Phenethylamine

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Moderate (with an MAO-B inhibitor)<ref name="TAAR1 and TA pharmacology 2016 review"/>Psychological: low–moderateTemplate:Citation needed
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Phenethylamine<ref group="note">Synonyms and alternate spellings include: phenylethylamine, β-phenylethylamine (Template:Nowrap), 2-phenylethylamine, Template:Nowrap, and Template:Nowrap.</ref> (PEA) 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.<ref name="TAAR1 and TA pharmacology 2016 review" /><ref name="PEA VMAT2 MEDRS review" /><ref name="Miller" /> To a lesser extent, it also acts as a neurotransmitter in the human central nervous system.<ref name="PEA 2">Template:Cite journal</ref> In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation.<ref name="Berry_2004">Template:Cite journal</ref> 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.<ref name="HMDB PEA">Template:Cite HMDB</ref> This means that for significant concentrations to reach the brain, the dosage must be higher than for other methods of administration.<ref name="HMDB PEA"/><ref name="PEA_MAO-A_and_B_Substrate-Suzuki">Template:Cite journal</ref><ref name="PEA_MAO-B_Substrate-Yang">Template:Cite journal</ref> Some authors have postulated that phenethylamine plays a role in affection without substantiating these claims with any direct evidence.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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;<ref name="Berry_2004" /><ref>Template:Cite journal</ref> 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.<ref name="pmid23896151">Template:Cite journal</ref>

Chemistry

Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group.<ref name="PubChem">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is a colourless liquid at room temperature that has a fishy odor, and is soluble in water, ethanol and ether.<ref name="PubChem" /> Its density is 0.964 g/ml and its boiling point is 195 °C.<ref name="PubChem" /> Upon exposure to air, it combines with carbon dioxide to form a solid carbonate salt.<ref name=Merck>Template:Cite book</ref> 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.<ref name="PubChem" /><ref>Template:Cite journal</ref> Its experimental log P is 1.41.<ref name="PubChem" />

Substituted derivatives

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Substituted phenethylamines are a chemical class of organic compounds based upon the phenethylamine structure;<ref group="note">In other words, all of the compounds that belong to this class are structural analogs of phenethylamine.</ref> 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 compoundsTemplate:Mdashincluding hormones, monoamine neurotransmitters, and many trace amines (e.g., dopamine, norepinephrine, adrenaline, tyramine, and others)Template:Mdashare 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

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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Phenethylamine can also be produced via the cathodic reduction of benzyl cyanide in a divided cell.<ref name="Shamelessly stolen from the Electrosynthesis article">Template:Cite journal</ref>

File:Benzyl cyanide electrolytic reduction.png

Electrosynthesis of phenethylamine from benzyl cyanide<ref name="Shamelessly stolen from the Electrosynthesis article"/>

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.<ref>Template:Cite journal</ref>

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.<ref name="Zinc and PEA"/> In treatment-responsive individuals, amphetamine and methylphenidate greatly increase urinary phenethylamine concentration.<ref name="Zinc and PEA">Template:Cite journal</ref> An ADHD biomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.<ref name="Zinc and PEA"/>

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.<ref name="Renaissance">Template:Cite journal</ref><ref name="PEA exercise primary">Template:Cite journal</ref><ref name="Neuropsychiatric">Template:Cite journal</ref> 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;<ref name="Renaissance"/><ref name="PEA exercise primary"/><ref name="Neuropsychiatric"/> 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.<ref name="Renaissance"/><ref name="PEA exercise primary"/><ref name="Neuropsychiatric"/><ref name="Vascular"/> In a resting state, phenethylamine is synthesized in catecholamine neurons from Template:Smallcaps all-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate as dopamine is produced.<ref name="Vascular">Template:Cite journal</ref> 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.<ref name="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. 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.<ref name="Renaissance"/><ref name="PEA exercise primary"/><ref name="Neuropsychiatric"/>

Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.<ref name="PubChem" /><ref name="Skydiving">Template:Cite journal</ref>

Biological activity

Template:Nowrap

Compound	Template:Abbrlink	Template:Abbrlink	Template:Abbrlink	Ref
Phenethylamine	10.9	39.5	>10,000	<ref name="ReithBLoughHong2015">Template:Cite journal</ref><ref name="Forsyth2012" /><ref name="Blough2008" />
Tyramine	40.6	119	2,775	<ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" />
Tryptamine	716	164	32.6	<ref name="BloughLandavazoDecker2014">Template:Cite journal</ref><ref name="BloughLandavazoPartilla2014">Template:Cite journal</ref>
Dextroamphetamine	6.6–7.2	5.8–24.8	698–1,765	<ref name="RothmanBaumannDersch2001">Template:Cite journal</ref><ref name="BaumannPartillaLehner2013">Template:Cite journal</ref>
Levoamphetamine	9.5	27.7	Template:Abbr	citation	CitationClass=web }}</ref><ref name="Blough2008">Template:Cite book</ref>
Dextromethamphetamine	12.3–13.8	8.5–24.5	736–1,292	<ref name="RothmanBaumannDersch2001" /><ref name="BaumannAyestasPartilla2012">Template:Cite journal</ref>
Levomethamphetamine	28.5	416	4,640	<ref name="RothmanBaumannDersch2001" />
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: <ref name="RothmanBaumann2003">Template:Cite journal</ref><ref name="RothmanBaumann2006">Template:Cite journal</ref>

Monoamine releasing agent

Phenethylamine, being similar to amphetamine in its action at their common biomolecular targets, is a releasing agent of norepinephrine and dopamine.<ref name="PEA VMAT2 MEDRS review"/><ref name="Miller"/><ref name="Cites Miller 2011 review"/> It is roughly equipotent to amphetamine in this regard in vitro.<ref name="Blough2008" /> 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).<ref name="Blough2008" />

TAAR1 agonist

Phenethylamine is a potent agonist of the mouse, rat, and human trace amine-associated receptor 1 (TAAR1).<ref name="GainetdinovHoenerBerry2018">Template:Cite journal</ref><ref name="Human trace amines and hTAARs October 2016 review">Template:Cite journal</ref> β-PEA is also an odorant binding TAAR4 in mice thought to mediate predator avoidance.<ref name="Liberles_2015">Template:Cite journal</ref> Similarly to the case of amphetamine, phenethylamine shows enhanced locomotor stimulation, a psychostimulant-like effect, in TAAR1 knockout mice.<ref name="WolinskySwansonSmith2007">Template:Cite journal</ref>

Monoaminergic activity enhancer

Phenethylamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its catecholamine-releasing activity.<ref name="ShimazuMiklya2004">Template:Cite journal</ref><ref name="Knoll2003">Template:Cite journal</ref><ref name="KnollMiklyaKnoll1996">Template:Cite journal</ref> That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /><ref name="KnollMiklyaKnoll1996" /> The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /><ref name="KnollMiklyaKnoll1996" /> The MAE actions of phenethylamine and other MAEs may be mediated by TAAR1 agonism.<ref name="HarsingKnollMiklya2022">Template:Cite journal</ref><ref name="HarsingTimarMiklya2023">Template:Cite journal</ref> Synthetic and more potent MAEs like phenylpropylaminopentane (PPAP) and selegiline (L-deprenyl) have been derived from phenethylamine.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" />

Other activities

Unlike its derivatives norepinephrine (noradrenaline) and epinephrine (adrenaline), phenethylamine is inactive as an agonist of the α- and β-adrenergic receptors.<ref name="PinckaersBlankesteijnMircheva2024">Template:Cite journal</ref>

Effects in animals and humans

According to Alexander Shulgin in PiHKAL, phenethylamine is completely inactive in humans at doses of up to 1,600Template:Nbspmg orally and 50Template:Nbspmg intravenously.<ref name="PiHKAL">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This can be attributed to its extremely rapid metabolic breakdown rather than pharmacodynamic inactivity.<ref name="PiHKAL" />

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.<ref name="YasarGoldbergGoldberg1996">Template:Cite book</ref><ref name="HeinonenLammintausta1991">Template:Cite journal</ref> 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.<ref name="ShimazuMiklya2004" /><ref name="JanssenLeysenMegens1999">Template:Cite journal</ref><ref name="BirkmayerRiedererLinauer1984">Template:Cite journal</ref><ref name="Sabelli1991">Template:Cite journal</ref><ref name="SabelliFinkFawcett1996">Template:Cite journal</ref> Misuse of phenethylamine in combination with selegiline has also been reported.<ref name="McKeanLeungDare2015">Template:Cite journal</ref><ref name="MonteithGlennBauer2016">Template:Cite journal</ref>

The Template:Abbrlink values of phenethylamine include 175Template:Nbspmg/kg i.p. in mice, 320Template:Nbspmg/kg s.c. in mice, 100Template:Nbspmg/kg i.v. in mice, 100Template:Nbspmg/kg parenterally in mice, 39Template:Nbspmg/kg intracervically in mice, and 200Template:Nbspmg/kg i.p. in guinea pigs.<ref name="PubChem" /> Its [[Lethal dose#Lowest lethal dose|Template:Abbr]] values include 800Template:Nbspmg/kg p.o. in rats, 100Template:Nbspmg/kg i.p. in rats, 450Template:Nbspμg/kg s.c. in rats, and 300Template:Nbspmg/kg via an unspecified route in mice.<ref name="PubChem" />

Pharmacokinetics

Template:Catecholamine and trace amine biosynthesis By oral route, phenethylamine's half-life is Template:Nowrap minutes;<ref name="PubChem" /> endogenously produced PEA in catecholamine neurons has a half-life of roughly 30 seconds.<ref name="Renaissance"/> In humans, PEA is metabolized by phenylethanolamine N-methyltransferase (PNMT),<ref name="Renaissance"/><ref name="Vascular"/><ref name="HMDB PEA"/><ref name="pmid7432557">Template:Cite journal</ref> monoamine oxidase A (Template:Nowrap),<ref name="HMDB PEA"/><ref name="PEA_MAO-A_and_B_Substrate-Suzuki"/> monoamine oxidase B (Template:Nowrap),<ref name="Renaissance"/><ref name="Vascular"/><ref name="HMDB PEA"/><ref name="PEA_MAO-B_Substrate-Yang"/> the semicarbazide-sensitive amine oxidases (SSAOs) AOC2 and AOC3,<ref name="HMDB PEA"/><ref name="SSAO">Template:Cite journal</ref> flavin-containing monooxygenase 3 (FMO3),<ref name="FMO">Template:Cite journal</ref><ref name="FMO3 catecholamines">Template:Cite journal</ref> and aralkylamine N-acetyltransferase (AANAT).<ref name="HMDB PEA"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:Nowrap, an isomer of amphetamine, is produced in humans via the metabolism of phenethylamine by PNMT.<ref name="Renaissance"/><ref name="Vascular"/><ref name="pmid7432557"/> β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism and subsequent aldehyde dehydrogenase metabolism.<ref name="HMDB PEA"/> Phenylacetaldehyde is the intermediate product which is produced by monoamine oxidase and then further metabolized into β-phenylacetic acid by aldehyde dehydrogenase.<ref name="HMDB PEA"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

When the initial phenylethylamine concentration in the brain is low, brain levels can be increased Template:Nowrap when taking a monoamine oxidase inhibitor (MAOI), particularly a MAO-B inhibitor, and by Template:Nowrap times when the initial concentration is high.<ref name=Sabelli78>Template:Cite journal</ref>

Legality

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite court</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

External links

• Phenethylamine MS Spectrum
• PEA (phenethylamine) - isomer design (PiHKAL entry)