Phenethylamine

Phenethylamine is produced by a wide range of species throughout the plant and animal kingdoms, including humans;{{cite journal |doi=10.1016/0031-9422(77)83004-5 |title=Phenethylamine and related compounds in plants |year=1977 | vauthors = Smith TA |journal=Phytochemistry |volume=16 |issue=1 |pages=9–18|bibcode=1977PChem..16....9S }} 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.{{cite journal | vauthors = Lynnes T, Horne SM, Prüß BM | title = β-Phenylethylamine as a novel nutrient treatment to reduce bacterial contamination due to Escherichia coli O157:H7 on beef meat | journal = Meat Science | volume = 96 | issue = 1 | pages = 165–171 | date = January 2014 | pmid = 23896151 | doi = 10.1016/j.meatsci.2013.06.030 | quote = 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. }}

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Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group.{{cite web | title=Phenethylamine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/1001 | access-date=10 November 2024 | quote= Plasma Pharmacokinetics of PEA Could Be Described By 1st-Order Kinetics With Estimated T/2 of Approx 5-10 Min.}} It is a colourless liquid at room temperature that has a fishy odor, and is soluble in water, ethanol and ether. Its density is 0.964 g/ml and its boiling point is 195 °C. Upon exposure to air, it combines with carbon dioxide to form a solid carbonate salt.{{cite book | veditors = O'Neil MJ | title = The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. | edition = 13th | location = Whitehouse Station, NJ | publisher = Merck and Co., Inc. | date = 2001 | page = 1296 }} Phenethylamine is strongly basic, pK_b = 4.17 (or pK_a = 9.83), as measured using the HCl salt, and forms a stable crystalline hydrochloride salt with a melting point of 217 °C.{{cite journal |doi=10.1021/ja01150a055 |title=Dissociation Constants of Adrenergic Amines |year=1951 | vauthors = Leffler EB, Spencer HM, Burger A |journal=Journal of the American Chemical Society |volume=73 |issue=6 |pages=2611–3}} Its experimental log P is 1.41.

{{Main|Substituted phenethylamine}}

Substituted phenethylamines are a chemical class of organic compounds based upon the phenethylamine structure;{{#tag:ref|In other words, all of the compounds that belong to this class are structural analogs of phenethylamine.|group="note"}} 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{{Mdash}}including hormones, monoamine neurotransmitters, and many trace amines (e.g., dopamine, norepinephrine, adrenaline, tyramine, and others){{Mdash}}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.

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

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.{{cite journal | vauthors = Robinson JC, Snyder HR |year=1955 |title=β-Phenylethylamine |url=http://www.orgsyn.org/Content/pdfs/procedures/CV3P0720.pdf |journal=Organic Syntheses, Collected Volume |volume=3 |page=720}}

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.{{cite journal | vauthors = Nystrom RF, Brown WG | title = Reduction of organic compounds by lithium aluminum hydride; halides, quinones, miscellaneous nitrogen compounds | journal = Journal of the American Chemical Society | volume = 70 | issue = 11 | pages = 3738–3740 | date = November 1948 | pmid = 18102934 | doi = 10.1021/ja01191a057 }}

Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.{{cite journal| vauthors = Krishnan V, Muthukumaran A, Udupa HV |title=The electroreduction of benzyl cyanide on iron and cobalt cathodes|journal=Journal of Applied Electrochemistry|year=1979|volume=9|issue=5|pages=657–659|doi=10.1007/BF00610957|s2cid=96102382 }}

File:Benzyl cyanide electrolytic reduction.png of phenethylamine from benzyl cyanide|thumb]]

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.{{cite journal | vauthors = Molander GA, Vargas F | title = Beta-aminoethyltrifluoroborates: efficient aminoethylations via Suzuki-Miyaura cross-coupling | journal = Organic Letters | volume = 9 | issue = 2 | pages = 203–206 | date = January 2007 | pmid = 17217265 | pmc = 2593899 | doi = 10.1021/ol062610v }}

{{Expand section||date=September 2016}}

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. In treatment-responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine concentration.{{cite journal | vauthors = Scassellati C, Bonvicini C, Faraone SV, Gennarelli M | title = Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 51 | issue = 10 | pages = 1003–1019.e20 | date = October 2012 | pmid = 23021477 | doi = 10.1016/j.jaac.2012.08.015 | quote = Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies^20,57,58 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 }} An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.

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.{{cite journal | vauthors = Lindemann L, Hoener MC | title = A renaissance in trace amines inspired by a novel GPCR family | journal = Trends in Pharmacological Sciences | volume = 26 | issue = 5 | pages = 274–281 | date = May 2005 | pmid = 15860375 | doi = 10.1016/j.tips.2005.03.007 | quote = 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]. }}{{cite journal | vauthors = Szabo A, Billett E, Turner J | title = Phenylethylamine, a possible link to the antidepressant effects of exercise? | journal = British Journal of Sports Medicine | volume = 35 | issue = 5 | pages = 342–343 | date = October 2001 | pmid = 11579070 | pmc = 1724404 | doi = 10.1136/bjsm.35.5.342 | quote = 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. }}{{cite journal | vauthors = Berry MD | title = The potential of trace amines and their receptors for treating neurological and psychiatric diseases | journal = Reviews on Recent Clinical Trials | volume = 2 | issue = 1 | pages = 3–19 | date = January 2007 | pmid = 18473983 | doi = 10.2174/157488707779318107 | quote = It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151]. | citeseerx = 10.1.1.329.563 }} 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; 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. In a resting state, phenethylamine is synthesized in catecholamine neurons from {{smallcaps all|L}}-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate as dopamine is produced.{{cite journal | vauthors = Broadley KJ | title = The vascular effects of trace amines and amphetamines | journal = Pharmacology & Therapeutics | volume = 125 | issue = 3 | pages = 363–375 | date = March 2010 | pmid = 19948186 | doi = 10.1016/j.pharmthera.2009.11.005 | quote = Trace amines are metabolized in the mammalian body via monoamine oxidase }} 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. 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.

Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.{{cite journal | vauthors = Paulos MA, Tessel RE | title = Excretion of beta-phenethylamine is elevated in humans after profound stress | journal = Science | volume = 215 | issue = 4536 | pages = 1127–1129 | date = February 1982 | pmid = 7063846 | doi = 10.1126/science.7063846 | quote = 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. | bibcode = 1982Sci...215.1127P }}

{{See also|Neurobiological effects of physical exercise#β-Phenylethylamine}}

{{Amphetamine pharmacodynamics|header=Phenethylamine pharmacodynamics in a TAAR1–dopamine neuron|caption=Both amphetamine and phenethylamine induce neurotransmitter release from VMAT2{{cite journal | vauthors = Wimalasena K | title = Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry | journal = Medicinal Research Reviews | volume = 31 | issue = 4 | pages = 483–519 | date = July 2011 | pmid = 20135628 | pmc = 3019297 | doi = 10.1002/med.20187 | quote = Phenylethylamine (10), amphetamine [AMPH (11 & 12)], methylenedioxy methamphetamine [METH (13)] and N-methyl-4-phenylpyridinium (15) are all more potent inhibitors of VMAT2... }}{{cite journal | vauthors = Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E | title = Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 10 | pages = 5166–5171 | date = May 1996 | pmid = 8643547 | pmc = 39426 | doi = 10.1073/pnas.93.10.5166 | doi-access = free | bibcode = 1996PNAS...93.5166E }}{{cite book |editor1=Offermanns, S |editor2= Rosenthal, W |title=Encyclopedia of Molecular Pharmacology |year=2008|publisher=Springer|location=Berlin|isbn=978-3540389163|pages=1219–1222|edition=2nd}} and bind to TAAR1.{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–176 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}{{cite journal | vauthors = Gozal EA, O'Neill BE, Sawchuk MA, Zhu H, Halder M, Chou CC, Hochman S | title = Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord | journal = Frontiers in Neural Circuits | volume = 8 | pages = 134 | year = 2014 | pmid = 25426030 | pmc = 4224135 | doi = 10.3389/fncir.2014.00134 | quote = 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). | doi-access = free }} 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. Phosphorylated DAT then either operates in reverse or withdraws into the axon terminal and ceases transport.|align=bottom}}

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, is a releasing agent of norepinephrine and dopamine. It is roughly equipotent to amphetamine in this regard in vitro. 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).

Phenethylamine is a potent agonist of the mouse, rat, and human trace amine-associated receptor 1 (TAAR1).{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}{{cite journal | vauthors = Khan MZ, Nawaz W | title = The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system | journal = Biomedicine & Pharmacotherapy | volume = 83 | pages = 439–449 | date = October 2016 | pmid = 27424325 | doi = 10.1016/j.biopha.2016.07.002 }} β-PEA is also an odorant binding TAAR4 in mice thought to mediate predator avoidance.{{cite journal | vauthors = Liberles SD | title = Trace amine-associated receptors: ligands, neural circuits, and behaviors | journal = Current Opinion in Neurobiology | volume = 34 | issue = | pages = 1–7 | date = October 2015 | pmid = 25616211 | pmc = 4508243 | doi = 10.1016/j.conb.2015.01.001 | url = }} Similarly to the case of amphetamine, phenethylamine shows enhanced locomotor stimulation, a psychostimulant-like effect, in TAAR1 knockout mice.{{cite journal | vauthors = Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP | title = The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia | journal = Genes Brain Behav | volume = 6 | issue = 7 | pages = 628–639 | date = October 2007 | pmid = 17212650 | doi = 10.1111/j.1601-183X.2006.00292.x | url = | quote = 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. }}

Phenethylamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its catecholamine-releasing activity.{{cite journal | vauthors = Shimazu S, Miklya I | title = Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 28 | issue = 3 | pages = 421–427 | date = May 2004 | pmid = 15093948 | doi = 10.1016/j.pnpbp.2003.11.016 | s2cid = 37564231 }}{{cite journal | vauthors = Knoll J | title = Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives | journal = Neurochem Res | volume = 28 | issue = 8 | pages = 1275–1297 | date = August 2003 | pmid = 12834268 | doi = 10.1023/a:1024224311289 | url = }}{{cite journal | vauthors = Knoll J, Miklya I, Knoll B, Markó R, Rácz D | title = Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain | journal = Life Sci | volume = 58 | issue = 23 | pages = 2101–2114 | date = 1996 | pmid = 8649195 | doi = 10.1016/0024-3205(96)00204-4 | url = }} That is, it enhances the action potential-mediated release of these monoamine neurotransmitters. The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines. The MAE actions of phenethylamine and other MAEs may be mediated by TAAR1 agonism.{{cite journal | vauthors = Harsing LG, Knoll J, Miklya I | title = Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum | journal = Int J Mol Sci | volume = 23 | issue = 15 | date = August 2022 | page = 8543 | pmid = 35955676 | pmc = 9369307 | doi = 10.3390/ijms23158543 | doi-access = free | url = }}{{cite journal | vauthors = Harsing LG, Timar J, Miklya I | title = Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline | journal = Int J Mol Sci | volume = 24 | issue = 17 | date = August 2023 | page = 13334 | pmid = 37686140 | pmc = 10487936 | doi = 10.3390/ijms241713334 | doi-access = free | url = }} Synthetic and more potent MAEs like phenylpropylaminopentane (PPAP) and selegiline (L-deprenyl) have been derived from phenethylamine.

Unlike its derivatives norepinephrine (noradrenaline) and epinephrine (adrenaline), phenethylamine is inactive as an agonist of the α- and β-adrenergic receptors.{{cite journal | vauthors = Pinckaers NE, Blankesteijn WM, Mircheva A, Shi X, Opperhuizen A, Schooten FV, Vrolijk MF | title = In Vitro Activation of Human Adrenergic Receptors and Trace Amine-Associated Receptor 1 by Phenethylamine Analogues Present in Food Supplements | journal = Nutrients | volume = 16 | issue = 11 | date = May 2024 | page = 1567 | pmid = 38892500 | pmc = 11174489 | doi = 10.3390/nu16111567 | doi-access = free | url = }}

According to Alexander Shulgin in PiHKAL, phenethylamine is completely inactive in humans at doses of up to 1,600{{nbsp}}mg orally and 50{{nbsp}}mg intravenously.{{cite web | title=#142 - Phenethylamine | website=Isomer Design | url=https://isomerdesign.com/pihkal/read/pk/142 | access-date=10 November 2024}} This can be attributed to its extremely rapid metabolic breakdown rather than pharmacodynamic inactivity.

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.{{cite book | vauthors = Yasar S, Goldberg JP, Goldberg SR | chapter = Are metabolites of l-deprenyl (Selegiline) useful or harmful? Indications from preclinical research | title = Deprenyl — Past and Future | series = Journal of Neural Transmission. Supplementum | pages = 61–73 | date = January 1, 1996 | volume = 48 | pmid = 8988462 | doi = 10.1007/978-3-7091-7494-4_6 | isbn = 978-3-211-82891-5 }}{{cite journal | vauthors = Heinonen EH, Lammintausta R | title = A review of the pharmacology of selegiline | journal = Acta Neurologica Scandinavica. Supplementum | volume = 136 | issue = | pages = 44–59 | date = 1991 | pmid = 1686954 | doi = 10.1111/j.1600-0404.1991.tb05020.x }} 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.{{cite journal | vauthors = Janssen PA, Leysen JE, Megens AA, Awouters FH | title = Does phenylethylamine act as an endogenous amphetamine in some patients? | journal = Int J Neuropsychopharmacol | volume = 2 | issue = 3 | pages = 229–240 | date = September 1999 | pmid = 11281991 | doi = 10.1017/S1461145799001522 | url = }}{{cite journal | vauthors = Birkmayer W, Riederer P, Linauer W, Knoll J | title = L-deprenyl plus L-phenylalanine in the treatment of depression | journal = J Neural Transm | volume = 59 | issue = 1 | pages = 81–87 | date = 1984 | pmid = 6425455 | doi = 10.1007/BF01249880 | url = }}{{cite journal | vauthors = Sabelli HC | title = Rapid treatment of depression with selegiline-phenylalanine combination | journal = J Clin Psychiatry | volume = 52 | issue = 3 | pages = 137 | date = March 1991 | pmid = 1900832 | doi = | url = https://psycnet.apa.org/record/1991-25376-001}}{{cite journal | vauthors = Sabelli H, Fink P, Fawcett J, Tom C | title = Sustained antidepressant effect of PEA replacement | journal = J Neuropsychiatry Clin Neurosci | volume = 8 | issue = 2 | pages = 168–71 | date = 1996 | pmid = 9081552 | doi = 10.1176/jnp.8.2.168 | url = }} Misuse of phenethylamine in combination with selegiline has also been reported.{{cite journal | vauthors = McKean AJ, Leung JG, Dare FY, Sola CL, Schak KM | title = The Perils of Illegitimate Online Pharmacies: Substance-Induced Panic Attacks and Mood Instability Associated With Selegiline and Phenylethylamine | journal = Psychosomatics | volume = 56 | issue = 5 | pages = 583–587 | date = 2015 | pmid = 26198572 | doi = 10.1016/j.psym.2015.05.003 | url = }}{{cite journal | vauthors = Monteith S, Glenn T, Bauer R, Conell J, Bauer M | title = Availability of prescription drugs for bipolar disorder at online pharmacies | journal = J Affect Disord | volume = 193 | issue = | pages = 59–65 | date = March 2016 | pmid = 26766033 | doi = 10.1016/j.jad.2015.12.043 | url = }}

The {{Abbrlink|LD₅₀|median lethal dose}} values of phenethylamine include 175{{nbsp}}mg/kg i.p. in mice, 320{{nbsp}}mg/kg s.c. in mice, 100{{nbsp}}mg/kg i.v. in mice, 100{{nbsp}}mg/kg parenterally in mice, 39{{nbsp}}mg/kg intracervically in mice, and 200{{nbsp}}mg/kg i.p. in guinea pigs. Its Lethal dose#Lowest lethal dose values include 800{{nbsp}}mg/kg p.o. in rats, 100{{nbsp}}mg/kg i.p. in rats, 450{{nbsp}}μg/kg s.c. in rats, and 300{{nbsp}}mg/kg via an unspecified route in mice.

{{Catecholamine and trace amine biosynthesis|align=right}}

By oral route, phenethylamine's half-life is {{nowrap|5–10}} minutes; endogenously produced PEA in catecholamine neurons has a half-life of roughly 30 seconds. In humans, PEA is metabolized by phenylethanolamine N-methyltransferase (PNMT),{{cite journal | vauthors = Pendleton RG, Gessner G, Sawyer J | title = Studies on lung N-methyltransferases, a pharmacological approach | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 313 | issue = 3 | pages = 263–268 | date = September 1980 | pmid = 7432557 | doi = 10.1007/BF00505743 | s2cid = 1015819 }} monoamine oxidase A ({{nowrap|MAO-A}}), monoamine oxidase B ({{nowrap|MAO-B}}), the semicarbazide-sensitive amine oxidases (SSAOs) AOC2 and AOC3,{{cite journal | vauthors = Kaitaniemi S, Elovaara H, Grön K, Kidron H, Liukkonen J, Salminen T, Salmi M, Jalkanen S, Elima K | title = The unique substrate specificity of human AOC2, a semicarbazide-sensitive amine oxidase | journal = Cellular and Molecular Life Sciences | volume = 66 | issue = 16 | pages = 2743–2757 | date = August 2009 | pmid = 19588076 | doi = 10.1007/s00018-009-0076-5 | quote = 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. | s2cid = 30090890 | pmc = 11115939 }} flavin-containing monooxygenase 3 (FMO3),{{cite journal | vauthors = Krueger SK, Williams DE | title = Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism | journal = Pharmacology & Therapeutics | volume = 106 | issue = 3 | pages = 357–387 | date = June 2005 | pmid = 15922018 | pmc = 1828602 | doi = 10.1016/j.pharmthera.2005.01.001 | quote = 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). }}{{cite journal | vauthors = Robinson-Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J, Yeung CK | title = Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients | journal = PLOS ONE | volume = 11 | issue = 8 | pages = e0161074 | date = August 2016 | pmid = 27513517 | pmc = 4981377 | doi = 10.1371/journal.pone.0161074 | quote = 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]. | doi-access = free | bibcode = 2016PLoSO..1161074R }} and aralkylamine N-acetyltransferase (AANAT).{{cite web|title=EC 2.3.1.87 – Aralkylamine N-acetyltransferase|url=http://www.brenda-enzymes.org/enzyme.php?ecno=2.3.1.87&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0|website=BRENDA|publisher=Technische Universität Braunschweig|access-date=10 November 2014|date=July 2014}} {{nowrap|N-Methylphenethylamine}}, an isomer of amphetamine, is produced in humans via the metabolism of phenethylamine by PNMT. β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism and subsequent aldehyde dehydrogenase metabolism. Phenylacetaldehyde is the intermediate product which is produced by monoamine oxidase and then further metabolized into β-phenylacetic acid by aldehyde dehydrogenase.{{cite web|title=Aldehyde dehydrogenase – Homo sapiens|url=http://www.brenda-enzymes.org/enzyme.php?ecno=1.2.1.3&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0|website=BRENDA|publisher=Technische Universität Braunschweig|access-date=13 April 2015|date=January 2015}}

When the initial phenylethylamine concentration in the brain is low, brain levels can be increased {{nowrap|1000-fold}} when taking a monoamine oxidase inhibitor (MAOI), particularly a MAO-B inhibitor, and by {{nowrap|3–4}} times when the initial concentration is high.{{cite journal | vauthors = Sabelli HC, Borison RL, Diamond BI, Havdala HS, Narasimhachari N | title = Phenylethylamine and brain function | journal = Biochemical Pharmacology | volume = 27 | issue = 13 | pages = 1707–1711 | year = 1978 | pmid = 361043 | doi = 10.1016/0006-2952(78)90543-9 }}

{{clear}}

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.https://caselaw.findlaw.com/court/us-8th-circuit/1155779.htmlhttps://ecf.ca8.uscourts.gov/opndir/00/07/991814U.pdfhttps://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/

{{Reflist|group=note}}

{{Reflist|30em}}

• [http://gmd.mpimp-golm.mpg.de/Spectrums/af2a22f3-4aa9-4e5c-9e61-bf278b87a7c4.aspx Phenethylamine MS Spectrum]
• [https://isomerdesign.com/pihkal/explore/142 PEA (phenethylamine) - isomer design] ([https://isomerdesign.com/pihkal/read/pk/142 PiHKAL entry])

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