Phenethylamine (PEA)[note 1] is anorganic compound,naturalmonoaminealkaloid, andtrace amine, which acts as acentral nervous systemstimulant in humans. In the brain, phenethylamine regulatesmonoamine neurotransmission by binding totrace amine-associated receptor 1 (TAAR1) and inhibitingvesicular monoamine transporter 2 (VMAT2) in monoamineneurons.[1][11][12] To a lesser extent, it also acts as aneurotransmitter in the humancentral nervous system.[13] In mammals, phenethylamineis produced from theamino acidL-phenylalanine by the enzymearomatic L-amino acid decarboxylase viaenzymaticdecarboxylation.[14] In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such aschocolate, especially aftermicrobialfermentation.
Phenethylamine is sold as adietary supplement for purportedmood andweight loss-relatedtherapeutic benefits; however, inorally ingested phenethylamine, a significant amount is metabolized in thesmall intestine bymonoamine oxidase B (MAO-B) and thenaldehyde dehydrogenase (ALDH), which converts it tophenylacetic acid.[5] This means that for significantconcentrations to reach thebrain, the dosage must be higher than for other methods of administration.[5][6][15] Some authors have postulated that phenethylamine plays a role inaffection without substantiating these claims with any direct evidence.[16][17]
Phenethylamines, or more properly,substituted phenethylamines, are the group of phenethylaminederivatives that contain phenethylamine as a "backbone"; in other words, thischemical class includesderivative compounds that are formed by replacing one or more hydrogen atoms in the phenethylamine core structure withsubstituents. The class ofsubstituted phenethylamines includes allsubstituted amphetamines, andsubstituted methylenedioxyphenethylamines (MDxx), and contains many drugs which act asempathogens,stimulants,psychedelics,anorectics,bronchodilators,decongestants, and/orantidepressants, among others.
Phenethylamine is produced by a wide range of species throughout the plant and animal kingdoms, including humans;[14][18] it is also produced by certainfungi andbacteria (genera:Lactobacillus,Clostridium,Pseudomonas and the familyEnterobacteriaceae) and acts as a potentantimicrobial against certain pathogenic strains ofEscherichia coli (e.g., theO157:H7 strain) at sufficient concentrations.[19]
Phenethylamine is a primary amine, the amino-group being attached to abenzene ring through a two-carbon, orethyl group.[10] It is a colourless liquid at room temperature that has a fishy odor, and is soluble in water,ethanol andether.[10] Its density is 0.964 g/ml and its boiling point is 195 °C.[10] Upon exposure to air, it combines withcarbon dioxide to form a solidcarbonatesalt.[20] Phenethylamine is stronglybasic, pKb = 4.17 (or pKa = 9.83), as measured using the HCl salt, and forms a stable crystallinehydrochloride salt with a melting point of 217 °C.[10][21] Its experimentallog P is 1.41.[10]
Substituted phenethylamines are achemical class oforganic compounds based upon the phenethylamine structure;[note 2] the class is composed of all thederivative compounds of phenethylamine which can be formed by replacing, orsubstituting, one or morehydrogen atoms in the phenethylamine core structure withsubstituents.
Many substituted phenethylamines are psychoactive drugs, which belong to a variety of different drug classes, includingcentral 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 andbronchodilators (e.g.,pseudoephedrine),antidepressants (e.g.bupropion),antiparkinson agents (e.g.,selegiline), andvasopressors (e.g.,ephedrine), among others. Many of these psychoactive compounds exert their pharmacological effects primarily by modulatingmonoamine neurotransmitter systems; however, there is no mechanism of action or biological target that is common to all members of this subclass.
Numerousendogenous compounds—includinghormones, monoamine neurotransmitters, and manytrace 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 asMDMA (ecstasy),methamphetamine, andcathinones, are also members of the class. All of thesubstituted amphetamines are phenethylamines, as well.
Pharmaceutical drugs that are substituted phenethylamines includephenelzine,phenformin, andfanetizole, among many others.
TheN-methylated derivative of phenethylamine isN-methylphenethylamine.
Analogues of phenethylamine with theethylamineside chain extended or shortened includephenylpropylamine andbenzylamine. Another related analogue isphenylalaninol.
One method for preparing β-phenethylamine, set forth in J. C. Robinson and H. R. Snyder'sOrganic Syntheses (published 1955), involves the reduction ofbenzyl cyanide withhydrogen in liquidammonia, in the presence of aRaney-Nickelcatalyst, at a temperature of 130 °C and a pressure of 13.8 MPa. Alternative syntheses are outlined in the footnotes to this preparation.[22]
A much more convenient method for the synthesis of β-phenethylamine is the reduction ofω-nitrostyrene bylithium aluminium hydride in ether, whose successful execution was first reported by R. F. Nystrom and W. G. Brown in 1948.[23]
Phenethylamine can also be produced via the cathodic reduction ofbenzyl cyanide in a divided cell.[24]
Assembling phenethylamine structures for synthesis of compounds such as epinephrine, amphetamines, tyrosine, and dopamine by adding the beta-aminoethyl side chain to thephenyl ring is possible. This can be done viaFriedel-Crafts acylation with N-protectedacyl chlorides when the arene is activated, or byHeck reaction of the phenyl with N-vinyloxazolone, followed byhydrogenation, or by cross-coupling with beta-aminoorganozinc reagents, or reacting a brominated arene with beta-aminoethylorganolithium reagents, or bySuzuki cross-coupling.[25]
Reviews that coverattention deficit hyperactivity disorder (ADHD) and phenethylamine indicate that several studies have found abnormally low urinary phenethylamine concentrations in ADHD individuals when compared with controls.[26] In treatment-responsive individuals, amphetamine andmethylphenidate greatly increase urinary phenethylamine concentration.[26] An ADHDbiomarker review also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[26]
Thirty minutes of moderate- to high-intensity physical exercise has been shown to induce an increase in urinaryphenylacetic acid, the primary metabolite of phenethylamine.[3][27][28] Two reviews noted a study where the mean 24 hour urinary phenylacetic acid concentration following just 30 minutes of intense exercise rose 77% above its base level;[3][27][28] the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30 seconds.[3][27][28][4] In a resting state, phenethylamine is synthesized incatecholamine neurons fromL-phenylalanine byaromatic amino acid decarboxylase at approximately the same rate as dopamine is produced.[4] 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, andserotonin, but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate.[14] 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-enhancingeuphoric effects of arunner's high, as both phenethylamine and amphetamine are potenteuphoriants.[3][27][28]
Skydiving has also been shown to induce a marked increase in urinary phenethylamine concentrations.[10][29]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref. |
|---|---|---|---|---|
| Phenethylamine | 10.9 | 39.5 | >10,000 | [30][31][32] |
| Tyramine | 40.6 | 119 | 2,775 | [33][32] |
| Tryptamine | 716 | 164 | 32.6 | [34][35] |
| Dextroamphetamine | 6.6–7.2 | 5.8–24.8 | 698–1,765 | [33][36] |
| Levoamphetamine | 9.5 | 27.7 | ND | [31][32] |
| Dextromethamphetamine | 12.3–13.8 | 8.5–24.5 | 736–1,292 | [33][37] |
| Levomethamphetamine | 28.5 | 416 | 4,640 | [33] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Refs:[38][39] | ||||
 viaAADC  |
Phenethylamine, being similar toamphetamine in its action at their commonbiomolecular targets, is areleasing agent ofnorepinephrine anddopamine.[11][12][42] It is roughlyequipotent to amphetamine in this regardin vitro.[32] Phenethylamine is inactive as apsychostimulant under normal circumstances due to rapidmetabolism bymonoamine oxidase (MAO), but can become active in the presence of amonoamine oxidase inhibitor (MAOI).[32]
Phenethylamine is apotentagonist of the mouse, rat, and humantrace amine-associated receptor 1 (TAAR1).[43][2] β-PEA is also anodorant bindingTAAR4 in mice thought to mediate predator avoidance.[44] Similarly to the case ofamphetamine, phenethylamine shows enhancedlocomotor stimulation, apsychostimulant-like effect, in TAAR1knockout mice.[45]
Phenethylamine is amonoaminergic activity enhancer (MAE) ofserotonin,norepinephrine, anddopamine in addition to its catecholamine-releasing activity.[46][47][48] That is, it enhances theaction potential-mediated release of thesemonoamine neurotransmitters.[46][47][48] The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines.[46][47][48] The MAE actions of phenethylamine and other MAEs may be mediated by TAAR1 agonism.[49][50]Synthetic and morepotent MAEs likephenylpropylaminopentane (PPAP) andselegiline (L-deprenyl) have beenderived from phenethylamine.[46][47]
Unlike its derivativesnorepinephrine (noradrenaline) andepinephrine (adrenaline), phenethylamine is inactive as an agonist of theα- andβ-adrenergic receptors.[51]
According toAlexander Shulgin inPiHKAL, phenethylamine is completely inactive in humans at doses of up to 1,600 mgorally and 50 mgintravenously.[52] This can be attributed to its extremely rapidmetabolic breakdown rather thanpharmacodynamic inactivity.[52]
Althoughexogenous phenethylamine on its own is inactive, its metabolism can be strongly inhibited and it can thereby become active, showingpsychostimulant effects, whencombined with amonoamine oxidase inhibitor (MAOI), specificallymonoamine oxidase B (MAO-B)inhibitors likeselegiline.[53][54] OralL-phenylalanine (aprecursor of phenethylamine) and/or phenethylamine itself in combination with selegiline has been studied in the treatment ofdepression and has been reported to be effective.[46][55][56][57][58]Misuse of phenethylamine in combination with selegiline has also been reported.[59][60]
TheLD50Tooltip median lethal dose 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.[10] ItsLDLo 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.[10]
 |
Byoral route, phenethylamine'shalf-life is5–10 minutes;[10] endogenously produced PEA in catecholamine neurons has a half-life of roughly 30 seconds.[3] In humans, PEA is metabolized byphenylethanolamineN-methyltransferase (PNMT),[3][4][5][64]monoamine oxidase A (MAO-A),[5][6]monoamine oxidase B (MAO-B),[3][4][5][15] thesemicarbazide-sensitive amine oxidases (SSAOs)AOC2 andAOC3,[5][7]flavin-containing monooxygenase 3 (FMO3),[8][9] andaralkylamine N-acetyltransferase (AANAT).[5][65]N-Methylphenethylamine, anisomer ofamphetamine, is produced in humans via the metabolism of phenethylamine by PNMT.[3][4][64]β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced viamonoamine oxidase metabolism and subsequentaldehyde dehydrogenase metabolism.[5]Phenylacetaldehyde is the intermediate product which is produced by monoamine oxidase and then further metabolized into β-phenylacetic acid by aldehyde dehydrogenase.[5][66]
When the initial phenylethylamine concentration in the brain is low, brain levels can be increased1000-fold when taking amonoamine oxidase inhibitor (MAOI), particularly aMAO-B inhibitor, and by3–4 times when the initial concentration is high.[67]
Phenylethylamine is not a scheduled substance in the United States. However, at least one person in the United States has been prosecuted under theFederal Analogue Act for selling phenylethylamine with the prosecutions argument that PEA is a structural analog of amphetamine and methamphetamine.[68][69][70]
Furthermore, evidence has accrued on the ability of TAs to modulate brain reward (i.e., the subjective experience of pleasure) and reinforcement (i.e., the strengthening of a conditioned response by a given stimulus; Greenshaw, 2021), suggesting the involvement of the TAs in the neurological adaptations underlying drug addiction, a chronic relapsing syndrome characterized by compulsive drug taking, inability to control drug intake and dysphoria when access to the drug is prevented (Koob, 2009). Consistent with its hypothesized role as "endogenous amphetamine," β-PEA was shown to possess reinforcing properties, a defining feature that underlies the abuse liability of amphetamine and other psychomotor stimulants. β-PEA was also as effective as amphetamine in its ability to produce conditioned place preference (i.e., the process by which an organism learns an association between drug effects and a particular place or context) in rats (Gilbert and Cooper, 1983) and was readily self-administered by dogs that had a stable history (i.e., consisting of early acquisition and later maintenance) of amphetamine or cocaine self-administration (Risner and Jones, 1977; Shannon and Thompson, 1984). In another study, high concentrations of β-PEA dose-dependently maintained responding in monkeys that were previously trained to self-administer cocaine, and pretreatment with a MAO-B inhibitor, which delayed β-PEA deactivation, further increased response rates (Bergman et al., 2001).
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].
Trace amines are metabolized in the mammalian body via monoamine oxidase
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.
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).
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].
Plasma Pharmacokinetics of PEA Could Be Described By 1st-Order Kinetics With Estimated T/2 of Approx 5-10 Min.
Phenylethylamine (10), amphetamine [AMPH (11 & 12)], methylenedioxy methamphetamine [METH (13)] and N-methyl-4-phenylpyridinium (15) are all more potent inhibitors of VMAT2...
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 andE. coli-contaminated meat pieces at 10°C for one week.
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
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.
It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].
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.
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).
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.
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