" /> phentermine,<ref name="Amphetamine - a substituted amphetamine" /> mephentermine,<ref name="Amphetamine - a substituted amphetamine" /> tranylcypromine,<ref name="ulrich2017">{{ cite journal | vauthors = Ulrich S, Ricken R, Adli M | journal=European Neuropsychopharmacology | title=Tranylcypromine in mind (Part I): Review of pharmacology | year=2017 | volume=27 | issue=8 | pages=697–713 | doi=10.1016/j.euroneuro.2017.05.007| pmid=28655495 | s2cid=4913721 | doi-access=free }}</ref> bupropion,<ref name="Amphetamine - a substituted amphetamine" /> methoxyphenamine,<ref name="Amphetamine - a substituted amphetamine" /> selegiline,<ref name="Amphetamine - a substituted amphetamine" /> amfepramone (diethylpropion),<ref name="Amphetamine - a substituted amphetamine" /> pyrovalerone,<ref name="Amphetamine - a substituted amphetamine" /> MDMA (ecstasy), and DOM (STP).

Some of amphetamine's substituted derivatives occur in nature, for example in the leaves of ''Ephedra'' and khat plants.<ref name="Amphetamine - a substituted amphetamine" /> Amphetamine was first produced at the end of the 19th century. By the 1930s, amphetamine and some of its derivative compounds found use as decongestants in the symptomatic treatment of colds and also occasionally as psychoactive agents. Their effects on the central nervous system are diverse, but can be summarized by three overlapping types of activity: stimulant, psychedelic, and entactogenic. Various substituted amphetamines may cause these actions either separately or in combination.

==Partial list of substituted amphetamines== {{Sticky}} {| class="wikitable sticky-header sortable" ! Generic or Trivial Name ! Chemical Name ! # of Subs |- | Amphetamine || α-Methyl-phenethylamine || 0 |- | Tranylcypromine || ''trans''-2-Phenylcyclopropylamine || 0{{#tag:ref|The isopropylamine side chain of amphetamine is cyclized into a cyclopropylamine ring structure in tranylcypromine.|name=tranylcypromine-chem|group=note}} |- | Methamphetamine || ''N''-Methylamphetamine || 1 |- | Ethylamphetamine || ''N''-Ethylamphetamine || 1 |- | Propylamphetamine || ''N''-Propylamphetamine || 1 |- | Isopropylamphetamine || ''N''-''iso''-Propylamphetamine || 1 |- | Butylamphetamine || ''N''-''n''-Butylamphetamine || 1 |- | Pheniprazine || ''N''-Aminoamphetamine || 1 |- | Phenatine || ''N''-Nicotinoylamphetamine || 1 |- | Lisdexamfetamine || <small>L</small>-Lysine–amphetamine conjugate, (''S'')- || 1 |- | Phentermine || α-Methylamphetamine || 1 |- | Phenylpropanolamine (PPA) || β-Hydroxyamphetamine, (1''R'',2''S'')- || 1 |- | Cathine || β-Hydroxyamphetamine, (1''S'',2''S'')- || 1 |- | Cathinone || β-Ketoamphetamine || 1 |- | Ortetamine || 2-Methylamphetamine || 1 |- | 2-Fluoroamphetamine (2-FA) || 2-Fluoroamphetamine || 1 |- | 3-Methylamphetamine (3-MA) || 3-Methylamphetamine || 1 |- | 2-Phenyl-3-aminobutane || 2-Phenyl-3-aminobutane || 1 |- | 3-Fluoroamphetamine (3-FA) || 3-Fluoroamphetamine || 1 |- | Gepefrine || 3-Hydroxyamphetamine || 1 |- | Norfenfluramine || 3-Trifluoromethylamphetamine || 1 |- | 4-Methylamphetamine (4-MA) || 4-Methylamphetamine || 1 |- | ''para''-Methoxyamphetamine (PMA) || 4-Methoxyamphetamine || 1 |- | ''para''-Ethoxyamphetamine || 4-Ethoxyamphetamine || 1 |- | 4-Methylthioamphetamine (4-MTA) || 4-Methylthioamphetamine || 1 |- | Norpholedrine (α-Me-TRA) || 4-Hydroxyamphetamine || 1 |- | ''para''-Bromoamphetamine (PBA, 4-BA) || 4-Bromoamphetamine || 1 |- | ''para''-Chloroamphetamine (PCA, 4-CA) || 4-Chloroamphetamine || 1 |- | ''para''-Fluoroamphetamine (PFA, 4-FA, 4-FMP) || 4-Fluoroamphetamine || 1 |- | ''para''-Iodoamphetamine (PIA, 4-IA) || 4-Iodoamphetamine || 1 |- | Mefenorex || ''N''-(3-Chloropropyl)amphetamine || 1 |- | Clobenzorex || ''N''-(2-Chlorobenzyl)amphetamine || 1 |- | Amfetaminil || ''N''-Cyanobenzylamphetamine || 1 |- | Amfecloral || ''N''-(2,2,2-Trichloroethylidene)amphetamine || 1 |- | Racefemine || ''N''-(1-Methyl-2-phenoxyethyl)amphetamine || 1 |- | Dextrofemine || ''N''-(1-Methyl-2-phenoxyethyl)amphetamine, (+)- || 1 |- | Fenproporex || ''N''-2-Cyanoethylamphetamine || 1 |- | Prenylamine || ''N''-(3,3-Diphenylpropyl)amphetamine || 1 |- | Fenethylline || Theophylline–amphetamine conjugate || 1 |- | Dimethylamphetamine || ''N'',''N''-Dimethylamphetamine || 2 |- | Benzphetamine || ''N''-Benzyl-''N''-methylamphetamine || 2 |- | Deprenyl || ''N''-Methyl-''N''-propargylamphetamine || 2 |- | <small>D</small>-Deprenyl || ''N''-Methyl-''N''-propargylamphetamine, (''S'')- || 2 |- | Selegiline || ''N''-Methyl-''N''-propargylamphetamine, (''R'')- || 2 |- | Metfendrazine || ''N''-Amino-''N''-methylamphetamine || 2 |- | Mephentermine || ''N''-Methyl-α-methylamphetamine || 2 |- | Phenpentermine || α,β-Dimethylamphetamine || 2 |- | Ephedrine || β-Hydroxy-''N''-methylamphetamine, (1''R'',2''S'')- || 2 |- | Pseudoephedrine (PSE) || β-Hydroxy-''N''-methylamphetamine, (1''S'',2''S'')- || 2 |- | Metaraminol || 3,β-Dihydroxyamphetamine, (1''R'',2''S'')- || 2 |- | Methcathinone || β-Keto-''N''-methylamphetamine || 2 |- | Ethcathinone || β-Keto-''N''-ethylamphetamine || 2 |- | Clortermine || 2-Chloro-α-methylamphetamine || 2 |- | Methoxymethylamphetamine (MMA) || 3-Methoxy-4-methylamphetamine || 2 |- | Fenfluramine || 3-Trifluoromethyl-''N''-ethylamphetamine || 2 |- | Dexfenfluramine || 3-Trifluoromethyl-''N''-ethylamphetamine, (''S'')- || 2 |- | 4-Methylmethamphetamine (4-MMA) || 4-Methyl-''N''-methylamphetamine || 2 |- | ''para''-Methoxymethamphetamine (PMMA) || 4-Methoxy-''N''-methylamphetamine || 2 |- | ''para''-Methoxyethylamphetamine (PMEA) || 4-Methoxy-''N''-ethylamphetamine || 2 |- | Pholedrine || 4-Hydroxy-''N''-methylamphetamine || 2 |- | Chlorphentermine || 4-Chloro-α-methylamphetamine || 2 |- | ''para''-Fluoromethamphetamine (PFMA, 4-FMA) || 4-Fluoro-''N''-methylamphetamine || 2 |- | Xylopropamine || 3,4-Dimethylamphetamine || 2 |- | α-Methyldopamine (α-Me-DA) || 3,4-Dihydroxyamphetamine || 2 |- | 3,4-Methylenedioxyamphetamine (MDA) || 3,4-Methylenedioxyamphetamine || 2 |- | Dimethoxyamphetamine (DMA) || X,X-Dimethoxyamphetamine || 2 |- | 6-APB || 6-(2-Aminopropyl)benzofuran || 2 |- | Phenylpropylaminopentane (PPAP) || α-Desmethyl-α,''N''-dipropylamphetamine || 2 |- | Furfenorex || ''N''-(2-Furylmethyl)-''N''-methylamphetamine || 2 |- | Fencamine || 8-Aminocaffeine–methamphetamine conjugate || 2 |- | Nordefrin (α-Me-NE) || β,3,4-Trihydroxyamphetamine, (''R'')- || 3 |- | Methylephedrine || β-Hydroxy-''N''-methylamphetamine, (1''R'',2''S'')- || 3 |- | Etafedrine || β-Hydroxy-''N''-ethylamphetamine, (1''R'',2''S'')- || 3 |- | Oxilofrine || β,4-Dihydroxy-''N''-methylamphetamine || 3 |- | Cinnamedrine || β-Hydroxy-''N''-methyl-''N''-cinnamylamphetamine || 3 |- | Methoxamine || 2,6-Dimethoxy-β-hydroxyamphetamine || 3 |- | Aleph || 2,5-Dimethoxy-4-methylthioamphetamine || 3 |- | Dimethoxybromoamphetamine (DOB) || 2,5-Dimethoxy-4-bromoamphetamine || 3 |- | Dimethoxychloroamphetamine (DOC) || 2,5-Dimethoxy-4-chloroamphetamine || 3 |- | Dimethoxyfluoroethylamphetamine (DOEF) || 2,5-Dimethoxy-4-fluoroethylamphetamine || 3 |- | Dimethoxyethylamphetamine (DOET) || 2,5-Dimethoxy-4-ethylamphetamine || 3 |- | Dimethoxyfluoroamphetamine (DOF) || 2,5-Dimethoxy-4-fluoroamphetamine || 3 |- | Dimethoxyiodoamphetamine (DOI) || 2,5-Dimethoxy-4-iodoamphetamine || 3 |- | Dimethoxymethylamphetamine (DOM) || 2,5-Dimethoxy-4-methylamphetamine || 3 |- | Dimethoxynitroamphetamine (DON) || 2,5-Dimethoxy-4-nitroamphetamine || 3 |- | Dimethoxypropylamphetamine (DOPR) || 2,5-Dimethoxy-4-propylamphetamine || 3 |- | Dimethoxytrifluoromethylamphetamine (DOTFM) || 2,5-Dimethoxy-4-trifluoromethylamphetamine || 3 |- | Methylenedioxymethamphetamine (MDMA) || 3,4-Methylenedioxy-''N''-methylamphetamine || 3 |- | Methylenedioxyethylamphetamine (MDEA) || 3,4-Methylenedioxy-''N''-ethylamphetamine || 3 |- | Methylenedioxyhydroxyamphetamine (MDOH) || 3,4-Methylenedioxy-''N''-hydroxyamphetamine || 3 |- | 2-Methyl-MDA || 3,4-Methylenedioxy-2-methylamphetamine || 3 |- | 5-Methyl-MDA || 4,5-Methylenedioxy-3-methylamphetamine || 3 |- | Methoxymethylenedioxyamphetamine (MMDA) || 3-Methoxy-4,5-methylenedioxyamphetamine || 3 |- | Trimethoxyamphetamine (TMA) || X,X,X-Trimethoxyamphetamine || 3 |- | Dimethylcathinone || β-Keto-''N'',''N''-dimethylamphetamine || 3 |- | Diethylcathinone || β-Keto-''N'',''N''-diethylamphetamine || 3 |- | Bupropion || β-Keto-3-chloro-''N''-''tert''-butylamphetamine || 3 |- | Mephedrone (4-MMC) || β-Keto-4-methyl-''N''-methylamphetamine || 3 |- | Methedrone (PMMC) || β-Keto-4-methoxy-''N''-methylamphetamine || 3 |- | Brephedrone (4-BMC) || β-Keto-4-bromo-''N''-methylamphetamine || 3 |- | Flephedrone (4-FMC) || β-Keto-4-fluoro-''N''-methylamphetamine || 3 |- | Ritodrine || 4,β-Dihydroxy-N-(4-hydroxyphenylethyl)amphetamine || 3 |- | Buphenine (nylidrin) || 4,β-Dihydroxy-''N''-'''(...)'''-amphetamine || 3 |- | Trecadrine || β-Hydroxy-''N''-methyl-''N''-'''(...)'''-amphetamine || 3 |- | Isoxsuprine || 4,β-Dihydroxy-''N''-'''(...)'''-amphetamine || 3 |- | Dioxifedrine || 3,4,β-Trihydroxy-''N''-methylamphetamine || 4 |- | Dioxethedrin || 3,4,β-Trihydroxy-''N''-ethylamphetamine || 4 |}

==Prodrugs of amphetamine/methamphetamine== A variety of prodrugs of amphetamine and/or methamphetamine exist, and include amfecloral, amfetaminil, benzphetamine, clobenzorex, <small>D</small>-deprenyl, deprenyl, dimethylamphetamine, ethylamphetamine, fencamine, fenethylline, fenproporex, furfenorex, lisdexamfetamine, lomardexamfetamine, mefenorex, prenylamine, and selegiline.<ref name="DettmeyerVerhoff2013">{{cite book|author1=Reinhard Dettmeyer|author2=Marcel A. Verhoff|author3=Harald F. Schütz|title=Forensic Medicine: Fundamentals and Perspectives|url=https://books.google.com/books?id=yHHABAAAQBAJ&pg=PA519|date=9 October 2013|publisher=Springer Science & Business Media|isbn=978-3-642-38818-7|pages=519–}}</ref>

==Russian amphetamines== {{See also|List of Russian drugs}}

A number of synthetic Russian amphetamine derivatives have been developed, including alafen (amphetamine–β-alanine), feprosidnine, gamofen (amphetamine–GABA), mesocarb, methylphenatine, pabofen (amphetamine–PABA), phenatine (amphetamine–niacin; ''N''-nicotinoylamphetamine), phenylphenamine (phenylamphetamine), propylphenamine (propylamphetamine), pyridoxiphen (amphetamine–pyridoxine), and thiophenatine (''N''-thionicotinoylamphetamine).

==Structure== [[File:Phenylethyl Amine General Formula V1.svg|class=skin-invert-image|thumb|250px|This shows phenethylamine in blue with its substitution points marked. Amphetamine and its substituted derivatives contain a CH₃ group at the alpha-position (R^α).]] [[File:Amphetamine numbered.svg|class=skin-invert-image|thumb|250px|This shows amphetamine with its substitution points marked, excluding the N-position at the NH₂ group which is unmarked. The wavy line between α carbon and CH₃ group indicates isomerism; the CH₃ group may either be towards or away from the viewer.]]

Amphetamines are a subgroup of the substituted phenethylamine class of compounds. Substitution of hydrogen atoms results in a large class of compounds. Typical reaction is substitution by methyl and sometimes ethyl groups at the amine and phenyl sites:<ref>Goldfrank, pp. 1125–1127</ref><ref>Glennon, pp. 184–187</ref><ref name="ref16">Schatzberg, p.843</ref>

{| class="wikitable sortable" ! rowspan=3|Substance ! colspan=7|Substituents ! rowspan=3|Structure ! rowspan=3|<small>Sources</small> |- ! rowspan=2|N ! rowspan=2|α ! rowspan=2|β ! colspan=4|phenyl group |- ! 2 ! 3 ! 4 ! 5 |- | Phenethylamine || || || || || || || || class=skin-invert-image|75px|Phenethylamine || style="text-align:center" | |- |Phenelzine | -NH₂ | | | | | | |class=skin-invert-image|83x83px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Phenelzine |url=https://pubchem.ncbi.nlm.nih.gov/compound/3675 |access-date=2025-12-27 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- | Amphetamine (α-methylphenylethylamine) | | -CH₃ | | | | | | class=skin-invert-image|75px|Amphetamine | style="text-align:center" | <ref name="Substituted amphetamine structures">{{cite book |author1=Barceloux DG |title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants |date=February 2012 |publisher=John Wiley & Sons |isbn=9781118106051 |page=5 |edition=First |chapter-url=https://books.google.com/books?id=9JLiJcjdqkcC&pg=PA5 |access-date=16 February 2019 |chapter=Chapter 1: Amphetamine and Methamphetamine}}</ref> |- | Methamphetamine (''N''-methylamphetamine) | -CH₃ | -CH₃ | | | | | | class=skin-invert-image|75px|Methamphetamine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | Phentermine (α-methylamphetamine) | | -(CH₃)₂ | | | | | | class=skin-invert-image|75px|Phentermine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- |Phenylpropanolamine | | -CH₃ | -OH | | | | |class=skin-invert-image|81x81px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Phenylpropanolamine |url=https://pubchem.ncbi.nlm.nih.gov/compound/10297 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- |Tranylcypromine | | colspan="2" | -CH₂- | | | | |class=skin-invert-image|89x89px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Tranylcypromine |url=https://pubchem.ncbi.nlm.nih.gov/compound/5530 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- |Phenylephrine | -CH₃ | | -OH | | -OH | | |class=skin-invert-image|84x84px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Phenylephrine |url=https://pubchem.ncbi.nlm.nih.gov/compound/6041 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- | Ephedrine | -CH₃ | -CH₃ | -OH | | | | | class=skin-invert-image|65px|(+)-Ephedrine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | Pseudoephedrine | -CH₃ | -CH₃ | -OH | | | | | class=skin-invert-image|65px|(+)-Pseudoephedrine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | Cathinone | | -CH₃ | =O | | | | | class=skin-invert-image|65px|Cathinone | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | Methcathinone (ephedrone) | -CH₃ | -CH₃ | =O | | | | | class=skin-invert-image|75px|Methcathinone | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- |Diethylpropion (amfepramone) | -CH₂-CH₃, -CH₂-CH₃ | -CH₃ |=O | | | | |class=skin-invert-image|85x85px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Diethylpropion |url=https://pubchem.ncbi.nlm.nih.gov/compound/7029 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- |Bupropion | -C(CH₃)₃ | -CH₃ |=O | | -Cl | | |class=skin-invert-image|89x89px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Bupropion |url=https://pubchem.ncbi.nlm.nih.gov/compound/444 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- |Desmethylselegiline | -CH₂-C≡CH | -CH₃ | | | | | |class=skin-invert-image|89x89px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Desmethylselegiline |url=https://pubchem.ncbi.nlm.nih.gov/compound/185859 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- |Selegiline | -CH₃, -CH₂-C≡CH | -CH₃ | | | | | |class=skin-invert-image|88x88px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Selegiline |url=https://pubchem.ncbi.nlm.nih.gov/compound/26757 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- |Benzphetamine | -CH₃, -CH₂-Ph{{Efn|1=Ph = phenyl group, consisting of a benzene ring}} | -CH₃ | | | | | |class=skin-invert-image|88x88px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Benzphetamine |url=https://pubchem.ncbi.nlm.nih.gov/compound/5311017 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- | MDA (3,4-methylenedioxyamphetamine) | | -CH₃ | | | colspan=2|-O-CH₂-O- | | class=skin-invert-image|75px|3,4-methylenedioxyamphetamine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | MDMA (3,4-methylenedioxymethamphetamine) | -CH₃ | -CH₃ | | | colspan=2|-O-CH₂-O- | | class=skin-invert-image|75px|3,4-methylenedioxymethamphetamine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | MDEA (3,4-methylenedioxy-''N''-ethylamphetamine) | -CH₂-CH₃ | -CH₃ | | | colspan=2|-O-CH₂-O- | | class=skin-invert-image|75px|methylenedioxyethylamphetamine | style="text-align:center" | <ref name="Substituted amphetamine structures" /> |- | EDMA (3,4-ethylenedioxy-N-methylamphetamine) | -CH₃ | -CH₃ | | | colspan=2|-O-CH₂-CH₂-O- | | class=skin-invert-image|75px|3,4-ethylenedioxy-N-methylamphetamine | style="text-align:center" | |- | MBDB (''N''-methyl-1,3-benzodioxolylbutanamine) | -CH₃ | -CH₂-CH₃ | | | colspan=2|-O-CH₂-O- | | class=skin-invert-image|75px|N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane | style="text-align:center" | |- | PMA (''para''-methoxyamphetamine) | | -CH₃ | | | | -O-CH₃ | | class=skin-invert-image|75px|para-methoxyamphetamine | style="text-align:center" | |- | PMMA (''para''-methoxymethamphetamine) | -CH₃ | -CH₃ | | | | -O-CH₃ | | class=skin-invert-image|75px|para-methoxymethamphetamine | style="text-align:center" | |- | 4-MTA (4-methylthioamphetamine) | | -CH₃ | | | | -S-CH₃ | | class=skin-invert-image|75px|4-methylthioamphetamine | style="text-align:center" | |- | 3,4-DMA (3,4-dimethoxyamphetamine) | | -CH₃ | | | -O-CH₃ | -O-CH₃ | | class=skin-invert-image|75px|dimethoxyamphetamine | style="text-align:center" | |- |Mescaline | | | | | -O-CH₃ | -O-CH₃ | -O-CH₃ |class=skin-invert-image|88x88px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Mescaline |url=https://pubchem.ncbi.nlm.nih.gov/compound/4076 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |- | 3,4,5-Trimethoxyamphetamine (α-methylmescaline) | | -CH₃ | | | -O-CH₃ | -O-CH₃ | -O-CH₃ | class=skin-invert-image|75px|trimethoxyamphetamine | style="text-align:center" | |- | DOM (2,5-dimethoxy-4-methylamphetamine) | | -CH₃ | | -O-CH₃ | | -CH₃ | -O-CH₃ | class=skin-invert-image|75px|2,5-dimethoxy-4-methylamphetamine | style="text-align:center" | |- | DOB (2,5-dimethoxy-4-bromoamphetamine) | | -CH₃ | | -O-CH₃ | | -Br | -O-CH₃ | class=skin-invert-image|75px|2,5-dimethoxy-4-bromoamphetamine | style="text-align:center" | |- |Fenfluramine | -CH₂-CH₃ | -CH₃ | | | -CF₃ | | |class=skin-invert-image|89x89px | style="text-align: center;" |<ref>{{Cite web |last=PubChem |title=Fenfluramine |url=https://pubchem.ncbi.nlm.nih.gov/compound/3337 |access-date=2025-12-28 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref> |} {{Notelist}}

==History== {{Main|History and culture of substituted amphetamines}}

Ephedra was used 5000 years ago in China as a medicinal plant; its active ingredients are alkaloids ephedrine, pseudoephedrine, norephedrine (phenylpropanolamine) and norpseudoephedrine (cathine). Natives of Yemen and Ethiopia have a long tradition of chewing khat leaves to achieve a stimulating effect. The active substances of khat are cathinone and, to a lesser extent, cathine.<ref>{{cite book|author = Paul M Dewick|title = Medicinal Natural Products. A Biosynthetic Approach. Second Edition|url = https://books.google.com/books?id=A4zptjOJfKQC&pg=PP1|year = 2002|publisher = Wiley|isbn = 978-0-471-49640-3|pages =383–384}}</ref>

Amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu, although its pharmacological effects remained unknown until the 1930s.<ref name="ref1">Snow, p. 1</ref> MDMA was produced in 1912 (in 1914, according to other sources<ref>{{cite journal|author = A. Richard Green|doi=10.1124/pr.55.3.3|title = The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)|pmid = 12869661|year = 2003|journal = Pharmacological Reviews|volume = 55|issue = 3|pages = 463–508|name-list-style=vanc|display-authors = 1|last2 = Mechan|first2 = AO|last3 = Elliott|first3 = JM|last4 = O'Shea|first4 = E|last5 = Colado|first5 = MI|s2cid=1786307}}</ref>) as an intermediate product. However, this synthesis also went largely unnoticed.<ref name="ref3">Goldfrank, p. 1125</ref> In the 1920s, both methamphetamine and the dextrorotatory optical isomer of amphetamine, dextroamphetamine, were synthesized. This synthesis was a by-product of a search for ephedrine, a bronchodilator used to treat asthma extracted exclusively from natural sources. Over-the-counter use of substituted amphetamines was initiated in the early 1930s by the pharmaceutical company Smith, Kline & French (now part of GlaxoSmithKline), as a medicine (Benzedrine) for colds and nasal congestion. Subsequently, amphetamine was used in the treatment of narcolepsy, obesity, hay fever, orthostatic hypotension, epilepsy, Parkinson's disease, alcoholism and migraine.<ref name="ref1"/><ref name="ref0">Goldfrank, p. 1119</ref> The "reinforcing" effects of substituted amphetamines were quickly discovered, and the misuse of substituted amphetamines had been noted as far back as 1936.<ref name="ref0"/>

thumb|right|200px|Amphetamine pills During World War II, amphetamines were used by the German military to keep their tank crews awake for long periods, and treat depression. It was noticed that extended rest was required after such artificially induced activity.<ref name="ref1"/> The widespread use of substituted amphetamines began in postwar Japan and quickly spread to other countries. Modified "designer amphetamines", such as MDA and PMA, have gained in popularity since the 1960s.<ref name="ref0"/> In 1970, the United States adopted "the Controlled Substances Act" that limited non-medical use of substituted amphetamines.<ref name = "ref0"/> Street use of PMA was noted in 1972.<ref>{{cite journal|author = Liang Han Ling|title = Poisoning with the recreational drug paramethoxyamphetamine ("death" )|url = http://www.mja.com.au/public/issues/174_09_070501/ling/ling.html|journal = The Medical Journal of Australia|year = 2001|volume = 174|pages = 453–5|pmid = 11386590|issue = 9|name-list-style = vanc|display-authors = 1|last2 = Marchant|first2 = C|last3 = Buckley|first3 = NA|last4 = Prior|first4 = M|last5 = Irvine|first5 = RJ|doi = 10.5694/j.1326-5377.2001.tb143372.x|url-status = live|archive-url = https://web.archive.org/web/20091126043611/http://www.mja.com.au/public/issues/174_09_070501/ling/ling.html|archive-date = 26 November 2009|df = dmy-all|hdl = 2440/14508|s2cid = 37596142|hdl-access = free}}</ref> MDMA emerged as a substitute for MDA in the early 1970s.<ref name="Foderaro 1988">{{cite news|last1=Foderaro|first1=Lisa W.|title=Psychedelic Drug Called Ecstasy Gains Popularity in Manhattan Nightclubs|url=https://www.nytimes.com/1988/12/11/nyregion/psychedelic-drug-called-ecstasy-gains-popularity-in-manhattan-nightclubs.html?pagewanted=2|access-date=27 August 2015|work=The New York Times|date=11 December 1988|url-status=live|archive-url=https://web.archive.org/web/20151117042408/http://www.nytimes.com/1988/12/11/nyregion/psychedelic-drug-called-ecstasy-gains-popularity-in-manhattan-nightclubs.html?pagewanted=2|archive-date=17 November 2015|df=dmy-all}}</ref> American chemist Alexander Shulgin first synthesized the drug in 1976 and through him the drug was briefly introduced into psychotherapy.<ref name="Shulgin">{{cite journal|last1=Benzenhöfer|first1=Udo|last2=Passie|first2=Torsten|title=Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin|journal=Addiction|date=9 July 2010|volume=105|issue=8|pages=1355–1361|doi=10.1111/j.1360-0443.2010.02948.x|pmid=20653618}}</ref> Recreational use grew and in 1985 MDMA was banned by the US authorities in an emergency scheduling initiated by the Drug Enforcement Administration.<ref>Snow, p. 71</ref>

Since the mid-1990s, MDMA has become a popular entactogenic drug among the youth and quite often non-MDMA substances were sold as ecstasy.<ref name="ref13">Goldfrank, p. 1121</ref> Ongoing trials are investigating its efficacy as an adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder (PTSD).<ref>{{cite journal|author = Mithoefer M.|title = The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study|journal = Journal of Psychopharmacology|year = 2011|volume=25|pages=439–52 |doi=10.1177/0269881110378371|name-list-style=vanc|display-authors = 1|last2 = Wagner|first2 = M. T.|last3 = Mithoefer|first3 = A. T.|last4 = Jerome|first4 = L.|last5 = Doblin|first5 = R.|issue = 4|pmid = 20643699|pmc = 3122379}}</ref>

==Legal status== {|class="wikitable" ! width="20%" rowspan=2|Agents ! colspan=4|Legal status by 2009.<ref>{{cite web |url=http://incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control |date=August 2003 |publisher=International Narcotics Control Board |url-status=unfit |archive-url=https://web.archive.org/web/20101125103728/http://incb.org/pdf/e/list/green.pdf |archive-date=25 November 2010 }} [http://www.incb.org/documents/Psychotropics/green_lists/Green_list_ENG_2010_53991_with_logo.pdf May 2010 Edition] {{webarchive|url=https://web.archive.org/web/20121224071633/http://www.incb.org/documents/Psychotropics/green_lists/Green_list_ENG_2010_53991_with_logo.pdf |date=24 December 2012 }}</ref><ref>{{cite web|url = http://www.justice.gov/dea/pubs/scheduling.html|title = DEA Drug Scheduling|work = U.S. Drug Enforcement Administration|access-date = 17 November 2009|url-status = live|archive-url = https://web.archive.org/web/20110207161752/http://www.justice.gov/dea/pubs/scheduling.html|archive-date = 7 February 2011|df = dmy-all}}</ref><ref name="ref80">{{cite web|url = http://base.garant.ru/12112176.htm|title = Resolution of RF Government of 30 June 1998 N 681 "On approval of list of drugs psychotropic substances and their precursors subject to control in the Russian Federation"|work = garant.ru|access-date = 15 November 2009|language = ru|url-status = live|archive-url = https://web.archive.org/web/20120120030118/http://base.garant.ru/12112176/|archive-date = 20 January 2012|df = dmy-all}}</ref><ref>{{cite web|url=https://www.tga.gov.au/publication/poisons-standard-susmp#electronic|title=The Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP)|work=Australian Therapeutic Goods Administration (TGA)|access-date=26 June 2015|url-status=live|archive-url=https://web.archive.org/web/20150627072620/https://www.tga.gov.au/publication/poisons-standard-susmp#electronic|archive-date=27 June 2015|df=dmy-all}}</ref> |-Amphetamine analogues or derivatives could be illegal for sell for human consumption in several countries or could be illegal under the several analogue acts in various countries. ! width="20%"|UN Convention on Psychotropic Substances of 1971<ref name=act>{{cite web|url=http://incb.org/pdf/e/conv/convention_1971_en.pdf |title=Convention on Psychotropic Substances, 1971 |work=United Nations |url-status=unfit |archive-url=https://web.archive.org/web/20101125121626/http://incb.org/pdf/e/conv/convention_1971_en.pdf |archive-date=25 November 2010 }}</ref> ! width="20%"|US ! width="20%"|Russia ! width="20%"|Australia

! width="20%"|United Nations (INCB)

|- | Amphetamine (racemic) | Schedule II | Schedule II | Schedule II | Schedule 8 |- | Dextroamphetamine (<small>D</small>-amphetamine) | Schedule II | Schedule II | Schedule I | Schedule 8 |- | Levoamphetamine (<small>L</small>-amphetamine) | Schedule II | Schedule II | Schedule III | Schedule 8 |- | Methamphetamine | Schedule II | Schedule II | Schedule I | Schedule 8 |- | Cathinone Methcathinone | Schedule I | Schedule I | Schedule I | Schedule 9 |- | MDA, MDMA, MDEA | Schedule I | Schedule I | Schedule I | Schedule 9 |- | PMA | Schedule I | Schedule I | Schedule I | Schedule 9 |- | DOB, DOM, 3,4,5-TMA | Schedule I | Schedule I | Schedule I | Schedule 9 |- |}

==See also== * Substituted phenethylamines * Substituted β-hydroxyamphetamines * Substituted methylenedioxyphenethylamines * Substituted cathinones * Substituted phenylmorpholines * Substituted methoxyphenethylamine * 2Cs, DOx, 4Cs, 25-NB, 3C, scaline, FLY * Substituted tryptamines * Substituted α-alkyltryptamines * ''PiHKAL'' * ''The Shulgin Index''

==References== {{Reflist|30em}}

==Notes== {{Reflist|group=note}}

==Bibliography== {{Refbegin}} * {{cite book|author = Ghodse, Hamid|title = Drugs and Addictive Behaviour. A Guide to Treatment. 3rd Edition|url = https://books.google.com/books?id=3WF79shLxB4C&pg=PP1|year = 2002|publisher = Cambridge University Press|pages = 501|isbn = 978-0-511-05844-8}} * {{cite book|author = Glennon, Richard A.|title = The American Psychiatric Publishing textbook of substance abuse treatment|chapter = Neurobiology of Hallucinogens|chapter-url = https://books.google.com/books?id=6wdJgejlQzYC&pg=PA181|year = 2008|publisher = American Psychiatric Publishing|isbn = 978-1-58562-276-4}} * {{cite book|author1 = Goldfrank, Lewis R.|author2 = Flomenbaum, Neal|name-list-style = amp|title = Goldfrank's Toxicologic Emergencies, 8th Edition|url = https://books.google.com/books?id=cvJuLqBxGUcC&pg=PP1|year = 2006|publisher = McGraw Hill|isbn = 978-0-07-147914-1}} * {{cite book|author = Katzung, Bertram G.|title = Basic & clinical pharmacology. 11th edition|url = https://books.google.com/books?id=srRLpM5miGYC&pg=PP1|year = 2009|publisher = McGraw-Hill Medical|isbn = 978-0-07-160405-5}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} * {{cite book|author = Ledgard, Jared |title = A Laboratory History of Narcotics. Volume 1. Amphetamines and Derivatives|year = 2007|publisher = Jared Ledgard|pages = 268|isbn = 978-0-615-15694-1}} * {{cite book|author1 = Schatzberg, Alan F.|author2 = Nemeroff, Charles B.|name-list-style = amp|title = The American Psychiatric Publishing Textbook of Psychopharmacology|url = https://books.google.com/books?id=Xx7iNGdV25IC&pg=PP1|year = 2009|publisher = The American Psychiatric Publishing|isbn = 978-1-58562-309-9}} * {{cite book|author =Snow, Otto |title = Amphetamine syntheses|year = 2002|publisher = Thoth Press|isbn = 978-0-9663128-3-6}} * {{cite book|vauthors=Veselovskaya NV, Kovalenko AE |title = Drugs. Properties, effects, pharmacokinetics, metabolism|year = 2000|location = MA|publisher = Triada-X|isbn = 978-5-94497-029-9}} {{Refend}}

==External links== * {{Commons category-inline|Amphetamines}}

{{Amphetamine|state=expanded}} {{Chemical classes of psychoactive drugs}} {{Monoamine releasing agents}} {{Serotonin receptor modulators}} {{Phenethylamines}} {{Authority control}}

{{DEFAULTSORT:Substituted Amphetamine}}

Category:Substituted amphetamines Category:Amphetamine Category:Chemical classes of psychoactive drugs