MAO-A and MAO-B: Neurotransmitter levels, genetics, and warrior gene studies

Key takeaways:
~ Monoamine oxidase (MAO) enzymes break down neurotransmitters, regulating the levels of dopamine, serotonin, and more.
~ Higher or lower MAO enzyme levels can affect mood by altering neurotransmitter levels.
~ Genetic variants in the MAOA and MAOB genes can increase the risk of mood disorders or aggression, under some circumstances.
~ There are natural supplements that affect MAO-A and MAO-B levels.

What is the MAO enzyme?

MAO, or monoamine oxidase, is an enzyme that breaks down neurotransmitters. There are two slightly different forms of MAO, MAO-A and MAO-B.

Specifically, monoamine oxidase (MAO) enzymes break down monoamine neurotransmitters – including serotonin, dopamine, and norepinephrine.[ref][ref]

The two enzymes differ a bit in their affinity for different monoamines.

• MAO-A preferentially breaks down norepinephrine, serotonin, epinephrine (adrenaline), melatonin, dopamine, kynuramine, tyramine, and tryptamine.
• MAO-B breaks down dopamine, 3-iodothyronamine, β– Phenylethylamine, kynuramine, and tyramine.

In addition to their roles in neurotransmitter metabolism, MAOs are also involved in the metabolism of certain drugs and biogenic amines. (More on this below in the Parkinson’s section.)

The monoamine oxidases are produced by cells in the brain, as well as throughout the body.

There are a couple of differences in the tissue distribution of the MAOs. MAO-A is most abundant in the heart muscle, platelets, gastrointestinal tract, and specific neurons in the brain.

In the brain, MAO-B is primarily found on the mitochondrial membranes in the astrocytes and specific types of neurons. MAO-B is also found in the heart, intestines, kidneys, and blood vessels.[ref][ref][ref]

MAOs in the Brain:

Neurotransmitter levels are tightly controlled in the brain. You want everything in balance, with neurons firing appropriately.

Neurons release neurotransmitters into the synapse — the area between the terminal of one neurotransmitter and the receptors on the dendrites for the next neuron. Neurotransmitters are the chemical signals that pass the message from one neuron to the next.

The MAO enzymes play an essential role in maintaining the appropriate amount of dopamine, serotonin, norepinephrine, and epinephrine. By breaking down the neurotransmitter, MAO prevents too much of the neurotransmitter from hanging around. Dopamine, for example, will cause damage and kill neurons when in excess.

MAO-A is found in the pre-synaptic neurons, controlling how much dopamine, norepinephrine, or serotonin is available to be released.

The MAO-B enzyme is expressed throughout the regions of the brain, primarily in astrocytes but also on the mitochondrial membrane in serotonergic neurons. Astrocytes are a type of brain cell that helps neurons function in a couple of ways, one of which is by clearing excess neurotransmitters.

In the process of metabolizing neurotransmitters, MAO-B uses FAD (derived from riboflavin) and produces hydrogen peroxide.[ref] Excess hydrogen peroxide causes oxidative stress, so MAO-B needs to be maintained at the right levels. More on this in a minute.

Other ways of balancing neurotransmitters:

Before we go any further, I wanted to point out that the MAO enzymes are just one way that serotonin, dopamine, epinephrine, and norepinephrine can be broken down. Other enzymes and pathways also influence the levels of monoamine neurotransmitters.

MAO and Mental Health:

The relationship between MAO levels and mental health is complex.

Imbalanced or rapidly changing neurotransmitter levels can lead to changes in mood and behavior.

Low levels of MAO have been linked to an increased risk for certain mental health conditions such as depression, aggression, and impulsive behavior. It is thought to be related to the role of MAO-A in regulating neurotransmitter levels in the brain. When MAO-A levels are low, neurotransmitters such as serotonin and dopamine may build up in the brain, which can lead to changes in mood and behavior.

On the other hand, studies have shown that individuals with genetically higher levels of MAOA may have a reduced risk for certain mental health conditions. Higher levels of MAOA could decrease neurotransmitter levels to maintain balanced levels of these chemicals in the brain.[ref]

The MAO-A variants can interact with environmental factors to influence mental health. For example, childhood trauma, stress, and exposure to toxins can affect the expression of the MAOA gene, leading to changes in MAO-A levels.[ref]

During childhood and early adolescence, brain structures are rapidly developing. Researchers have found that traumatic events, such as physical or sexual abuse, during childhood can affect adult brain function in some people. The MAO-A genetic variants are linked to an increased risk of aggressive behavior in men exposed to childhood trauma.[ref]

One study found that low MAO-A levels combined with childhood trauma, increased the risk of higher aggression scores in men.[ref]

Stress, Cortisol, and MAO-A:

Stress, whether physical, social, or mental, causes cortisol to be released from the adrenal glands. Cortisol is a hormone that impacts a number of systems in the body including increasing metabolism and reducing immune response, and cortisol can interact with MAO-A.

Acute stress, like a hard workout or a difficult test, causes a swift rise in cortisol levels. Brain imaging studies show that acute stress – and the subsequent cortisol release – reduces whole-brain MAO-A levels. Corticosteroid medications, such as dexamethasone, also significantly decrease MAOA activity.[ref] A sudden suppression of MAO-A could increase dopamine and other neurotransmitter levels, sharpening awareness and quick decision-making, which makes sense in a situation that is suddenly stressful.

However, chronic stress seems to result in the opposite – an increase in MAO-A levels, at least in certain regions of the brain. The increased MAO-A levels in chronic social stress result in decreased serotonin and dopamine release, playing a role in depression from chronic stress.[ref]

MAO-A, MAOIs, and Tyramine:

MAO enzymes, particularly MAO-A, are involved in the breakdown of tyramine, a naturally occurring amine found in certain foods. Tyramine is found in fermented foods, like aged cheese and cured meats, as well as chocolate, non-pasteurized beer, and some wines.

The MAO-A enzyme is one of several enzymes that can break down tyramine.

Related article: Tyramine metabolism

MAO inhibitors (MAOIs) are psychiatric medications that block the MAO-A enzyme, thus increasing serotonin and dopamine levels. They are most commonly prescribed for depression.

When MAO inhibitors (MAOIs) are used as psychiatric medications, they can prevent the breakdown of tyramine, leading to elevated levels in the body. People on MAOIs are cautioned not to eat foods containing high levels of tyramines. When tyramine levels are too high, a hypertensive crisis can occur – dangerously raising blood pressure and causing stroke-like symptoms.[ref]

MAO, Parkinson’s, and Toxins:

While the monoamine oxidase enzymes mainly break down substances produced in the body (e.g. neurotransmitters), they also can interact with the way that a few drugs are broken down and some environmental toxicants. This interaction can play a role in Parkinson’s disease, which is caused by damage to dopaminergic neurons in a specific region of the brain.

One chemical that is metabolized by MAO-B is 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP itself is non-toxic and can cross the blood-brain barrier. In the brain, MAO-B converts it into a neurotoxin, MPP+, which can cause cell death in dopamine-producing neurons in the substantia nigra. The death of dopamine-producing neurons in the substantia nigra causes Parkinson’s disease.[ref]

MPTP was discovered as a contaminant in illegal drugs that caused immediate and irreversible Parkinson’s symptoms. Within a few years of its discovery, MAO B was identified as the enzyme that turned MPTP into the neurotoxic MPP+. Researchers now use MPP+ extensively to create animal models of Parkinson’s.[ref] You can read more about MPTP and its discovery here.

While you’re not likely to run into MPTP (unless you’re taking synthetic street drugs), it is chemically similar to a commonly used herbicide called paraquat.[ref] Subsequently, a number of studies have shown that higher paraquat exposure increases the risk of Parkinson’s disease.[ref]

Monoamine Oxidase increases ROS:

When monoamine oxidase breaks down a monoamine (neurotransmitters, tyramine, etc.), the reaction produces hydrogen peroxide and possibly ammonia, which are reactive oxygen species (ROS). This production of ROS is normal, and cells produce anti-oxidants to balance out the ROS. In the brain, glutathione is the antioxidant that counteracts the hydrogen peroxide created by MAOs.[ref]

However, when cellular antioxidants are overwhelmed by too much ROS, a state of oxidative stress occurs in the cell. When MAO is upregulated, such as when exposed to lipopolysaccharide (gram-negative bacteria), oxidative stress can occur.

In addition to changing neurotransmitter levels, MAO inhibitor drugs also can decrease inflammation. The research on this is pretty new, but it will be interesting to see whether part of the reason MAO inhibitors work for depression is due, at least in part, to decreasing neuroinflammation, which is a root cause of depression for some people.[ref]

Related article: Inflammation as a cause of depression

Genetics and MAO Levels:

Genetic variants, or SNPs, in the MAOA and MAOB genes can impact the levels of these two enzymes.  For MAOA, researchers have discovered common variants (covered below in the genotype report) and also variable number tandem repeats, or repeated sections of the gene, which are unavailable in your genotype data.

Importantly, genetic variants are not the only determinants of mental health. Studies show that the relationship between MAO-A levels and mental health is complex, and can be influenced by various other genetic and environmental factors.

Studies that show no link between a genetic variant and a trait are also important to consider. For example, a study of attention to task found that MAOA variants did not play a role.[ref]

The MAOA and MAOB genes are located on the X chromosome, so men only have one copy of the gene. For women, only one X chromosome is active in a cell, but it can vary in different tissues as to which copy of the X chromosome is silenced.[ref]

Low MAOA: Warrior Gene or Criminal?

MAO-A has been nicknamed the “Warrior” or “Criminal gene” due to early research in mice and in men showing that low MAO-A levels are linked to aggression and impulsiveness. Some studies refer to this as MAOA-L, which stands for low MAO-A.[ref] One study found that the low MAOA (MAOA-L) genotype along with a CDH13 genetic variant was more common in violent criminals.[ref]

Aggression studies in animals, such as those done in rats, clearly point to a role for MAOA in aggression. However, MAOA more strongly affects dopamine levels in rodents than in humans. For example, mice that are not bred to have the MAOA gene are much more aggressive.[ref]

Newer and more in-depth research shows that the MAOA low genotype doesn’t cause aggression in most people. Instead, the research gives us a more nuanced picture of how MAOA variants impact personality. Many studies have tried to tease out the differences between lower or higher MAOA levels. It’s not as simple as “low MAO-A causes aggression”. Instead, research points to the interaction of low MAO-A and childhood neglect or mistreatment in males increasing the relative risk of aggression.[ref]

Really rare mutations that significantly decrease MAOA levels in humans cause a genetic disease called Brunner syndrome, and the symptoms include impulsive and antisocial behavior.[ref] So the effect of low MAOA on impulsivity is real, but it isn’t necessarily caused by the common variants that decrease MAOA.

Benefits of low MAO-A:

With a positive childhood and good parenting, low MAO-A levels are linked to a decreased risk of aggression in both men and women.[ref]

While parental acceptance and involvement benefit all teen boys, a study showed that teen boys with higher MAO-A levels exhibited even higher sensitivity toward parental involvement.[ref]

Interestingly, women with the ‘warrior gene’ version of MAOA are at a lower risk of ADHD.[ref]

COMT and MAOA:

The COMT enzyme also breaks down catecholamines (dopamine, norepinephrine, and epinephrine). It is mainly found in the cytosol of cells, while MAO is found in the mitochondria.[ref]

Recent studies on aggression and mood have looked at the interaction between slow COMT activity along with low MAOA activity.

• In teen boys, having the low versions of both MAOA and COMT was protective against ‘non-suicidal self-injury’. The study was done on males who had been abused as children.[ref]
• An interaction between COMT and MAOB has also been seen in research on the susceptibility to OCD (obsessive-compulsive disorder).[ref] This possible link seems to be specific to MAO B and not MAO-A. Other research points to no interaction between COMT, MOA A, and OCD.[ref]

You can check your COMT variants below and learn more in this article: COMT and Neurotransmitters

Lifehacks:

If you are a low MAO producer, should you try to increase it? I don’t know that the answer to that question is clear. There may be long-term tradeoffs for higher MAO A or MAO B levels in terms of neurodegenerative diseases.[ref]

If you are on any medication, talk with your doctor before taking any supplements that impact MAO.

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Cofactor for the MAO enzymes:

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