IngredientsPhenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. Its systematic IUPAC name is 2-phenylethan-1-amine, and it carries the molecular formula C8H11N. Synonyms and alternate spellings include: phenylethylamine, β-phenylethylamine (β-PEA), 2-phenylethylamine, 1-amino-2-phenylethane, and 2-phenylethan-1-amine.
β-Phenylethylamine is the parent compound of a group of endogenous amines commonly known as trace amines, a name that emphasizes their low plasma and tissue levels relative to those observed for the classical neurotransmitter amines. 2-Phenylethylamine is a water-soluble amine with a fishy odor.
Probably the best representatives of the 2-phenethylamine chemical space are the endogenous catecholamines L-DOPA, dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), biosynthetically produced in cascade from phenylalanine/tyrosine. Thus, PEA itself is the parent scaffold for a very large family of biologically active molecules.
Phenethylamine was first isolated and identified by Marceli Nencki in 1876. 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 via the reduction of benzyl cyanide with sodium in ethanol.
2-Phenylethylamine occurs widely in nature: in animals, plants, fungi, and bacteria alike. Phenethylamine is produced by a wide range of species throughout the plant and animal kingdoms, including humans; it is also produced by certain fungi and bacteria (genera: Lactobacillus, Clostridium, Pseudomonas, and the family Enterobacteriaceae).
Phenethylamine is a chemical that is naturally found in the brain and in a wide range of vegetables, fruits, nuts, and spices. Several studies have shown that PEA is present in cocoa beans and chocolate. PEA can be found naturally in cacao, algae, fungi, and bacteria as well as clover, beans, peas, and some food products such as natto and eggs. Among plant-based concentrated sources, Aphanizomenon flos-aquae (AFA) is a particular strain of blue-green algae that has been found to have many times more PEA than chocolate.
In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. Aromatic amino-acid decarboxylase converts phenylalanine to phenylethylamine — this is the same enzyme that converts phenylalanine into dopamine, and it converts it at a rate comparable to the synthesis of dopamine.
Phenethylamine is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits. On the commercial market it is available primarily as:
It is also sometimes used as a food flavoring. Phenethylamine is naturally found in a wide range of vegetables, fruits, nuts, and spices. Phenethylamine is a food flavoring that is generally recognized as safe (GRAS) by the Food and Drug Administration (FDA) at levels naturally found in or added to foods. The FDA has not reviewed phenethylamine supplements for safety and effectiveness.
PEA as a discrete isolated chemical entity has no ancient or traditional medicinal history in the conventional sense — it was only chemically characterized in the late 19th century. However, several of its richest natural sources do carry documented traditional use.
Theobroma cacao, as well as other Theobroma species, comprises various compounds that have an effect on mood, including PEA. These mood enhancers are thought to confer an energetic and happy feeling and motivation. Cacao was cultivated and consumed ceremonially by Mesoamerican cultures (Olmec, Maya, and Aztec) for millennia, with written records of its use in ritual and elite contexts dating from at least the Classic Maya period. While pre-Columbian users of cacao did not know PEA by name, the compound is now understood to be one of cacao's bioactive constituents. PEA concentrations are especially high in cacao that is well fermented and roasted, and traditionally cacao was always roasted in preparation.
In the 1980s and 1990s, Alexander Shulgin, a biochemist and pharmacologist, reported the synthesis of numerous new psychoactive compounds. This included the 'D series' (e.g., DOC, DOI) and the '2C series' (e.g., 2C-T-7, 2C-T-2) of phenethylamines. Simple variations on the mescaline molecule — a natural phenylethylamine — led to the synthesis of powerful hallucinogenic substances. Mescaline itself (3,4,5-trimethoxyphenethylamine), a naturally occurring PEA derivative found in the peyote cactus (Lophophora williamsii) and San Pedro cactus (Echinopsis pachanoi), has been used ritually in indigenous cultures of North America and the Andes for thousands of years.
The modern scientific investigation of PEA as a neuroactive compound and potential therapeutic agent began in the 1970s, when researchers Sabelli and Mosnaim at the Chicago Medical School formulated the "phenylethylamine hypothesis of affective behavior," connecting PEA levels to mood disorders. Phenethylamine and its derivatives have been studied for their potential stimulant and mood-enhancing effects, tracing back to early research in the mid-20th century.
Phenethylamine (β-PEA) is defined as a trace amine generated by the decarboxylation of the amino acid phenylalanine, functioning as a precursor to various biologically active secondary amines and interacting with specific receptors such as TAAR1.
In humans, PEA is metabolized by phenylethanolamine N-methyltransferase (PNMT), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), the semicarbazide-sensitive amine oxidases (SSAOs) AOC2 and AOC3, flavin-containing monooxygenase 3 (FMO3), and aralkylamine N-acetyltransferase (AANAT). β-Phenylacetic acid is the primary urinary metabolite of phenethylamine and is produced via monoamine oxidase metabolism and subsequent aldehyde dehydrogenase metabolism. N-Methylphenethylamine, an isomer of amphetamine, is produced in humans via the metabolism of phenethylamine by PNMT.
PEA is not retained in neuronal vesicles like dopamine is stored. Instead, monoamine oxidase-B (MAO-B) quickly degrades PEA. This rapid catabolism by MAO-B is a critical pharmacokinetic limitation for oral supplementation (see Section 6).
Trace amines are endogenous molecules that are present in the mammal brain in low concentrations. The trace amines include phenethylamines (phenethylamine, n-methylphenethylamine, phenylethanolamine), m- and p-tyramine, 3-methoxytyramine, n-methyltyramine, m- and p-octopamine, synephrine, and tryptamine.
The human trace amine-associated receptor 1 (hTAAR1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. hTAAR1 has emerged in the past 15 years as a key modulator in monoaminergic neurotransmission as a rheostatic feedback mechanism. Shortly after its initial cloning and confirmation as a high-affinity receptor for the trace amines β-phenethylamine (β-PEA) and tyramine, reports of micromolar potency of amphetamine and methamphetamine at TAAR1, as well as its localization in several monoaminergic nuclei, suggested that it may play a key role in mediating the effects of amphetamine-type psychostimulants.
In vitro, TAAR1 is activated with nanomolar to micromolar affinity by some endogenous amines, particularly p-tyramine, beta-phenylethylamine, and 3-iodothyronamine (T1AM), the latter representing a novel branch of thyroid hormone signaling.
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. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system.
Trace amines have well-characterized presynaptic amphetamine-like effects on monoamine neurons via TAAR1 activation; specifically, by activating TAAR1 in neurons they promote the release and prevent reuptake of monoamine neurotransmitters from the synaptic cleft as well as inhibit neuronal firing.
TAAR1 mRNA and protein expression is enriched in the limbic system and in brain areas associated with the major aminergic pathways, including ascending dopaminergic and serotonergic projections. The distribution of TAAR1 is predominantly intracellular, with diffuse expression within the perikaryon and axonal processes and sparse membrane-bound localization at synaptic sites, thus being uniquely positioned to regulate aminergic activity.
Previous in vitro and in vivo evidence suggests that TAAR1 stimulation exerts inhibitory control over monoaminergic neurotransmission. Indeed, transgenic mice lacking Taar1 exhibited a markedly elevated discharge rate of dopamine and serotonin neurons in the midbrain, and increased DA transmission in the nucleus accumbens.
In studies using MAO-B knockout mice, only PEA levels were markedly elevated in the paraventricular thalamic nucleus of Maob KO mice, confirming MAO-B as the primary enzyme responsible for PEA degradation in the central nervous system.
PEA primarily demonstrates a high affinity for TAAR1, which is a G-protein coupled receptor identified in 2001. Taar1 mRNA is expressed in monoaminergic nuclei such as the VTA and dorsal raphe, and TAAR1 activation can modulate monoaminergic neural activity and animal behavior.
A 2020 preclinical study published on PubMed Central demonstrated an additional antidepressant-related mechanism: PEA exerts antidepressant effects by modulating the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element binding protein (CREB) signaling pathway. Treatment with CORT (corticosterone) altered dendritic spine architecture; however, treatment with PEA rescued dendritic spine formation via regulation of BDNF/TrkB/CREB signaling. This finding was derived from cell culture and mouse models and has not yet been replicated in human studies.
2-Phenylethylamine is a central nervous system stimulant and is related to many psychoactive compounds such as the amphetamines and catecholamines. While not trace amines themselves, the classical monoamines norepinephrine, serotonin, and histamine are all partial agonists at the human TAAR1 receptor; dopamine is a high-affinity agonist at human TAAR1.
The most developed clinical hypothesis concerning PEA is its postulated role in depression. Sabelli and Mosnaim (1974) presented experimental evidence to support the hypothesis that PEA and its metabolites modulate affective behavior. Values for the urinary excretion of PEA were lower for 71 percent of a group of depressed patients than the lowest values obtained from control subjects, which suggests that a large percentage of endogenous depressions may be due to a deficit of PEA in the brain.
The monoamine oxidase B (MAO-B) enzyme in the body selectively metabolizes phenylethylamine to phenylacetic acid, and it has been reported that the concentration of phenylacetic acid is significantly reduced in the urine, plasma, and cerebrospinal fluid of depressed patients.
The most frequently cited clinical intervention study in this area is an open-label trial by Sabelli et al. (1996): Phenylethylamine (PEA), an endogenous neuroamine, increases attention and activity in animals and has been shown to relieve depression in 60% of depressed patients. It has been proposed that PEA deficit may be the cause of a common form of depressive illness. Fourteen patients with major depressive episodes that responded to PEA treatment (10–60 mg orally per day, with 10 mg/day selegiline to prevent rapid PEA destruction) were reexamined 20 to 50 weeks later. The antidepressant response had been maintained in 12 patients. Effective dosage did not change with time. There were no apparent side effects.
Evidence assessment: These data are drawn from small, open-label, uncontrolled trials. No adequately powered, double-blind, placebo-controlled randomized controlled trial (RCT) of PEA for depression has been published to date. The evidence must therefore be characterized as preliminary and insufficient to draw firm clinical conclusions.
Corticosterone increases depression-like behavior, with some effects on anxiety-like behavior. PEA is a monoamine alkaloid that acts as a central nervous system stimulant in humans. Animal and cell studies show that PEA exerts antidepressant effects by modulating the BDNF/TrkB/CREB signaling pathway in corticosterone-induced depression. These preclinical findings support the mechanistic plausibility but do not substitute for human clinical evidence.
Trace aminergic hypofunction is particularly relevant to ADHD, since urinary and plasma phenethylamine concentrations are significantly lower in individuals with ADHD relative to controls, and the two most commonly prescribed drugs for ADHD, amphetamine and methylphenidate, increase phenethylamine biosynthesis in treatment-responsive individuals with ADHD. A systematic review of ADHD biomarkers also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.
Reviews that cover 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.
Evidence assessment: The current evidence is predominantly observational and biomarker-based. There are no published, adequately powered RCTs of PEA supplementation as a direct treatment for ADHD. The observation that standard ADHD medications normalize PEA levels does not establish that exogenous PEA supplementation would replicate their benefits. Evidence is indirect and preliminary.
It was suspected that an endorphin-like substance, phenylethylamine, might be responsible for the well-being associated with exercise. On non-exercising days, urine samples were tested for phenylacetic acid, a by-product of phenylethylamine turnover. Urine samples were again collected after treadmill exercise in which heart rate had climbed to at least 70% of maximal heart rate capacity. Phenylacetic acid levels increased by approximately 77% after exercise.
Urinary concentrations of phenylacetic acid are increased following exercise, suggesting that phenylethylamine may be involved in the "runner's high," the state of euphoria associated with a level of physical exercise.
A small human study at Nottingham Trent University provided additional detail: The Nottingham Trent University research team studied 20 healthy young men. The men had their PEA levels measured after one day of no exercise and after one day of moderate exercise (30 minutes on a treadmill at 70% of their maximum heart rate). All but 2 of the men had increased PEA levels 24 hours after their exercise. The amount of PEA increase varied from person to person. Only 3 of the men rated the exercise as "hard," and two of these men had the greatest increase in PEA.
Evidence assessment: The association between exercise and elevated urinary PEA metabolites is consistent across small studies, but whether administering exogenous PEA supplements replicates the exercise-induced mood benefit has not been directly tested in clinical trials. Evidence is mechanistically plausible but not clinically established.
A study examining urinary PEA in healthy volunteers measured PEA using the Minnesota Multiphasic Personality Inventory (MMPI): In the female subgroup, a significant positive correlation between PEA and hypomania (rs = .50; p < .05) and a significant negative correlation between PEA and depression (rs = −.65; p < .01) was found, supporting the phenylethylamine hypothesis. Furthermore, PEA correlated significantly negatively with hypochondriasis (rs = −.58; p < .01), paranoia (rs = −.49; p < .05), and social introversion (rs = −.60; p < .05).
Evidence assessment: Correlational data from observational studies. Causality cannot be inferred from urinary PEA biomarker levels alone.
Elevated PEA has been investigated in the context of psychotic disorders. Research referenced in the literature has found elevated urinary PEA in some patients with paranoid schizophrenia and overproduction in aggressive psychopaths (Potkin et al., 1979; Sandler et al., 1978, as cited in published pharmacological reviews). A recent study reported that a TAAR1 agonist showed significant therapeutic effects in patients with schizophrenia. The putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.
Evidence assessment: The relationship between PEA and schizophrenia is bidirectional and complex. TAAR1 agonists are an active area of pharmaceutical development for schizophrenia, but this is distinct from PEA supplementation. Exogenous PEA supplementation in individuals with psychosis carries risk (see Section 7).
Research has found fluctuating PEA levels in bipolar patients. As noted in the literature (Semba et al., 1988, cited in peer-reviewed reviews), there have been observations of increases in urinary β-phenylethylamine preceding the switch from mania to depression in a rapid-cycling patient. Use of phenethylamine might cause people with bipolar disorder to convert from depression to mania. This concern is based on the stimulant-like, dopamine-amplifying properties of PEA.
Evidence assessment: Evidence for PEA as a treatment in bipolar disorder is absent. The association between elevated PEA and mania is a concern rather than a therapeutic target.
β-Phenylethylamine provides the basic chemical structure for an extensive number of endogenous and exogenous bioactive compounds. Many are already used for their medicinal effects, and others consumed for recreational purposes or advertised as weight-loss adjuvants, memory, and general performance enhancers.
Pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function.
Evidence assessment: Claims regarding cognitive enhancement by PEA supplementation in healthy humans are currently unsupported by controlled clinical evidence. Mechanistic plausibility exists from animal and in vitro data, but direct human trial data are lacking.
PEA's primary documented physiological role is in the CNS. Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. Its modulation of dopaminergic, serotonergic, and noradrenergic pathways via TAAR1 means it is conceptually linked to mood regulation, arousal, attention, and reward processing.
Dietary supplements usually contain much higher doses of phenethylamine that can have effects on the brain and heart. At these higher doses, phenethylamine can act like a stimulant and may also copy the effects of some important brain chemicals, such as dopamine and serotonin. The sympathomimetic properties of PEA mean it can elevate heart rate and blood pressure, particularly at supplemental doses.
PEA could be a valuable neuromodulator that reflects external and internal environments, such as diet and gut microbiota, and MAO-B could be a regulator of this PEA signaling.
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. This extensive first-pass intestinal metabolism is the primary reason oral PEA has low CNS bioavailability.
The amounts that are naturally found in foods or added to foods are very small and are not thought to cause any health effects. Dietary supplements, on the other hand, usually contain much higher doses of phenethylamine that can have effects on the brain and heart.
The most specific dosage data from a published clinical study is from the Sabelli et al. (1996) open-label antidepressant trial: patients were treated with 10–60 mg orally per day, with 10 mg/day selegiline to prevent rapid PEA destruction. This study represents the only published human clinical dosage range from a peer-reviewed source.
Phenethylamine is sold as a dietary supplement; however, in orally ingested phenethylamine, a significant amount is metabolized in the small intestine by MAO-B and then aldehyde dehydrogenase. This means that for significant concentrations to reach the brain, the dosage must be higher than for other methods of administration.
The appropriate dose of phenethylamine depends on several factors such as the user's age, health, and several other conditions. At this time there is not enough scientific information to determine an appropriate range of doses for phenethylamine.
Common side effects may include headache, dizziness, nervousness, irritability, fast heartbeat, and trouble sleeping. Serious side effects may include heart effects, behavior changes, and mood changes.
Phenethylamine supplements can have stimulant-like effects, especially with higher doses. This may cause or worsen psychotic-like behaviors, such as hallucinations or mania. People who already have a mental health condition, such as bipolar disorder, may be at higher risk of these side effects.
Use of phenethylamine might worsen symptoms of schizophrenia, including hallucinations or delusions. Use of phenethylamine might cause people with bipolar disorder to convert from depression to mania.
People with a disorder like phenylketonuria (PKU) that cause the body to store excess phenylalanine should avoid PEA. These disorders prevent the metabolism of phenylalanine in the body, which can lead to negative side effects, such as severe headaches and hypertension, or even psychosis.
The interaction between PEA and MAO inhibitors is the most clinically significant pharmacological concern. The drug-drug interactions between oral sympathomimetic amines and monoamine oxidase (MAO) inhibitors have been well studied in the literature. The most common adverse effect is high blood pressure. Other adverse effects include headache, chest pain, cardiac arrhythmias, and circulatory insufficiency. MAO inhibitors inhibit presystemic and systemic metabolism of some sympathomimetic amines, which are substrates for MAO, resulting in elevated levels of these sympathomimetic amines in circulation.
While the clinical studies of Sabelli et al. combined PEA with selegiline (a selective MAO-B inhibitor) deliberately to extend PEA's half-life for a therapeutic purpose, certain foods and beverages contain high levels of pharmacologically active substances such as tyramine that normally undergoes inactivation by MAO-A in the gut. Consuming certain cheeses rich in tyramine can provoke a dangerous hypertensive crisis in people treated with irreversible MAO inhibitors, known as the "cheese effect." The same mechanism applies to exogenous PEA combined with nonselective or broad MAO inhibitors.
Phenethylamine is cleared from the body by a certain protein. Desipramine (Norpramin) can affect how quickly this protein clears phenethylamine. Taking phenethylamine along with desipramine might increase the levels and the effects of phenethylamine. This might cause too much serotonin in the brain and could result in serious side effects including heart problems, shivering, and anxiety.
Regulatory and analytical investigations have highlighted phenethylamine in some weight loss and performance supplements as a compound with amphetamine-like effects and potential cardiovascular toxicity, especially when combined with caffeine and other stimulants.
Phenethylamine is a food flavoring that is generally recognized as safe (GRAS) by the FDA at food-level quantities. The FDA has not reviewed phenethylamine supplements for safety and effectiveness. Separate from PEA itself, due to the public health risks associated with BMPEA (beta-methylphenethylamine), this compound has been banned by the FDA of the United States, and dietary products containing this compound are prohibited from sale. Phenylethylamine itself 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 prosecution's argument that PEA is a structural analog of amphetamine and methamphetamine.
The US FDA has issued warnings to supplement manufacturers that their products contained forms of phenethylamines called beta-methylphenethylamine (BMPEA).
Phenethylamine and its derivatives are classified as stimulants under the World Anti-Doping Agency's (WADA) Prohibited List.
Phenethylamine might affect the central nervous system. This could interfere with surgery. Stopping phenethylamine at least 2 weeks before a scheduled surgery is advised.
PEA is a well-characterized endogenous trace amine with a clearly elucidated biochemical role as a TAAR1 agonist and monoamine neuromodulator. Its relationship to mood, ADHD biomarkers, and exercise-related affect is supported by consistent observational and mechanistic data. However, phenethylamine (PEA) supplements are commonly used to increase energy levels and improve physical performance and thinking skills; however, the benefits of phenethylamine for any use are not well defined. The principal obstacle to oral PEA supplementation is its extremely rapid first-pass degradation by intestinal and hepatic MAO-B. A significant amount is metabolized in the small intestine, meaning that for significant concentrations to reach the brain, the dosage must be higher than for other methods of administration. Clinical research is sparse, predominantly composed of small, open-label studies, and no adequately powered randomized controlled trials have been conducted to date for any of the proposed applications. The overall body of clinical evidence must be considered insufficient and preliminary across all areas of purported use.
Health conditions that Phenethylamine may help support.
Body systems that Phenethylamine may help support.
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