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Title: Phenethylamine  
Author: World Heritage Encyclopedia
Language: English
Subject: Dopamine, Amphetamine, Methamphetamine, MDMA, Octopamine
Collection: Amphetamine, Euphoriants, Norepinephrine-Dopamine Releasing Agents, Phenethylamines, Stimulants, Taar1 Agonists, Trace Amines, Vmat Inhibitors
Publisher: World Heritage Encyclopedia


Image of the phenethylamine skeleton
Ball-and-stick model of phenethylamine
Systematic (IUPAC) name
Clinical data
Legal status
  • AU: Unscheduled
  • CA: Unscheduled
  • NZ: Illegal (catch-all) [1]
  • UK: Unscheduled
  • US: Unscheduled
  • UN: Unscheduled
Psychological: low–moderate
Physical: none
None (without an MAO-B inhibitor)
Moderate (with an MAO-B inhibitor)
Routes of
Pharmacokinetic data

Minor routes:

MAO-A, SSAOs, PNMT, AANAT, FMO3, and others
Biological half-life Exogenous: 5–10 minutes[2]
Endogenous: ~30 seconds[3]
CAS Registry Number  Y
ATC code None
PubChem CID:
DrugBank  Y
ChemSpider  Y
Synonyms 1-amino-2-phenylethane
Chemical data
Formula C8H11N
Molecular mass 121.18 g/mol
Physical data
Density 0.9640 g/cm3
Melting point −60 °C (−76 °F) [4]
Boiling point 197.5 °C (387.5 °F) [4]

Phenethylamine (PEA), also known as β-phenylethylamine (β-PEA) and 2-phenylethylamine is an natural monoamine alkaloid, a trace amine, and also the name of a class of chemicals with many members that are well known for their psychoactive and stimulant effects.[5]

Phenylethylamine functions as a monoaminergic microbial fermentation. It is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, orally ingested phenethylamine experiences extensive first-pass metabolism by monoamine oxidase B (MAO-B) and then aldehyde dehydrogenase (ALDH), which metabolize it into phenylacetic acid.[8] This prevents significant concentrations from reaching the brain when taken in low doses.[9][10]

The group of phenethylamine derivatives is referred to as the phenethylamines. Substituted phenethylamines, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include empathogens, stimulants, psychedelics, anxiolytics (hypnotics) and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others.


  • Natural occurrence 1
  • Physical and chemical properties 2
    • Synthesis 2.1
  • Pharmacology 3
    • Pharmacodynamics 3.1
    • Pharmacokinetics 3.2
  • See also 4
  • References 5
  • External links 6

Natural occurrence

Phenethylamine is widely distributed throughout the plant kingdom and also present in animals, such as humans;[7][11][12] it is also produced by certain fungi and bacteria (genus: Lactobacillus, Clostridium, Pseudomonas, and Enterobacteriaceae) and acts as a potent anti-microbial against certain pathogenic strains of Escherichia coli (e.g., the O157:H7 strain) at sufficient concentrations.[12][13]

Physical and chemical properties

Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group.[14] It is a colourless liquid at room temperature that has a fishy odour and is soluble in water, ethanol and ether.[14] Its density is 0.964 g/ml and its boiling point is 195 °C.[14] Upon exposure to air, it forms a solid carbonate salt with carbon dioxide.[15] Phenethylamine is strongly basic, pKb = 4.17 (or pKa = 9.83), as measured using the HCl salt and forms a stable crystalline hydrochloride salt with a melting point of 217 °C.[14][16]


One method for preparing β-phenethylamine, set forth in J. C. Robinson's and H. R. Snyder's Organic Syntheses (published 1955), involves the reduction of benzyl cyanide with hydrogen in liquid ammonia, in the presence of a Raney-Nickel catalyst, at a temperature of 130 °C and a pressure of 13.8 MPa. Alternative syntheses are outlined in the footnotes to this preparation.[17]

A much more convenient method for the synthesis of β-phenethylamine is the reduction of ω-nitrostyrene by lithium aluminum hydride in ether, whose successful execution was first reported by R. F. Nystrom and W. G. Brown in 1948.[18] Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.[19]

Electrosynthesis of phenethylamine from benzyl cyanide[19]



Phenethylamine pharmacodynamics in a TAAR1–dopamine neuron
via AADC
Both amphetamine and phenethylamine induce neurotransmitter release from VMAT2[20][21][22] and bind to TAAR1.[23][24] When either binds to TAAR1, it reduces dopamine receptor firing rate and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation.[23][24] Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport.[23][24]

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, releases norepinephrine and dopamine.[20][23][24] Phenethylamine also appears to induce acetylcholine release via a glutamate-mediated mechanism.[25]

Reviews that cover attention deficit hyperactivity disorder (ADHD) and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine content in ADHD individuals when compared with controls.[12][26] In treatment responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine content.[12][26] An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[12][26]

Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary phenylacetic acid, the primary metabolite of phenethylamine.[3][27][28] Two reviews noted a study where the mean 24 hour urinary phenylacetic acid concentration following just 30 minutes of intense exercise rose 77% above its base level;[3][27][28] the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30 seconds.[3][27][28][29] In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate as dopamine is produced.[29] Because of the pharmacological relationship between phenethylamine and amphetamine, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both phenethylamine and amphetamine are potent euphoriants.[3][27][28]


Human biosynthesis pathway for trace amines and catecholamines[3][29]
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine.

By oral route, phenylethylamine's half-life is 5–10 minutes;[2] endogenously produced PEA in catecholamine neurons has a half-life of roughly 30 seconds.[3] It is metabolized by phenylethanolamine N-methyltransferase,[3][30] MAO-A,[10] MAO-B,[9] semicarbazide-sensitive amine oxidases (SSAOs),[31] aldehyde dehydrogenase,[32] and flavin-containing monooxygenase 3.[33] N-methylphenethylamine, an isomer of amphetamine, is produced in humans via the metabolism of phenethylamine by phenylethanolamine N-methyltransferase.[3][29][30] When the initial phenylethylamine brain concentration is low, brain levels can be increased 1000-fold when taking a monoamine oxidase inhibitor (MAOI), particularly a MAO-B inhibitor, and by 3–4 times when the initial concentration is high.[34] β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism.[8]

See also


  1. ^ Psychoactive Substances Act 2013 p9
  2. ^ a b "Pharmacology and Biochemistry". Phenethylamine. PubChem Compound. NCBI. 
  3. ^ a b c d e f g h i Lindemann L, Hoener MC (2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281.  
  4. ^ a b "Chemical and Physical Properties". Phenethylamine. Pubchem Compound. NCBI. Retrieved 17 February 2015. 
  5. ^ Glen R. Hanson, Peter J. Venturelli, Annette E. Fleckenstein (3 November 2005). Drugs and society (Ninth Edition). Jones and Bartlett Publishers.  
  6. ^ Sabelli, HC; Mosnaim, AD; Vazquez, AJ; Giardina, WJ; Borison, RL; Pedemonte, WA (1976). "Biochemical plasticity of synaptic transmission: A critical review of Dale's Principle". Biological Psychiatry 11 (4): 481–524.  
  7. ^ a b Berry, MD (July 2004). "Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators." (PDF). Journal of Neurochemistry 90 (2): 257–71.  
  8. ^ a b "Phenethylamine". Human Metabolome Database. Retrieved 17 February 2015. 
  9. ^ a b Yang, HY; Neff, NH (1973). "Beta-phenylethylamine: A specific substrate for type B monoamine oxidase of brain". The Journal of Pharmacology and Experimental Therapeutics 187 (2): 365–71.  
  10. ^ a b Suzuki O, Katsumata Y, Oya M (1981). "Oxidation of beta-phenylethylamine by both types of monoamine oxidase: examination of enzymes in brain and liver mitochondria of eight species". J. Neurochem. 36 (3): 1298–301.  
  11. ^ Smith, Terence A. (1977). "Phenethylamine and related compounds in plants". Phytochemistry 16 (1): 9–18.  
  12. ^ a b c d e Irsfeld M, Spadafore M, Prüß BM; Spadafore; Prüß (September 2013). "β-phenylethylamine, a small molecule with a large impact". Webmedcentral 4 (9).  
  13. ^ Lynnes T, Horne SM, Prüß BM (2014). "ß-Phenylethylamine as a novel nutrient treatment to reduce bacterial contamination due to Escherichia coli O157:H7 on beef meat". Meat Sci. 96 (1): 165–71.  
  14. ^ a b c d United States Government. "Phenethylamine". PubChem Compound.  
  15. ^ O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1296
  16. ^ Leffler, Esther B.; Spencer, Hugh M.; Burger, Alfred (1951). "Dissociation Constants of Adrenergic Amines". Journal of the American Chemical Society 73 (6): 2611–3.  
  17. ^ Robinson, J. C.; Snyder, H. R. (1955). "β-Phenylethylamine" (PDF). Organic Syntheses, Coll 3: 720. 
  18. ^ Nystrom, Robert F.; Brown, Weldon G. (1948). "Reduction of Organic Compounds by Lithium Aluminum Hydride. III. Halides, Quinones, Miscellaneous Nitrogen Compounds1". Journal of the American Chemical Society 70 (11): 3738–40.  
  19. ^ a b Krishnan, V.; Muthukumaran, A.; Udupa, H. V. K. (1979). "The electroreduction of benzyl cyanide on iron and cobalt cathodes". Journal of Applied Electrochemistry 9 (5): 657–659.  
  20. ^ a b Wimalasena K (July 2011). "Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry". Med Res Rev 31 (4): 483–519.  
  21. ^ Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E (May 1996). "Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter". Proc. Natl. Acad. Sci. U.S.A. 93 (10): 5166–5171.  
  22. ^ Offermanns, S; Rosenthal, W, eds. (2008). Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222.  
  23. ^ a b c d Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176.  
  24. ^ a b c d Gozal EA, O'Neill BE, Sawchuk MA, Zhu H, Halder M, Chou CC, Hochman S (2014). "Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord". Front Neural Circuits 8: 134.  
  25. ^ Deepak N, Sara T, Andrew H, Darrell DM, Glen BB (2011). "Trace amines and their relevance to psychiatry and neurology: a brief overview". Bulletin of Clinical Psychopharmacology 21 (1): 73–79.  
  26. ^ a b c Scassellati C, Bonvicini C, Faraone SV, Gennarelli M; Bonvicini; Faraone; Gennarelli (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses" (PDF). J. Am. Acad. Child Adolesc. Psychiatry 51 (10): 1003–1019.e20.  
  27. ^ a b c d Szabo A, Billett E, Turner J (2001). "Phenylethylamine, a possible link to the antidepressant effects of exercise?". Br J Sports Med 35 (5): 342–343.  
  28. ^ a b c d Berry MD (2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials 2 (1): 3–19.  
  29. ^ a b c d Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. PMID 19948186. doi:10.1016/j.pharmthera.2009.11.005. Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
    Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
  30. ^ a b Pendleton, Robert G.; Gessner, George; Sawyer, John (1980). "Studies on lung N-methyltransferases, a pharmacological approach". Naunyn-Schmiedeberg's Archives of Pharmacology 313 (3): 263–8.  
  31. ^ Kaitaniemi, S; Elovaara, H; Grön, K; Kidron, H; Liukkonen, J; Salminen, T; Salmi, M; Jalkanen, S; Elima, K (2009). "The unique substrate specificity of human AOC2, a semicarbazide-sensitive amine oxidase". Cell. Mol. Life Sci. 66 (16): 2743–57.  
  32. ^ "aldehyde dehydrogenase - Homo sapiens". BRENDA. Technische Universität Braunschweig. January 2015. Retrieved 13 April 2015. 
  33. ^ Krueger SK, Williams DE; Williams (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387.  
  34. ^ Sabelli, Hector C.; Borison, Richard L.; Diamond, Bruce I.; Havdala, Henri S.; Narasimhachari, Nedathur (1978). "Phenylethylamine and brain function". Biochemical Pharmacology 27 (13): 1707–11.  

External links

  • Phenethylamine MS Spectrum
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