Phenylethylamine: from Cacao to the Brain, the Chemistry of Mood

Coming full circle: back to cacao

This series began with theobromine and caffeine, the cacao alkaloids that affect wakefulness. We went through the polyphenols, the fermentation acids and the aroma pyrazines. Then we moved away to glucose, capsaicin, ethanol, citric acid, carotenoids, ATP, vitamin C, cholesterol and water.

We close where we began: with cacao. And with a molecule that links the chemistry of chocolate to something much more personal: mood, euphoria, falling in love.

Phenylethylamine (PEA, 2-phenylethylamine, C₈H₁₁N) is a trace amine found in the human brain as a natural neuromodulator, and also in cacao in small but biologically interesting amounts. It is the molecule behind the claim, chemically imprecise but poetically true, that chocolate "mimics being in love".

Structure: the simplest amine with the richest family tree

Phenylethylamine has an almost minimalist structure: a benzene ring attached to an ethylamine chain (–CH₂–CH₂–NH₂). Molar mass: 121.18 g/mol. It is the simplest biologically active aromatic amine.

What makes this small molecule remarkable is that it is the structural skeleton of a huge family of biologically active compounds:

• Dopamine (adds two –OH groups to the ring: 3,4-dihydroxyphenethylamine)
• Adrenaline (epinephrine) (dopamine + –OH on the chain + N-methyl)
• Noradrenaline (norepinephrine) (dopamine + –OH on the chain)
• Serotonin (indole-ethylamine: a different ring but the same chain)
• Amphetamine (phenylethylamine + a methyl on the α carbon)
• Methamphetamine (amphetamine + N-methyl)
• MDMA (ecstasy) (methamphetamine + methylenedioxy on the ring)
• Mescaline (phenylethylamine + three methoxy groups on the ring)

Phenylethylamine is literally the molecular scaffold on which nature built most monoamine neurotransmitters and many of the most potent psychoactive drugs known. A two-carbon chain and a benzene ring that change everything.

Synthesis in the body: from phenylalanine to PEA

In the human brain, phenylethylamine is made from the amino acid phenylalanine by aromatic L-amino acid decarboxylase (AADC, the same enzyme that makes dopamine and serotonin) in a simple decarboxylation that removes the –COOH group:

L-Phenylalanine → Phenylethylamine + CO₂

This happens mainly in dopamine neurons (with cell bodies in the substantia nigra and ventral tegmental area, and terminals in the striatum and nucleus accumbens). The PEA produced acts as a trace amine, present at concentrations about 1,000 times lower than dopamine or serotonin but biologically active at those tiny levels.

How it works: an amplifier of the catecholamines

Phenylethylamine does not act by binding directly to dopamine or serotonin receptors. Its mechanism is more indirect and resembles that of amphetamine, its structural relative: it enters neurons through the dopamine transporter and makes dopamine and noradrenaline flow out into the synapse. In addition:

It activates TAAR1 receptors (trace amine-associated receptor 1), a family of G-protein-coupled receptors discovered in 2001 that respond specifically to trace amines such as PEA, tyramine and tryptamine. TAAR1 is expressed in dopamine and serotonin neurons of the limbic system.

TAAR1 modulates the monoamine transporters and the activity of those neurons. PEA's net effect is to raise dopamine and noradrenaline in the synapse, not by making more but by releasing the existing stores. In that sense PEA works as an amplifier of the dopamine system.

The result is more dopamine activity in the reward system, heightened alertness, mild euphoria and sharper focus: the neurochemical profile of falling in love, intense exercise and certain states of mental "flow".

PEA in cacao: amounts and bioavailability

Cacao contains phenylethylamine at concentrations on the order of micrograms per gram in fermented, roasted beans, varying with genotype and degree of fermentation (PEA increases during fermentation as bacterial decarboxylases act on phenylalanine).

Here comes the bioavailability problem. Oral phenylethylamine is well absorbed from the gut, but the enzyme MAO-B (monoamine oxidase B) breaks it down extremely fast in both the gut wall and the liver; its half-life in the body is just 5–10 minutes. Its main metabolite, phenylacetic acid, has no activity at TAAR1.

This means that for chocolate's PEA to reach the brain at levels high enough to activate TAAR1, you would have to eat enormous amounts of chocolate, probably more than anyone could enjoy. At dietary doses, MAO-B is an almost insurmountable barrier.

So chocolate doesn't make you fall in love?

The honest answer: not through PEA directly, at least not in the amounts found in chocolate.

But the story does not end there. Chocolate also contains:

• Anandamide (N-arachidonoylethanolamine), the body's own endocannabinoid, again in very small amounts that are probably too low to have an effect of their own. In the brain it activates CB1 receptors, producing relaxation and mild euphoria.
• N-oleoylethanolamine and N-linoleoylethanolamine, inhibitors of FAAH (the enzyme that breaks down the body's own anandamide). Their presence in chocolate could prolong the activity of naturally produced anandamide.
• Theobromine and caffeine (covered in article #01): mild, sustained stimulation.
• Magnesium (~500 mg/100 g in pure cocoa), a cofactor for more than 300 enzymes, including those involved in making serotonin.

The sensory and emotional experience of chocolate comes from this synergy of compounds, not from any single one, and not mainly from PEA. It is a perfect example of how complex foods produce effects that cannot be reduced to one molecule.

PEA, exercise and the "runner's high"

Brain phenylethylamine does seem to play a role in a different setting: intense physical exercise. For decades the "runner's high", the euphoria some runners feel after prolonged exercise, was attributed entirely to beta-endorphins. Today endocannabinoids are thought to play a major role, and PEA may contribute: a 2001 study found that 30 minutes of moderate exercise raised urinary excretion of phenylacetic acid (PEA's metabolite) by 77 % on average.

The current hypothesis is that a combination of endorphins (pain relief), endocannabinoids (euphoria, relaxation) and PEA (dopamine activation, euphoria) produces the neurochemical cocktail of the runner's high. Cacao and exercise, curiously, pull some of the same molecular levers.

PEA deficiency and depression

There is an interesting clinical angle: patients with major depression consistently show lower urinary levels of phenylacetic acid, a sign of lower production or faster breakdown of the body's own PEA. Increased MAO activity has also been reported in the brains of people with depression, which would speed up the breakdown of monoamines, PEA included.

MAO-B inhibitors (such as selegiline, used in Parkinson's disease) raise brain PEA levels and have documented antidepressant effects, although at antidepressant doses selegiline loses its selectivity and the dietary interactions with tyramine appear (another MAO substrate found in aged cheeses, red wine and processed meats).

The TAAR1/PEA pathway is an active target of drug research: several synthetic TAAR1 agonists have been tested in schizophrenia and depression. The most advanced, ulotaront, looked promising in phase II but failed to beat placebo in two phase III trials in 2023, and research continues.

This series of 15 articles has travelled through the chemistry of cacao, from its alkaloids to its aromas, by way of food biochemistry and the fundamental molecules of life. If you want to explore any of the molecules mentioned across these articles, ChemModel's Studio is available, with every molecule just a click away.