Substituted amphetamine

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Substituted amphetamine
Drug class
Racemic amphetamine skeleton
Class identifiers
Chemical class Substituted derivatives of amphetamine
Optical isomers of amphetamine
L-amphetamine.svg D-amphetamine.svg
L-amphetamine-3D-vdW.png D-amphetamine-3D-vdW.png
L-amphetamine D-amphetamine

Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents.[1][2] The compounds in this class span a variety of pharmacological subclasses, including stimulants, entactogens, hallucinogens, among others. Examples of substituted amphetamines are amphetamine (itself),[1] methamphetamine, ephedrine, cathinone, MDMA (ecstasy), and DOM (STP).

Some of amphetamine's substituted derivatives occur in nature, for example in the leaves of Ephedra and khat plants. These have been used since antiquity for their pharmacological effects. 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: psychoanaleptic, hallucinogenic and empathogenic. Various substituted amphetamines may cause these actions either separately or in combination.

Partial list of substituted amphetamines

Generic or Trivial Name Chemical Name # of Subs
Amphetamine α-Methyl-phenethylamine 0
Methamphetamine N-Methylamphetamine 1
Ethylamphetamine N-Ethylamphetamine 1
Propylamphetamine N-Propylamphetamine 1
Isopropylamphetamine N-iso-Propylamphetamine 1
Phentermine α-Methylamphetamine 1
Phenylpropanolamine (PPA) β-Hydroxyamphetamine, (1R,2S)- 1
Cathine β-Hydroxyamphetamine, (1S,2S)- 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
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
Clobenzorex N-(2-chlorobenzyl)-1-phenylpropan-2-amine 1
Dimethylamphetamine N,N-Dimethylamphetamine 2
Benzphetamine N-Benzyl-N-methylamphetamine 2
Selegiline N-Methyl-N-propargylamphetamine, (R)- 2
Mephentermine N-Methyl-α-methylamphetamine 2
Phenpentermine α,β-Dimethylamphetamine 2
Ephedrine β-Hydroxy-N-methylamphetamine, (1R,2S)- 2
Pseudoephedrine (PSE) β-Hydroxy-N-methylamphetamine, (1S,2S)- 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
Methylenedioxyamphetamine (MDA) 3,4-Methylenedioxyamphetamine 2
Dimethoxyamphetamine (DMA) X,X-Dimethoxyamphetamine 2
Nordefrin (α-Me-NE) β,3,4-Trihydroxyamphetamine, (R)- 3
Oxilofrine β,4-Dihydroxy-N-methylamphetamine 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

Prodrugs of amphetamine/methamphetamine

A variety of prodrugs of amphetamine and/or methamphetamine exist, and include amfecloral, amphetaminil, benzphetamine, clobenzorex, D-deprenyl, dimethylamphetamine, ethylamphetamine, fencamine, fenethylline, fenproporex, furfenorex, lisdexamfetamine, mefenorex, mesocarb, prenylamine, selegiline, and tranylcypromine.[3]


This shows phenethylamine in blue with its substitution points marked. Amphetamine and its substituted derivatives contain a CH3 group at the alpha-position (Rα).
This shows amphetamine with its substitution points marked, excluding the N-position at the NH2 group which is unmarked.

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:[4][5][6]

Substance Substituents Structure
N α β phenyl group
2 3 4 5
Phenethylamine Phenethylamine
Amphetamine (α-methylphenylethylamine) -CH3 Amphetamine
Methamphetamine (N-methylamphetamine) -CH3 -CH3 Methamphetamine
Ephedrine pseudoephedrine -CH3 -CH3 -OH Pseudoephedrine
Cathinone -CH3 =O Cathinone
Methcathinone (ephedrone) -CH3 -CH3 =O Methcathinone
MDA (3,4-methylenedioxyamphetamine) -CH3 -O-CH2-O- 3,4-methylenedioxyamphetamine
MDMA (3,4-methylenedioxymethamphetamine) -CH3 -CH3 -O-CH2-O- 3,4-methylenedioxymethamphetamine
MDEA (3,4-methylenedioxy-N-ethylamphetamine) -CH2-CH3 -CH3 -O-CH2-O- methylenedioxyethylamphetamine
EDMA (3,4-ethylenedioxy-N-methylamphetamine) -CH3 -CH3 -O-CH2-CH2-O- 3,4-ethylenedioxy-N-methylamphetamine
MBDB (N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane) -CH3 -CH2-CH3 -O-CH2-O- N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane
PMA (para-methoxyamphetamine) -CH3 -O-CH3 para-methoxyamphetamine
PMMA (para-methoxymethamphetamine) -CH3 -CH3 -O-CH3 para-methoxymethamphetamine
4-MTA (4-methylthioamphetamine) -CH3 -S-CH3 4-methylthioamphetamine
3,4-DMA (3,4-dimethoxyamphetamine) -CH3 -O-CH3 -O-CH3 dimethoxyamphetamine
3,4,5-TMA (3,4,5-trimethoxyamphetamine, α-methylmescaline) -CH3 -O-CH3 -O-CH3 -O-CH3 trimethoxyamphetamine
DOM (2,5-dimethoxy-4-methylamphetamine) -CH3 -O-CH3 -CH3 -O-CH3 2,5-dimethoxy-4-methylamphetamine
DOB (2,5-dimethoxy-4-bromoamphetamine) -CH3 -O-CH3 -Br -O-CH3 2,5-dimethoxy-4-bromoamphetamine


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.[7]

Amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu, although its pharmacological effects remained unknown until the 1930s.[8] MDMA was produced in 1912 (according to other sources in 1914[9]) as an intermediate product. However, this synthesis also went largely unnoticed.[10] 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.[8][11] The "reinforcing" effects of substituted amphetamines were quickly discovered, and the misuse of substituted amphetamines had been noted as far back as 1936.[11]

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.[8]

The widespread use of substituted amphetamines began in postwar Japan and quickly spread to other countries. Modified "designer amphetamines" gained popularity since the 1960s, such as MDA and PMA.[11] In 1970, the United States adopted "the Controlled Substances Act" that limited non-medical use of substituted amphetamines.[11] Street use of PMA was noted in 1972.[12] MDMA emerged as a substitute to MDA in the early 1970s.[13] American chemist Alexander Shulgin in synthesized the drug in 1976 and through him the drug was briefly introduced into psychotherapy.[14] Recreational use grew and in 1985 MDMA was banned by the US authorities in an emergency scheduling initiated by the Drug Enforcement Administration.[15]

Since the mid-1990s, MDMA has become a popular entactogenic drug among the youth and quite often non-MDMA substances were sold as ecstasy.[16] Ongoing trials are investigating its efficacy as an adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder (PTSD).[17]

Legal status

Agents Legal status by 2009.[18][19][20][21]
UN Convention on Psychotropic Substances of 1971[22] US Russia Australia
Amphetamine (racemic) Schedule II Schedule II Schedule II Schedule 8
Dextroamphetamine (D-amphetamine) Schedule II Schedule II Schedule I Schedule 8
Levoamphetamine (L-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


  1. 1.0 1.1 Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. Retrieved 11 September 2015. 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). <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  3. Reinhard Dettmeyer; Marcel A. Verhoff; Harald F. Schütz (9 October 2013). Forensic Medicine: Fundamentals and Perspectives. Springer Science & Business Media. pp. 519–. ISBN 978-3-642-38818-7.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  4. Goldfrank, pp. 1125–1127
  5. Glennon, pp. 184–187
  6. Schatzberg, p.843
  7. Paul M Dewick (2002). Medicinal Natural Products. A Biosynthetic Approach. Second Edition. Wiley. pp. 383–384. ISBN 0-471-49640-5.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. 8.0 8.1 8.2 Snow, p. 1
  9. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  10. Goldfrank, p. 1125
  11. 11.0 11.1 11.2 11.3 Goldfrank, p. 1119
  12. Liang Han Ling, et al. (2001). "Poisoning with the recreational drug paramethoxyamphetamine ("death" )". The Medical Journal of Australia. 174 (9): 453–5. PMID 11386590.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  13. Foderaro, Lisa W. (11 December 1988). "Psychedelic Drug Called Ecstasy Gains Popularity in Manhattan Nightclubs". The New York Times. The New York Times Company. Retrieved 27 August 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  14. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  15. Snow, p. 71
  16. Goldfrank, p. 1121
  17. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  18. "List of psychotropic substances under international control" (PDF). International Narcotics Control Board. August 2003.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> May 2010 Edition
  19. "DEA Drug Scheduling". U.S. Drug Enforcement Administration. Retrieved 17 November 2009.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  20. "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"". (in русский). Retrieved 15 November 2009.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  21. "The Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP)". Australian Therapeutic Goods Administration (TGA). Retrieved 26 June 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  22. "Convention on Psychotropic Substances, 1971" (PDF). United Nations.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>