monoamine oxidase

Monoamine oxidase (MAO) is an enzyme responsible for breaking down monoamine neurotransmitters — principally serotonin, dopamine, and norepinephrine — once they have been used. It acts as a chemical disposal system, keeping neurotransmitter levels from climbing unchecked between signals.

Two distinct isoforms exist: MAO-A preferentially degrades serotonin, norepinephrine, and tyramine; MAO-B preferentially degrades dopamine and phenethylamine. Both sit on the outer membrane of mitochondria and are found throughout the brain, gut wall, and liver.

Because MAO sets the baseline clearance rate for several key neurotransmitters, blocking it — with a class of drugs called monoamine oxidase inhibitors, or MAOIs — has outsized effects on mood, energy, and perception, and introduces some of the most significant drug-interaction risks in psychopharmacology.

How it works · its role

MAO breaks down its target molecules through oxidative deamination: it strips an amine group from the neurotransmitter, converting it into an inactive aldehyde that is then cleared by the body. This happens continuously in synapses and in the gut wall, where MAO-A in particular metabolises dietary amines such as tyramine before they reach circulation.

When MAO is inhibited, neurotransmitters that would normally be cleared instead accumulate. The effect is not immediate: irreversible MAOIs permanently disable the enzyme, and full activity only returns as the body synthesises fresh MAO — a process that can take two weeks or more. Reversible inhibitors (sometimes called RIMAs) bind temporarily, with activity recovering in hours rather than weeks.

Relevance to substances & effects

MAOIs were among the first antidepressants discovered and are still prescribed for treatment-resistant depression, with MAO-B selective inhibitors also used in Parkinson's disease to slow dopamine breakdown.

In the context of psychoactive substances, MAO inhibition is most directly relevant to ayahuasca. The brew combines DMT-containing plant material with plants rich in harmala alkaloids — reversible MAO-A inhibitors — that prevent the gut and liver from degrading DMT before it reaches the brain. Without that inhibition, orally consumed DMT is inactive.

Stimulants such as amphetamines also interact with MAO pathways, since MAO contributes to their metabolism and to the breakdown of dopamine and norepinephrine they release. Combining stimulants with MAOIs is associated with greatly amplified and unpredictable effects.

Clinical · risk note

MAOIs carry two well-established interaction risks that are relevant to harm reduction.

The first is the tyramine reaction. MAO-A in the gut wall normally breaks down tyramine found in aged cheeses, cured meats, and fermented foods. When MAO-A is inhibited, dietary tyramine passes into the bloodstream and triggers the release of norepinephrine, potentially causing a sudden, severe rise in blood pressure. This is sometimes called the cheese effect and can be a medical emergency.

The second is serotonin syndrome. Combining an MAOI with any other serotonergic drug — including MDMA, most antidepressants, opioids such as tramadol or meperidine, or even some over-the-counter cough suppressants — can push serotonin to dangerous levels. Symptoms range from agitation and rapid heartbeat to muscle rigidity and dangerously elevated body temperature.

Because irreversible MAOIs remain active for up to two weeks after the last dose, these interactions can occur well after someone has stopped taking the drug. Both risks apply to plant-based MAOIs, such as the harmala alkaloids in ayahuasca, as well as to pharmaceutical ones.