Biology:Phenethylamine

From HandWiki

Phenethylamine (PEA)[note 1] is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons.[1][2][3] To a lesser extent, it also acts as a neurotransmitter in the human central nervous system.[4] In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation.[5] In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

Phenethylamine is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, in orally ingested phenethylamine, a significant amount is metabolized in the small intestine by monoamine oxidase B (MAO-B) and then aldehyde dehydrogenase (ALDH), which converts it to phenylacetic acid.[6] This means that for significant concentrations to reach the brain, the dosage must be higher than for other methods of administration.[6][7][8] Some authors have postulated that phenethylamine plays a role in affection without substantiating these claims with any direct evidence.[9][10]

Phenethylamines, or more properly, substituted phenethylamines, are the group of phenethylamine derivatives that contain phenethylamine as a "backbone"; in other words, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the phenethylamine core structure with substituents. The class of substituted phenethylamines includes all substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx), and contains many drugs which act as empathogens, stimulants, psychedelics, anorectics, bronchodilators, decongestants, and/or antidepressants, among others.

Natural occurrence

Phenethylamine is produced by a wide range of species throughout the plant and animal kingdoms, including humans;[5][11] it is also produced by certain fungi and bacteria (genera: Lactobacillus, Clostridium, Pseudomonas and the family Enterobacteriaceae) and acts as a potent antimicrobial against certain pathogenic strains of Escherichia coli (e.g., the O157:H7 strain) at sufficient concentrations.[12]

Chemistry

PEA hydrochloride powder and crystals

Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group.[13] It is a colourless liquid at room temperature that has a fishy odor, and is soluble in water, ethanol and ether.[13] Its density is 0.964 g/ml and its boiling point is 195 °C.[13] Upon exposure to air, it combines with carbon dioxide to form a solid carbonate salt.[14] 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.[13][15] Its experimental log P is 1.41.[13]

Analogues and derivatives

See also: Chemistry:Substituted phenethylamine

Substituted phenethylamines are a chemical class of organic compounds based upon the phenethylamine structure;[note 2] the class is composed of all the derivative compounds of phenethylamine which can be formed by replacing, or substituting, one or more hydrogen atoms in the phenethylamine core structure with substituents.

Many substituted phenethylamines are psychoactive drugs, which belong to a variety of different drug classes, including central nervous system stimulants (e.g., amphetamine), hallucinogens (e.g., 2,5-dimethoxy-4-methylamphetamine), entactogens (e.g., 3,4-methylenedioxyamphetamine), appetite suppressants (e.g. phentermine), nasal decongestants and bronchodilators (e.g., pseudoephedrine), antidepressants (e.g. bupropion), antiparkinson agents (e.g., selegiline), and vasopressors (e.g., ephedrine), among others. Many of these psychoactive compounds exert their pharmacological effects primarily by modulating monoamine neurotransmitter systems; however, there is no mechanism of action or biological target that is common to all members of this subclass.

Numerous endogenous compounds—including hormones, monoamine neurotransmitters, and many trace amines (e.g., dopamine, norepinephrine, adrenaline, tyramine, and others)—are substituted phenethylamines. Dopamine is simply phenethylamine with a hydroxyl group attached to the 3 and 4 position of the benzene ring. Several notable recreational drugs, such as MDMA (ecstasy), methamphetamine, and cathinones, are also members of the class. All of the substituted amphetamines are phenethylamines, as well.

Pharmaceutical drugs that are substituted phenethylamines include phenelzine, phenformin, and fanetizole, among many others.

The N-methylated derivative of phenethylamine is N-methylphenethylamine.

A deuterated isotopologue of phenethylamine with resistance to monoamine oxidase (MAO)-mediated metabolism is α,α-dideuterophenethylamine.[16][17][18][19][20]

A notable prodrug of phenethylamine with sustained effects is N-(2-cyanoethyl)phenethylamine (CEPEA).[21][22][23] Other prodrugs of phenethylamine have been described as well.[23][21][24]

Analogues of phenethylamine with the ethylamine side chain extended or shortened include phenylpropylamine and benzylamine. Another related analogue is phenylalaninol.

Synthesis

One method for preparing β-phenethylamine, set forth in J. C. Robinson 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.[25]

A much more convenient method for the synthesis of β-phenethylamine is the reduction of ω-nitrostyrene by lithium aluminium hydride in ether, whose successful execution was first reported by R. F. Nystrom and W. G. Brown in 1948.[26]

Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.[27]

Electrosynthesis of phenethylamine from benzyl cyanide[27]

Assembling phenethylamine structures for synthesis of compounds such as epinephrine, amphetamines, tyrosine, and dopamine by adding the beta-aminoethyl side chain to the phenyl ring is possible. This can be done via Friedel-Crafts acylation with N-protected acyl chlorides when the arene is activated, or by Heck reaction of the phenyl with N-vinyloxazolone, followed by hydrogenation, or by cross-coupling with beta-amino organozinc reagents, or reacting a brominated arene with beta-aminoethyl organolithium reagents, or by Suzuki cross-coupling.[28]

Detection in body fluids

Reviews that cover attention deficit hyperactivity disorder (ADHD) and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine concentrations in ADHD individuals when compared with controls.[29] In treatment-responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine concentration.[29] An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[29]

Thirty minutes of moderate- to high-intensity physical exercise has been shown to induce an increase in urinary phenylacetic acid, the primary metabolite of phenethylamine.[30][31][32] 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;[30][31][32] 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.[30][31][32][33] 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.[33] Monoamine oxidase 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 completely deaminated in the gut as it is a selective substrate for MAO-B, which is not primarily 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.[5] 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. 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.[30][31][32]

Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.[13][34]

Pharmacology

Monoamine release of phenethylamine and related agents (EC50, nM)
Compound NE DA 5-HT Ref.
Phenethylamine 10.9 39.5 >10,000 [35][36][37]
Tyramine 40.6 119 2,775 [38][37]
Tryptamine 716 164 32.6 [39][40]
Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [38][41]
Levoamphetamine 9.5 27.7 ND [36][37]
Dextromethamphetamine 12.3–13.8 8.5–24.5 736–1,292 [38][42]
Levomethamphetamine 28.5 416 4,640 [38]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:[43][44]
Phenethylamine pharmacodynamics in a TAAR1–dopamine neuron
v · d · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Both amphetamine and phenethylamine induce neurotransmitter release from VMAT2[2][45][46] and bind to TAAR1.[3][47] When either binds to TAAR1, it reduces neuron firing rate and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation.[3][47] Phosphorylated DAT then either operates in reverse or withdraws into the axon terminal and ceases transport.[3][47]

Pharmacodynamics

Monoamine releasing agent

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, is a releasing agent of norepinephrine and dopamine.[2][3][47] It is roughly equipotent to amphetamine in this regard in vitro.[37] Phenethylamine is inactive as a psychostimulant under normal circumstances due to rapid metabolism by monoamine oxidase (MAO), but can become active in the presence of a monoamine oxidase inhibitor (MAOI).[37]

TAAR1 agonist

Phenethylamine is a potent agonist of the mouse, rat, and human trace amine-associated receptor 1 (TAAR1).[48][49] β-PEA is also an odorant binding TAAR4 in mice thought to mediate predator avoidance.[50] Similarly to the case of amphetamine, phenethylamine shows enhanced locomotor stimulation, a psychostimulant-like effect, in TAAR1 knockout mice.[51]

Monoaminergic activity enhancer

Phenethylamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its catecholamine-releasing activity.[52][53][54] That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.[52][53][54] The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines.[52][53][54] The MAE actions of phenethylamine and other MAEs may be mediated by TAAR1 agonism.[55][56] Synthetic and more potent MAEs like phenylpropylaminopentane (PPAP) and selegiline (L-deprenyl) have been derived from phenethylamine.[52][53]

Other activities

Unlike its derivatives norepinephrine (noradrenaline) and epinephrine (adrenaline), phenethylamine is inactive as an agonist of the α- and β-adrenergic receptors.[57]

Effects in animals and humans

According to Alexander Shulgin in PiHKAL, phenethylamine is completely inactive in humans at doses of up to 1,600 mg orally and 50 mg intravenously.[58] This can be attributed to its extremely rapid metabolic breakdown rather than pharmacodynamic inactivity.[58]

Although exogenous phenethylamine on its own is inactive, its metabolism can be strongly inhibited and it can thereby become active, showing psychostimulant effects, when combined with a monoamine oxidase inhibitor (MAOI), specifically monoamine oxidase B (MAO-B) inhibitors like selegiline.[59][60] Oral L-phenylalanine (a precursor of phenethylamine) and/or phenethylamine itself in combination with selegiline has been studied in the treatment of depression and has been reported to be effective.[52][61][62][63][64] Misuse of phenethylamine in combination with selegiline has also been reported.[65][66]

The LD50 values of phenethylamine include 175 mg/kg i.p. in mice, 320 mg/kg s.c. in mice, 100 mg/kg i.v. in mice, 100 mg/kg parenterally in mice, 39 mg/kg intracervically in mice, and 200 mg/kg i.p. in guinea pigs.[13] Its LDLo values include 800 mg/kg p.o. in rats, 100 mg/kg i.p. in rats, 450 μg/kg s.c. in rats, and 300 mg/kg via an unspecified route in mice.[13]

Pharmacokinetics

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primary
pathway
brain
CYP2D6
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By oral route, phenethylamine's half-life is 5–10 minutes;[13] endogenously produced PEA in catecholamine neurons has a half-life of roughly 30 seconds.[30] In humans, PEA is metabolized by phenylethanolamine N-methyltransferase (PNMT),[30][33][6][69] monoamine oxidase A (MAO-A),[6][7] monoamine oxidase B (MAO-B),[30][33][6][8] the semicarbazide-sensitive amine oxidases (SSAOs) AOC2 and AOC3,[6][70] flavin-containing monooxygenase 3 (FMO3),[71][72] and aralkylamine N-acetyltransferase (AANAT).[6][73] N-Methylphenethylamine, an isomer of amphetamine, is produced in humans via the metabolism of phenethylamine by PNMT.[30][33][69] β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism and subsequent aldehyde dehydrogenase metabolism.[6] Phenylacetaldehyde is the intermediate product which is produced by monoamine oxidase and then further metabolized into β-phenylacetic acid by aldehyde dehydrogenase.[6][74]

When the initial phenylethylamine concentration in the brain 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.[75]

History

Phenethylamine was first isolated and identified by Marceli Nencki in 1876.[76][77][78] Subsequently, it was first synthesized by Treat B. Johnson and Herbert H. Guest in 1909.[79][80]

Society and culture

United States

Phenylethylamine is not a scheduled substance in the United States. However, at least one person in the United States has been prosecuted under the Federal Analogue Act for selling phenylethylamine with the prosecutions argument that PEA is a structural analog of amphetamine and methamphetamine.[81][82][83]

See also

Notes

  1. ↑ Synonyms and alternate spellings include: phenylethylamine, β-phenylethylamine (β-PEA), 2-phenylethylamine, 1-amino-2-phenylethane, and 2-phenylethan-1-amine.
  2. ↑ In other words, all of the compounds that belong to this class are structural analogs of phenethylamine.

References

  1. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named TAAR1 and TA pharmacology 2016 review
  2. ↑ 2.0 2.1 2.2 "Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry". Medicinal Research Reviews 31 (4): 483–519. July 2011. doi:10.1002/med.20187. PMID 20135628. "Phenylethylamine (10), amphetamine [AMPH (11 & 12)], methylenedioxy methamphetamine [METH (13)] and N-methyl-4-phenylpyridinium (15) are all more potent inhibitors of VMAT2...". 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry 116 (2): 164–176. January 2011. doi:10.1111/j.1471-4159.2010.07109.x. PMID 21073468. 
  4. ↑ "Biochemical plasticity of synaptic transmission: a critical review of Dale's Principle". Biological Psychiatry 11 (4): 481–524. August 1976. PMID 9160. 
  5. ↑ 5.0 5.1 5.2 "Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators". Journal of Neurochemistry 90 (2): 257–271. July 2004. doi:10.1111/j.1471-4159.2004.02501.x. PMID 15228583. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Wishart, David S.; Djombou Feunang, Yannick; Marcu, Ana; Guo, An Chi; Liang, Kevin; Vázquez Fresno, Rosa; Sajed, Tanvir; Johnson, Daniel et al.. "Showing metabocard for Phenylethylamine (HMDB0012275)". https://hmdb.ca/metabolites/HMDB0012275. 
  7. ↑ 7.0 7.1 "Oxidation of beta-phenylethylamine by both types of monoamine oxidase: examination of enzymes in brain and liver mitochondria of eight species". Journal of Neurochemistry 36 (3): 1298–1301. March 1981. doi:10.1111/j.1471-4159.1981.tb01734.x. PMID 7205271. 
  8. ↑ 8.0 8.1 "Beta-phenylethylamine: a specific substrate for type B monoamine oxidase of brain". The Journal of Pharmacology and Experimental Therapeutics 187 (2): 365–371. November 1973. doi:10.1016/S0022-3565(25)29682-3. PMID 4748552. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=4748552. 
  9. ↑ "The Shapes of Neurotransmitters by Millimeter-Wave Spectroscopy: 2-Phenylethylamine". Journal of the American Chemical Society 117 (31): 8204–8210. 1995-08-01. doi:10.1021/ja00136a019. ISSN 0002-7863. Bibcode: 1995JAChS.117.8204G. 
  10. ↑ "Hormonal changes when falling in love". Psychoneuroendocrinology 29 (7): 931–936. August 2004. doi:10.1016/j.psyneuen.2003.08.006. PMID 15177709. 
  11. ↑ "Phenethylamine and related compounds in plants". Phytochemistry 16 (1): 9–18. 1977. doi:10.1016/0031-9422(77)83004-5. Bibcode: 1977PChem..16....9S. 
  12. ↑ "β-Phenylethylamine as a novel nutrient treatment to reduce bacterial contamination due to Escherichia coli O157:H7 on beef meat". Meat Science 96 (1): 165–171. January 2014. doi:10.1016/j.meatsci.2013.06.030. PMID 23896151. "Acetoacetic acid (AAA) and ß-phenylethylamine (PEA) performed best in this experiment. On beef meat pieces, PEA reduced the bacterial cell count by 90% after incubation of the PEA-treated and E. coli-contaminated meat pieces at 10°C for one week.". 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 "Phenethylamine". https://pubchem.ncbi.nlm.nih.gov/compound/1001. "Plasma Pharmacokinetics of PEA Could Be Described By 1st-Order Kinetics With Estimated T/2 of Approx 5-10 Min." 
  14. ↑ The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. (13th ed.). Whitehouse Station, NJ: Merck and Co., Inc.. 2001. p. 1296. 
  15. ↑ "Dissociation Constants of Adrenergic Amines". Journal of the American Chemical Society 73 (6): 2611–3. 1951. doi:10.1021/ja01150a055. Bibcode: 1951JAChS..73.2611L. 
  16. ↑ "Phenylethylamine in the CNS: effects of monoamine oxidase inhibiting drugs, deuterium substitution and lesions and its role in the neuromodulation of catecholaminergic neurotransmission". Journal of Neural Transmission. Supplementum 29: 119–129. 1990. doi:10.1007/978-3-7091-9050-0_12. ISBN 978-3-211-82142-8. PMID 2193105. 
  17. ↑ "Potentiation of the Biochemical Effects of β-Phenylethylamine and Tryptamine by Deuterium Substitution". Neuropsychopharmacology of the Trace Amines. Totowa, NJ: Humana Press. 1985. pp. 75–86. doi:10.1007/978-1-4612-5010-4_7. ISBN 978-1-4612-9397-2. http://link.springer.com/10.1007/978-1-4612-5010-4_7. Retrieved 28 May 2026. 
  18. ↑ "The Trace Amines: Recent Overview and Future Pointers". Neuropsychopharmacology of the Trace Amines. Totowa, NJ: Humana Press. 1985. pp. 3–12. doi:10.1007/978-1-4612-5010-4_1. ISBN 978-1-4612-9397-2. http://link.springer.com/10.1007/978-1-4612-5010-4_1. Retrieved 28 May 2026. 
  19. ↑ "Deuterium isotope effects on the enzymatic oxidative deamination of trace amines". Biochemical Pharmacology 30 (22): 3089–3094. November 1981. doi:10.1016/0006-2952(81)90497-4. PMID 7337725. 
  20. ↑ "Effects of deuterium substitution on the catabolism of beta-phenylethylamine: an in vivo study". Journal of Neurochemistry 46 (2): 399–404. February 1986. doi:10.1111/j.1471-4159.1986.tb12982.x. PMID 3941313. 
  21. ↑ 21.0 21.1 "Prodrugs of Trace Amines". Neuropsychopharmacology of the Trace Amines. Totowa, NJ: Humana Press. 1985. pp. 175–180. doi:10.1007/978-1-4612-5010-4_15. ISBN 978-1-4612-9397-2. 
  22. ↑ "Neuropharmacological and neurochemical properties of N-(2-cyanoethyl)-2-phenylethylamine, a prodrug of 2-phenylethylamine". British Journal of Pharmacology 92 (2): 243–255. October 1987. doi:10.1111/j.1476-5381.1987.tb11318.x. PMID 2890391. 
  23. ↑ 23.0 23.1 "Prodrugs of β-Phenylethylamine and Tryptamine: Studies in the Rat". Trace Amines. Totowa, NJ: Humana Press. 1988. pp. 321–334. doi:10.1007/978-1-4612-4602-2_30. ISBN 978-1-4612-8945-6. 
  24. ↑ "Carbamate prodrugs of phenylethylamines: a neurochemical investigation". Proc West Pharmacol Soc 27: 523–525. 1984. PMID 6494193. https://archive.org/details/carbamate-prodrugs-of-phenylethylamines-a-neurochemical-investigation-baker-et-al.-1984. 
  25. ↑ "β-Phenylethylamine". Organic Syntheses, Collected Volume 3: 720. 1955. https://www.orgsyn.org/Content/pdfs/procedures/CV3P0720.pdf. 
  26. ↑ "Reduction of organic compounds by lithium aluminum hydride; halides, quinones, miscellaneous nitrogen compounds". Journal of the American Chemical Society 70 (11): 3738–3740. November 1948. doi:10.1021/ja01191a057. PMID 18102934. 
  27. ↑ 27.0 27.1 "The electroreduction of benzyl cyanide on iron and cobalt cathodes". Journal of Applied Electrochemistry 9 (5): 657–659. 1979. doi:10.1007/BF00610957. 
  28. ↑ "Beta-aminoethyltrifluoroborates: efficient aminoethylations via Suzuki-Miyaura cross-coupling". Organic Letters 9 (2): 203–206. January 2007. doi:10.1021/ol062610v. PMID 17217265. 
  29. ↑ 29.0 29.1 29.2 "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". Journal of the American Academy of Child and Adolescent Psychiatry 51 (10): 1003–1019.e20. October 2012. doi:10.1016/j.jaac.2012.08.015. PMID 23021477. "Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls. ... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,20,60 suggesting that ADHD treatments normalize PEA levels. ... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,20,57,58 for treatment efficacy,20,60 and associated with symptoms of inattentivenesss.59 ... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110". 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences 26 (5): 274–281. May 2005. doi:10.1016/j.tips.2005.03.007. PMID 15860375. "The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55].". 
  31. ↑ 31.0 31.1 31.2 31.3 "Phenylethylamine, a possible link to the antidepressant effects of exercise?". British Journal of Sports Medicine 35 (5): 342–343. October 2001. doi:10.1136/bjsm.35.5.342. PMID 11579070. "The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. ... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels3, and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise. ... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise.". 
  32. ↑ 32.0 32.1 32.2 32.3 "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Reviews on Recent Clinical Trials 2 (1): 3–19. January 2007. doi:10.2174/157488707779318107. PMID 18473983. "It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].". 
  33. ↑ 33.0 33.1 33.2 33.3 33.4 "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics 125 (3): 363–375. March 2010. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. "Trace amines are metabolized in the mammalian body via monoamine oxidase". 
  34. ↑ "Excretion of beta-phenethylamine is elevated in humans after profound stress". Science 215 (4536): 1127–1129. February 1982. doi:10.1126/science.7063846. PMID 7063846. Bibcode: 1982Sci...215.1127P. "The urinary excretion rate of the endogenous, amphetamine-like substance beta-phenethylamine was markedly elevated in human subjects in association with an initial parachuting experience. The increases were delayed in most subjects and were not correlated with changes in urinary pH or creatinine excretion.". 
  35. ↑ "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  36. ↑ 36.0 36.1 "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". 22 May 2012. https://scholarworks.uno.edu/td/1436/. 
  37. ↑ 37.0 37.1 37.2 37.3 37.4 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  38. ↑ 38.0 38.1 38.2 38.3 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  39. ↑ "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology 231 (21): 4135–4144. October 2014. doi:10.1007/s00213-014-3557-7. PMID 24800892. 
  40. ↑ "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters 24 (19): 4754–4758. October 2014. doi:10.1016/j.bmcl.2014.07.062. PMID 25193229. 
  41. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  42. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  43. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  44. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  45. ↑ "Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter". Proceedings of the National Academy of Sciences of the United States of America 93 (10): 5166–5171. May 1996. doi:10.1073/pnas.93.10.5166. PMID 8643547. Bibcode: 1996PNAS...93.5166E. 
  46. ↑ Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. 2008. pp. 1219–1222. ISBN 978-3-540-38916-3. 
  47. ↑ 47.0 47.1 47.2 47.3 "Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord". Frontiers in Neural Circuits 8: 134. 2014. doi:10.3389/fncir.2014.00134. PMID 25426030. "TAAR1 activity appears to depress monoamine transport and limit dopaminergic and serotonergic neuronal firing rates via interactions with presynaptic D2 and 5-HT1A autoreceptors, respectively (Wolinsky et al., 2007; Lindemann et al., 2008; Xie and Miller, 2008; Xie et al., 2008; Bradaia et al., 2009; Revel et al., 2011; Leo et al., 2014).  ... TAAR1 and TAAR4 labeling in all neurons appeared intracellular, consistent with previous reported results for TAAR1 (Miller, 2011). A cytoplasmic location of ligand and receptor (e.g., tyramine and TAAR1) supports intracellular activation of signal transduction pathways, as suggested previously (Miller, 2011). ... Additionally, once transported intracellularly, they could act on presynaptic TAARs to alter basal activity (Miller, 2011). ... As reported for TAAR1 in HEK cells (Bunzow et al., 2001; Miller, 2011), we observed cytoplasmic labeling for TAAR1 and TAAR4, both of which are activated by the TAs (Borowsky et al., 2001). A cytoplasmic location of the ligand and the receptor (e.g., tyramine and TAAR1) would support intracellular activation of signal transduction pathways (Miller, 2011). Such a co-localization would not require release from vesicles and could explain why the TAs do not appear to be found there (Berry, 2004; Burchett and Hicks, 2006).". 
  48. ↑ "Trace Amines and Their Receptors". Pharmacol Rev 70 (3): 549–620. July 2018. doi:10.1124/pr.117.015305. PMID 29941461. 
  49. ↑ "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomedicine & Pharmacotherapy 83: 439–449. October 2016. doi:10.1016/j.biopha.2016.07.002. PMID 27424325. 
  50. ↑ "Trace amine-associated receptors: ligands, neural circuits, and behaviors". Current Opinion in Neurobiology 34: 1–7. October 2015. doi:10.1016/j.conb.2015.01.001. PMID 25616211. 
  51. ↑ "The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia". Genes Brain Behav 6 (7): 628–639. October 2007. doi:10.1111/j.1601-183X.2006.00292.x. PMID 17212650. "Most notably, Caron & Gainetdinov (personal communication) have recently observed that group-housed TA1 KO mice show enhanced sensitivity to the locomotor stimulating effects of both amphetamine and β-PEA relative to group-housed WT littermates, as well as normal habituation to an open field.". 
  52. ↑ 52.0 52.1 52.2 52.3 52.4 "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (3): 421–427. May 2004. doi:10.1016/j.pnpbp.2003.11.016. PMID 15093948. 
  53. ↑ 53.0 53.1 53.2 53.3 "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochem Res 28 (8): 1275–1297. August 2003. doi:10.1023/a:1024224311289. PMID 12834268. 
  54. ↑ 54.0 54.1 54.2 "Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain". Life Sci 58 (23): 2101–2114. 1996. doi:10.1016/0024-3205(96)00204-4. PMID 8649195. 
  55. ↑ "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". Int J Mol Sci 23 (15): 8543. August 2022. doi:10.3390/ijms23158543. PMID 35955676. 
  56. ↑ "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". Int J Mol Sci 24 (17). August 2023. doi:10.3390/ijms241713334. PMID 37686140. 
  57. ↑ "In Vitro Activation of Human Adrenergic Receptors and Trace Amine-Associated Receptor 1 by Phenethylamine Analogues Present in Food Supplements". Nutrients 16 (11): 1567. May 2024. doi:10.3390/nu16111567. PMID 38892500. 
  58. ↑ 58.0 58.1 "#142 - Phenethylamine". https://isomerdesign.com/pihkal/read/pk/142. 
  59. ↑ "Are metabolites of l-deprenyl (Selegiline) useful or harmful? Indications from preclinical research". Deprenyl — Past and Future. Journal of Neural Transmission. Supplementum. 48. January 1, 1996. pp. 61–73. doi:10.1007/978-3-7091-7494-4_6. ISBN 978-3-211-82891-5. 
  60. ↑ "A review of the pharmacology of selegiline". Acta Neurologica Scandinavica. Supplementum 136: 44–59. 1991. doi:10.1111/j.1600-0404.1991.tb05020.x. PMID 1686954. 
  61. ↑ "Does phenylethylamine act as an endogenous amphetamine in some patients?". Int J Neuropsychopharmacol 2 (3): 229–240. September 1999. doi:10.1017/S1461145799001522. PMID 11281991. 
  62. ↑ "L-deprenyl plus L-phenylalanine in the treatment of depression". J Neural Transm 59 (1): 81–87. 1984. doi:10.1007/BF01249880. PMID 6425455. 
  63. ↑ "Rapid treatment of depression with selegiline-phenylalanine combination". J Clin Psychiatry 52 (3): 137. March 1991. PMID 1900832. https://psycnet.apa.org/record/1991-25376-001. 
  64. ↑ "Sustained antidepressant effect of PEA replacement". J Neuropsychiatry Clin Neurosci 8 (2): 168–71. 1996. doi:10.1176/jnp.8.2.168. PMID 9081552. 
  65. ↑ "The Perils of Illegitimate Online Pharmacies: Substance-Induced Panic Attacks and Mood Instability Associated With Selegiline and Phenylethylamine". Psychosomatics 56 (5): 583–587. 2015. doi:10.1016/j.psym.2015.05.003. PMID 26198572. 
  66. ↑ "Availability of prescription drugs for bipolar disorder at online pharmacies". J Affect Disord 193: 59–65. March 2016. doi:10.1016/j.jad.2015.12.043. PMID 26766033. 
  67. ↑ "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. May 2005. doi:10.1016/j.tips.2005.03.007. PMID 15860375. 
  68. ↑ "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. February 2014. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. 
  69. ↑ 69.0 69.1 "Studies on lung N-methyltransferases, a pharmacological approach". Naunyn-Schmiedeberg's Archives of Pharmacology 313 (3): 263–268. September 1980. doi:10.1007/BF00505743. PMID 7432557. 
  70. ↑ "The unique substrate specificity of human AOC2, a semicarbazide-sensitive amine oxidase". Cellular and Molecular Life Sciences 66 (16): 2743–2757. August 2009. doi:10.1007/s00018-009-0076-5. PMID 19588076. "The preferred in vitro substrates of AOC2 were found to be 2-phenylethylamine, tryptamine and p-tyramine instead of methylamine and benzylamine, the favored substrates of AOC3.". 
  71. ↑ "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacology & Therapeutics 106 (3): 357–387. June 2005. doi:10.1016/j.pharmthera.2005.01.001. PMID 15922018. "The biogenic amines, phenethylamine and tyramine, are N-oxygenated by FMO to produce the N-hydroxy metabolite, followed by a rapid second oxygenation to produce the trans-oximes (Lin & Cashman, 1997a, 1997b). This stereoselective N-oxygenation to the trans-oxime is also seen in the FMO-dependent N-oxygenation of amphetamine (Cashman et al., 1999) ... Interestingly, FMO2, which very efficiently N-oxygenates N-dodecylamine, is a poor catalyst of phenethylamine N-oxygenation. The most efficient human FMO in phenethylamine N-oxygenation is FMO3, the major FMO present in adult human liver; the Km is between 90 and 200 μM (Lin & Cashman, 1997b).". 
  72. ↑ "Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients". PLOS ONE 11 (8). August 2016. doi:10.1371/journal.pone.0161074. PMID 27513517. Bibcode: 2016PLoSO..1161074R. "TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). ... FMO3 catalyzes the oxidation of catecholamine or catecholamine-releasing vasopressors, including tyramine, phenylethylamine, adrenaline, and noradrenaline [32, 33].". 
  73. ↑ "EC 2.3.1.87 – Aralkylamine N-acetyltransferase". Technische Universität Braunschweig. July 2014. http://www.brenda-enzymes.org/enzyme.php?ecno=2.3.1.87&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0. 
  74. ↑ "Aldehyde dehydrogenase – Homo sapiens". Technische Universität Braunschweig. January 2015. http://www.brenda-enzymes.org/enzyme.php?ecno=1.2.1.3&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0. 
  75. ↑ "Phenylethylamine and brain function". Biochemical Pharmacology 27 (13): 1707–1711. 1978. doi:10.1016/0006-2952(78)90543-9. PMID 361043. 
  76. ↑ "The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse". Journal of Medicinal Chemistry 60 (7): 2605–2628. April 2017. doi:10.1021/acs.jmedchem.7b00085. PMID 28244748. "The simplest phenylethylamine, phenylethylamine (1) itself, also known as 2-phenylethylamine, 2-phenylaminoethane, phenethylamine, β-phenylethylamine, or simply PEA. PEA (1; Figure 2), was first isolated and identified by the Polish chemist Marceli Nencki in 1876 (as reviewed by Grandy3).". 
  77. ↑ "Trace amine-associated receptor 1-Family archetype or iconoclast?". Pharmacology & Therapeutics 116 (3): 355–390. December 2007. doi:10.1016/j.pharmthera.2007.06.007. PMID 17888514. 
  78. ↑ "Trace Amines and Their Receptors: Historical Context and Contribution of Genetic Models to Research". Russian Journal of Genetics 61 (11): 1533–1540. 2025. doi:10.1134/S1022795425701091. ISSN 1022-7954. 
  79. ↑ "Molecule of the Week Archive: 2-Phenylethylamine: I’m the basic structure of a large family of psychoactives. What molecule am I?". 22 May 2023. https://www.acs.org/molecule-of-the-week/archive/p/2-phenylethylamine.html. "2-Phenylethylamine occurs widely in nature: in animals, plants, fungi, and bacteria alike. It has been known since at least 1890; and it was synthesized in 1909 by Treat B. Johnson and Herbert H. Guest at Yale University (New Haven, CT) via the reduction of benzyl cyanide with sodium in ethanol. Later synthetic methods included benzyl cyanide reduction with hydrogen over a Raney nickel catalyst and the reduction of β-nitrostyrene with lithium aluminum hydride." 
  80. ↑ "CLXX.—Researches on Amines: Synthesis of Methylphenylethylamine.". American Chemical Journal 42: 340–353. 1909. https://babel.hathitrust.org/cgi/pt?id=uiuo.ark:/13960/t7dr36r4f&view=1up&seq=357. 
  81. ↑ "UNITED STATES v. McKINNEY (1996)". https://caselaw.findlaw.com/court/us-8th-circuit/1155779.html. 
  82. ↑ United States v. McKinney, 99-1814/2436 (8th Cir. 2000).
  83. ↑ "Request for all records regarding the legal status of Phenethylamine under the Federal Analogue Act". 5 August 2022. https://www.muckrock.com/foi/united-states-of-america-10/request-for-all-records-regarding-the-legal-status-of-phenethylamine-under-the-federal-analogue-act-132398/. 

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