MAO-A

MAO-A (monoamine oxidase A) is an enzyme found on the outer membrane of mitochondria throughout the body — in neurons, the gut lining, and the liver. It belongs to a pair of closely related isoforms (MAO-A and MAO-B) that together clear monoamine neurotransmitters after use. MAO-A preferentially degrades serotonin and norepinephrine, and to a lesser degree dopamine and tyramine.

Because it governs how quickly these neurotransmitters are removed, MAO-A functions as a volume control on monoaminergic signalling. It also acts as a first-pass barrier in the gut and liver: most monoamines ingested orally — including some psychoactive compounds — are destroyed there before reaching the bloodstream.

How it works · its role

MAO-A breaks monoamines down through oxidative deamination — removing the amine group to yield an aldehyde, which is then further metabolised and excreted. This happens in neurons after neurotransmitter reuptake and, critically, in the gut wall and liver before a compound enters systemic circulation.

Two classes of drug inhibit it. Irreversible MAOIs permanently disable the enzyme; the body must synthesise new MAO-A — a process taking roughly two weeks — before normal metabolism fully resumes. Reversible inhibitors of MAO-A (RIMAs) bind transiently and can be displaced by competing substrates, giving them a narrower and shorter-lived interaction window.

Relevance to substances & effects

MAO-A inhibition is most widely recognised as the mechanism that makes ayahuasca orally active. DMT — the brew's primary psychedelic compound — is rapidly destroyed by gut MAO-A when taken alone. The harmala alkaloids in the vine component (harmine, harmaline, tetrahydroharmine) reversibly inhibit MAO-A, allowing sufficient DMT to survive digestion and reach the brain.

Irreversible MAOIs such as phenelzine and tranylcypromine were among the earliest antidepressants, elevating synaptic serotonin and norepinephrine by slowing their breakdown. Moclobemide, a RIMA, selectively targets MAO-A with a somewhat narrower interaction profile. Because MAO-A sits at the centre of serotonin clearance, its inhibition is relevant to a wide range of drug interactions.

Clinical · risk note

Inhibiting MAO-A creates two well-characterised risks. The first is serotonin syndrome: combining a MAO-A inhibitor with a serotonin releaser (such as MDMA), a reuptake inhibitor (such as SSRIs or SNRIs), or other serotonergic agents can allow serotonin to accumulate to dangerous levels. Symptoms include agitation, rapid heartbeat, hyperthermia, and muscle rigidity; severe cases are a medical emergency.

The second is the tyramine reaction. MAO-A normally degrades dietary tyramine in the gut; when the enzyme is blocked, tyramine from aged cheese, cured meats, and fermented foods can enter circulation and trigger a sudden, sharp rise in blood pressure. This risk is most pronounced with irreversible MAOIs and is somewhat reduced — though not eliminated — with RIMAs.