Tuesday, October 19, 2021
Mitochondrial Health Optimal Health

Why Is MAOA Important + How To Change MAOA Activity


Introduction to MAOA

What Is the MAOA Gene?

The MAOA gene codes for monoamine oxidase, an enzyme that helps break down the chemical messengers (neurotransmitters) serotonin, dopamine, and norepinephrine. Collectively, these messengers are referred to as monoamine neurotransmitters because of their chemical structure [1].

Monoamine oxidase also breaks down other compounds with a monoamine structure, such as phenethylamine and tyramine. In all cases, the higher the monoamine oxidase activity, the lower the levels of these compounds. Since the byproducts of this reaction are toxic, they need to undergo further processing by other enzymes [2, 3].

There are two slightly different versions of monoamine oxidase (MAOA and MAOB), each one encoded by a different gene [4, 5, 6]:

  • MAOA: preferentially breaks down serotonin, norepinephrine, and dopamine (in humans). This version is most abundant in the brain, placenta, liver, lungs, small intestine, and connective tissue. Drugs that inhibit MAOA are typically used in the treatment of depression.
  • MAOB: preferentially breaks down phenethylamine and dopamine (in rodents). This version is most abundant in the brain, intestine, liver, platelets, and immune cells. Drugs that inhibit MAOB are typically used in the treatment of Parkinson’s disease.

Importantly, both genes are found on the X chromosome. Because women have two X chromosomes, they have two copies of each gene. Conversely, men have one X and one Y chromosome, meaning that they have only one copy of each gene [7]. However, one random X chromosome becomes inactivated during female embryo development and most of its genes (including MAOA) are not used to make proteins. This means that it’s virtually impossible to tell which variant of MAOA is actively producing proteins in women heterozygous for this gene [8].

Why Is MAOA Important?

Because of its role in breaking down so many different types of neurotransmitters and other compounds, the MAOA gene is one of the most highly-studied genes out there.

As a result, scientists have identified many significant variants that different people can carry in the MAOA gene. These variants, in turn, may increase or decrease the production of the MAOA enzyme, or modify its structure — all of which can have major effects on a person’s overall level of MAOA activity.

MAOA is involved in multiple biological processes, and variations in its levels have been associated with many different traits and health conditions, including:

  • Aggressive and antisocial behavior
  • Suicide
  • Depression
  • Anxiety disorders
  • Neurodevelopmental disorders (ADHD and autism spectrum disorder)
  • Schizophrenia
  • Substance abuse
  • Neurodegenerative disorders (Parkinson’s disease and Alzheimer’s disease)
  • Chronic fatigue syndrome
  • Gout
  • Obesity
  • Migraines

Effects of Low MAOA Activity

As expected, studies in engineered mice lacking MAOA show increased levels of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine as a result of absent MAOA activity [9, 10].

Lack of MAOA increased brain activity in a region involved in emotional processing (the amygdala) but reduced it in another area implicated in complex cognitive behavior (the prefrontal cortex) and impaired connectivity between different brain regions [11, 12, 13, 14].

Interestingly, these alterations are typically observed in people with reactive aggressive behavior and autism spectrum disorder. In line with this, mice lacking MAOA showed increased aggressiveness, social and communication deficits, and repetitive behaviors [14, 9, 12].

In the sections below, we’ll review some of the health- and behavior-related effects that have been reported to be associated with MAOA activity levels that are relatively lower than average.

However, it is important to keep in mind that research on the health effects of MAOA is very complex, and often results in mixed or inconsistent findings. Therefore, some of these associations are stronger than others, while some don’t have clear implications.

Aggressive and Antisocial Behavior

The association of MAOA with aggressiveness, which has earned it the nickname “the Warrior gene,” was first described with the identification of a hereditary condition called Brunner syndrome in a Dutch family. Male carriers of a mutation at the rs72554632 polymorphism showed low IQ, high monoamine levels, and unusual violence in response to anger, frustration, or fear [15, 16].

More recently, an MAOA polymorphism with different numbers of repeats (2, 3, 3.5, 4, 5, and 6) of a specific genetic sequence has been extensively studied. Variants with a reduced number of repeats (2R and 3R) are associated with lower MAOA levels and higher levels of monoamines. The opposite is true for 3.5R and 4R, while the effects of 5R and 6R remain unclear [17, 18, 19].

Multiple studies have associated the 3R variant with a range of aggressive and antisocial behaviors in boys and men, including [20, 21, 22]:

  • Adolescent conduct disorders
  • Reduced social cooperation
  • Physical aggression
  • Criminal violence
  • Recidivism.

Interestingly, this variant is only linked to this type of behavior as a reaction to perceived provocation or traumatic events in early life. When combined with positive parenting and lack of traumatic experiences, it may even prevent aggressiveness. This suggests that this variant makes carriers more responsive to both negative and positive factors [23, 24, 21].

Conversely, the 4R variant seems to be the one associated with aggressive and antisocial behaviors in response to negative life experiences in women. Some researchers suggested that the potential effects of male and female sex hormones on MAOA activity could account for these differences between men and women [25, 26, 27, 28].

A SNP resulting in lower MAOA activity (‘T’ at rs6323) has also been associated with increased aggressiveness in response to negative factors in both men and women [29, 30].

The discovery of these associations received high media coverage and raised the ethical question of whether carriers of certain variants should be held fully responsible for their actions. This led to the MAOA genotype being used as a legal argument in criminal court trials, which even resulted in sentence reductions in some cases [31, 32].

Autism

An excess of serotonin has been suggested to be involved in the onset of autism and other developmental and psychiatric disorders, implying that low MAOA activity may also play a role by reducing the breakdown of this neurotransmitter [33, 34].

In line with this, total absence of MAOA activity (from rare mutations or changes in chromosome structure) has been reported to cause syndromes with autistic features, as well as other behavioral and cognitive abnormalities, in humans and mice [35, 36, 37, 13]. Similarly, low MAOA activity has been measured in the brains of people with autism spectrum disorder [38].

A few studies have associated low-activity MAOA variants (such as 3R and ‘T’ at rs6323) with increased incidence and severity of symptoms, lower IQ, and larger volume of certain brain regions in people with autism spectrum disorder [39, 40, 41, 42, 43, 44].

However, other studies found more severe autistic behaviors and lower IQ in children with the high-activity 4R variant born to mothers homozygous for this variant. The authors of one of them suggested a potential effect of maternal MAOA activity during pregnancy [45, 46, 47].

Schizophrenia

Schizophrenia is a serious mental disorder mainly characterized by psychosis (a break from reality), which typically consists of hallucinations and delusions. Other symptoms of schizophrenia include [48]:

  • Disorganized thinking and behavior
  • Emotional blunting
  • Cognitive impairment

Excessive dopamine activity is believed to contribute to the symptoms of this condition [48].

Variants with reduced MAOA activity (such as 3R and ‘T’ at rs6323), which lead to enhanced dopamine levels, have been associated with schizophrenia — especially in men [49, 50, 51, 52]. Similarly, DNA methylation at this gene (likely resulting in lower MAOA levels) has been linked to increased schizophrenia rates [53, 54].

However, high-activity variants (such as 4R, ‘G’ at rs6323, ‘T’ at rs1137070, and ‘A’ at rs3027407) were linked to emotional blunting in people suffering from this condition [55, 56].

Suicide

Serotonin plays a complex role in suicidal behavior: while excessive activity of this neurotransmitter (such as in people taking SSRI antidepressants) has been associated with increased self-aggression and risk of suicide [57, 58], low serotonin production may also contribute to suicidal behavior by causing depression [57, 59].

Low MAOA activity has been associated with suicide attempts. Planned, complex suicide characterized by increased aggressiveness is especially common among carriers of low-activity MAOA variants such as 3R and ‘C’ at rs1137070 [60, 61, 62, 63].

Conversely, non-complex suicide associated with depression is more common among carriers of variants that result in high MAOA activity, such as 4R and ‘G’ at rs6323 [64, 60, 65].

Substance Abuse

Dopamine and serotonin play a crucial role in addiction. Addictive substances such as alcohol, cocaine, and heroin increase the production of these neurotransmitters in the reward regions of the brain, causing pleasure and euphoria [66, 67, 68].

In men, the low-activity 3R variant has been associated with a slightly increased incidence of alcoholism, younger onset of alcohol use, abuse of other drugs, and antisocial behavior after drinking [69, 70, 71, 72, 73]. Heavy alcohol use was also linked to low MAOA levels in monkeys [74]. Conversely, the highly-active 4R variant is associated with binge drinking and aggressive behavior in young women [75, 76, 77].

In the cases of cocaine and heroin, variants resulting in low MAOA activity have been associated with increased likelihood of addiction and worse effects of these drugs on cognitive function, mood, and behavior [78, 79, 80, 81].

Obesity

Both dopamine and serotonin promote weight gain through their roles in food intake:

  • Eating carbohydrates triggers the release of serotonin, ultimately improving mood. As a result, people with low mood tend to overeat carbohydrates to feel better [82].
  • A lot of foods stimulate dopamine production in the brain, thus activating its reward circuits. This favors the increased intake of these foods, especially in people with low levels of this neurotransmitter (such as those with obesity) [83].

By breaking down these neurotransmitters, MAOA may help prevent overeating. Interestingly, a common adverse effect of MAOA inhibitors is weight gain [84, 85].

In line with this, MAOA variants with reduced activity (such as 3R and ‘T’ at rs6323) have been associated with higher BMI, body fat, and obesity rates [86, 87, 88], while the high-activity 4R variant favored a low body weight, especially in the absence of emotional stress [89, 90].

Effects of High MAOA Activity

The enzymatic activity of MAOA lowers dopamine, serotonin, and norepinephrine levels. Although their rapid breakdown is essential for the correct functioning of the brain, it may contribute to disorders characterized by low levels of these neurotransmitters, such as [91, 92, 5]:

  • Depression
  • OCD
  • Panic disorder
  • ADHD
  • Schizophrenia

Moreover, the breakdown of monoamine neurotransmitters by MAOA produces toxic byproducts such as hydrogen peroxide, ammonia, aldehydes, and quinone oxidation products. These compounds cause oxidative stress, inflammation, and cell death in the brain, thus contributing to depression and neurodegenerative disorders [93, 94].

Two variants with increased MAOA activity (‘G’ at rs6323 and ‘T’ at rs1137070) have been widely investigated and associated with these conditions [95, 96, 97, 98, 99, 100] and others such as migraines [101, 102] and chronic fatigue syndrome [103].

Importantly, the activity of the MAOA gene is largely influenced by a modification called methylation. As is the case with other genes, the more methylated, the lower the levels of MAOA it will produce [104]. Lower-than-average MAOA methylation, likely causing high MAOA levels, has been associated with panic disorder [105, 106], OCD [107], depression [108, 109], and fear of heights (acrophobia) [110].

In the sections below, we’ll review some of the health- and behavior-related effects that have been reported to be associated with MAOA levels that are relatively higher than average.

However, it is important to keep in mind that the health effects of MAOA are very complex, and research on this topic often results in mixed or inconsistent findings. Therefore, some of these associations are stronger than others, while some may not produce any strong conclusions at all.

Depression

MAOA levels are elevated in several brain regions (such as the thalamus, cingulate cortex, and prefrontal cortex) of people with major depression. The resulting lower serotonin and dopamine levels may contribute to depression (according to the “monoamine hypothesis”). Furthermore, monoamine breakdown products may cause the death of brain cells, which may further aggravate mental illness [111, 112, 113].

Greater MAOA activity persists after treatment with SSRIs, possibly reducing the rates of response to these drugs [114].

In line with this, MAOA variants increasing the activity of this enzyme (such as 4R and ‘T’ at rs1137070) have been associated with depression in men [115, 98].

These variants have also been associated with depression in pre- or postmenopausal women [116, 117, 118, 119], populations characterized by low estrogen levels. Estrogens are female sex hormones that may lower MAOA levels, which may explain why these variants are not linked to depression in women of childbearing age [120].

Moreover, high-activity variants have been associated with reduced effectiveness of different antidepressant medications [121, 122, 123].

Drugs that block MAOA are commonly prescribed for mood disorders; this effect was discovered by chance in people receiving them for tuberculosis. Those that permanently block MAOA (such as tranylcypromine) may raise blood pressure to dangerous levels after eating monoamine-rich foods such as cheese [124]. They may furthermore cause serotonin toxicity in people also taking SSRIs [125]. Following your doctor’s recommendations regarding prescription drugs and dietary changes helps prevent these unwanted effects [126].

Selective inhibitors of MAOB such as selegiline (which also blocks MAOA if used at high doses) and reversible MAOA inhibitors such as moclobemide are less effective, but they can be used as alternatives with lower risk of these unwanted effects [127, 128].

Anxiety and Related Disorders

Panic disorder is a disorder characterized by sudden, recurrent panic attacks. People with this condition often have increased norepinephrine and glutamate activity, but reduced serotonin and GABA levels [129].

MAOA variants resulting in high levels of the enzyme (such as 3.5R and 4R) have been associated with increased incidence of panic disorder and worse response to therapy in women, but not in men [130, 131, 132, 133, 134].

Similarly, reduced methylation of this gene (causing higher MAOA levels) was identified as a risk factor for panic disorder in both men and women. A clinical trial found that the benefits of psychotherapy in panic disorder could in part be explained by the reversal of this low methylation level [106, 105].

Obsessive-compulsive disorder (OCD) is a disorder characterized by recurring, unwanted thoughts (obsessions) and the urge to act on these obsessions (compulsions). People with OCD often have increased dopamine and glutamate activity, but reduced GABA and serotonin levels [135, 136, 137].

High-activity MAOA variants (such as 4R and ‘T’ at rs1137070) have been associated with OCD in men [138, 97, 139]. Conversely, the low-activity ‘C’ variant at rs1137070 increased OCD risk in women [97, 140]. As was the case with panic disorder, psychotherapy corrected the low level of methylation observed as a risk factor for OCD [107].

Post-traumatic stress disorder (PTSD) is a disorder with flashbacks, nightmares, and severe anxiety related to a past traumatic event. People with PTSD have excessive levels of epinephrine, norepinephrine, and glutamate [141, 142, 143].

There is no connection between MAOA activity and risk of PTSD, but carriers of the low-activity 3R variant may have more success managing this condition [144, 145].

As was the case with depression, MAOA inhibitors can be used in the treatment of all these disorders [146, 147, 148].

ADHD

Attention-deficit hyperactivity disorder (ADHD) is a psychiatric disorder combining symptoms of inattention and hyperactivity. People with this condition have impaired activity of dopamine and norepinephrine; they are often prescribed drugs that increase the levels and activity of these neurotransmitters (e.g. amphetamine and methylphenidate) [149, 150].

Variants resulting in high MAOA activity (such as 3.5R, 4R, ‘G’ at rs6323, and ‘T’ at rs1137070) have been associated with increased incidence of ADHD and worse performance in attention tests [151, 152, 153, 154, 155, 96, 99, 156, 157, 158], but also with better response to methylphenidate (Ritalin) [159, 151].

Interestingly, the 4R variant has also been associated with Tourette syndrome, a disorder characterized by repeated involuntary movements and sounds that shares many features with ADHD [160, 161].

However, variants with low activity (such as 3R, ‘T’ at rs6323, and ‘C’ at rs1137070) have also been associated with ADHD in some populations, increased impulsiveness, and conduct problems [162, 163, 164, 165, 166, 167]. These variants predicted greater rates of remission from childhood to adolescence, but increased risk of continuity and susceptibility to negative life events from early to middle adolescence [168, 169].

Smoking

Substances in tobacco other than nicotine function as MAOA inhibitors and reduce the activity of this enzyme in the brains of smokers [170, 171]. Because MAOA breaks down the reward neurotransmitters released in response to nicotine (such as dopamine), its inhibition by tobacco substances increases the addictive potential of tobacco [172, 173, 174].

People who stop smoking experience a reduction in MAOA inhibitors in their blood, leading to restored MAOA activity. This leads to the depressed mood typically experienced by smokers giving up this habit [175]. For this reason, the use of MAOA inhibitors such as moclobemide may help with smoking cessation [176].

Several studies suggest that low-activity variants (such as 3R and ‘C’ at rs1137070) reduce the risk of heavy smoking, possibly because carriers need to consume fewer cigarettes to achieve MAOA inhibition and its rewarding effects. Similarly, these variants increase the effectiveness of smoking cessation therapies because carriers have higher baseline dopamine levels [177, 178, 179].

It is less clear whether MAOA genotype is associated with the general risk of becoming a smoker (regardless of the number of cigarettes smoked). Different, contradictory studies link risk of smoking to either high or low activity [180, 181, 182, 183].

Neurodegenerative Disorders

As previously described, the breakdown of monoamine neurotransmitters by MAOA produces toxic byproducts that damage brain cells. These compounds can cause oxidative stress, which may also contribute to the buildup of beta-amyloid in the brain. Beta-amyloid is a protein thought to be involved early in Alzheimer’s disease development [93, 94].

In line with the toxic effects of monoamine breakdown products on brain cells, some high-activity MAOA variants (such as 3.5R, 4R, and ‘G’ at rs6323) have been associated with increased incidence and severity of neurodegenerative disorders, such as Parkinson’s disease [95, 184, 185] and Alzheimer’s disease [186].

MAOA inhibitors have been prescribed to people with Parkinson’s disease, especially to improve depression. However, drugs that block MAOB are more common and effective for other symptoms such as motor disorders and brain cell death [187]. Preliminary research suggests that these drugs and similar compounds under development may also help with Alzheimer’s disease [188].

Fatigue

The role of monoamine neurotransmitters in fatigue is complex: while norepinephrine and dopamine cause arousal and alertness, serotonin may counteract their activity and induce sleepiness. However, low overall monoamine levels are associated with chronic fatigue syndrome, a condition with prolonged low energy [189, 190].

In line with this, MAOA variants with high activity (‘T’ at rs1137070, ‘A’ at rs979605, and ‘C’ at rs979606) and increased monoamine breakdown have been associated with chronic fatigue syndrome [103]. An MAOA inhibitor has furthermore been successfully used to improve this condition [190]. However, the low-activity 3R variant has been associated with fatigue after stroke in women [191].

Migraines

Low blood levels of serotonin or its precursor tryptophan cause the widening of blood vessels, which plays a key role in the onset of migraines. In line with this, drugs that activate serotonin receptors are commonly used to treat these types of headaches [192, 193].

Variants increasing MAOA activity (such as ‘G’ at rs6323, ‘G’ at rs3027400, and ‘C’ at rs2072743) have been associated with increased predisposition to migraines and worse severity of symptoms such as hypersensitivity to light [194, 101, 102]. Carriers of the high-activity 4R variant were more sensitive to experimental pain, including pain caused by stimulating a nerve involved in migraines (the trigeminal nerve) [195, 196].

Alternative Strategies For Altering MAOA Activity

Below are a number of lifestyle, dietary, and supplement-based approaches that you could consider using to potentially increase or decrease MAOA activity.

However, keep in mind that both “high-” and “low-activity” MAOA variants have each been associated with a number of different relative benefits and drawbacks. Therefore, altering your MAOA activity could solve some problems, while also potentially causing other problems to arise in their place.

In other words, there are some potential pitfalls to changing MAOA activity too drastically, and it’s important to be aware of these possibilities when choosing from the strategies described below.

Overall, the best approach is to select a handful of strategies that can help “nudge” your MAOA activity in the right direction, while also directly addressing the desired aspects of health.

As always, we strongly encourage you to discuss any potential lifestyle changes or new supplements with your doctor first, in order to avoid any potential negative interactions.

Alternative Strategies For Increasing MAOA Activity

1) Stress Management

Moderate, occasional stress may help you adapt to stressful situations and increase coping behavior. Research shows that acute stress reduces MAOA activity, leading to higher dopamine and serotonin levels [197].

Conversely, chronic stress causes MAOA overactivation. The resulting depletion of monoamines combined with the increased oxidative stress from their breakdown products may play key roles in stress-related disorders such as depression [198, 199].

People with low MAOA activity are more likely to develop impaired HPA axis function from chronic stress. This may result in health conditions such as PTSD and chronic fatigue syndrome [200].

Multiple studies suggest that emotional stress during childhood and adolescence further increases the risk of antisocial, aggressive, and hyperactive behavior, as well as increases the risk of depression, clogged arteries, and obesity, in carriers of the low-activity MAOA variants 3R and ‘T’ at rs6323 [201, 202, 203, 29, 204, 169, 205, 20, 206, 207].

Oil workers carrying the ‘TT’ genotype of rs6323 were more likely to experience physical symptoms from emotional stress (somatization) [208].

However, some studies in girls and women found that high-activity variants were the ones associated with worse outcomes in response to stress. The studies associated these variants with aggression, depression, and burnout [28, 26, 27, 209].

Importantly, “risk” MAOA variants have also been shown to enhance the effects of beneficial psychosocial factors, such as positive parenting, reduced exposure to traumatic experiences, and high resilience [24, 210, 211].

Negative life events experienced by pregnant women have been shown to affect their children, particularly if the children carried low-activity MAOA variants. A study of women who were pregnant during Superstorm Sandy found reduced production of MAOA (among other proteins) in the placenta, which resulted in their children having worse temperament [212, 213, 214].

We recommend addressing sources of stress in your life, either by taking up a stress-busting hobby (such as yoga or meditation) or seeking professional help.

2) Giving Up Smoking

Substances in tobacco other than nicotine function as MAOA inhibitors, possibly worsening the negative effects of variants that reduce MAOA activity [215, 174, 216, 217].

Importantly, women who continue smoking during pregnancy increase the risk of their children developing antisocial behavior, because nicotine and other components of tobacco interfere with the development of the brain. A study found that exposure to cigarette smoke during pregnancy further increased the odds of developing conduct disorders in carriers of risk MAOA variants (3R in boys and 4R in girls) [218, 219, 220].

3) Reducing Dietary Monoamines

In addition to monoamine neurotransmitters, MAOA also breaks down dietary monoamines such as tyramine, phenethylamine, tryptamine, and histamine. The main food sources of these compounds are aged cheese, cured or smoked meat and fish, pickled or fermented vegetables, alcoholic drinks, chocolate, soy products, and shellfish [221, 222, 223].

Alternatively, the body makes these amines from dietary amino acids such as tyrosine, phenylalanine, tryptophan, and histidine. Protein-rich foods such as meat, poultry, fish, eggs, dairy products, and beans are typical dietary sources of these amino acids [224].

These compounds stimulate the production of monoamines such as serotonin and dopamine, which may be an issue for people with less active MAOA versions [225, 226].

4) Reducing Carbohydrate Intake

Diets rich in carbohydrates and low in proteins increase the levels of tryptophan in the brain and thus increase serotonin production [227, 228, 82]. This may promote excessive food intake by potentiating its rewarding effects, especially in people with reduced serotonin breakdown from low MAOA activity. Carriers of low-activity MAOA variants are at increased risk of obesity and may especially benefit from reducing the amount of carbohydrates in their diets.

Low-carbohydrate, protein-rich diets are most effective at increasing fat burning and promoting weight loss. For instance, a meta-analysis of 13 studies and over 1,500 people concluded that low-carbohydrate ketogenic diets are more effective than low-fat diets for losing weight [229].

When we eat foods rich in high-glycemic-index carbohydrates—such as sugar-sweetened drinks, baked goods, candy, white bread, and rice—the increase in blood glucose is accompanied by a raise in insulin to lower its levels. In the long term, frequent insulin spikes cause insulin resistance, a major cause of obesity and type 2 diabetes [230, 231].

5) White Mulberry

In a rut study, physical exercise greatly reduced MAOA activity. The oral administration of white mulberry extract restored this activity to normal values [232].

Preliminary research suggests that white mulberry may help with excess weight. Supplementation with mulberry extract enhanced weight loss in a clinical trial of overweight people, and in several animal studies. Because low MAOA activity is associated with obesity, carriers of low-activity variants may especially benefit from supplementing with white mulberry [233, 234, 235].

Alternative Strategies For Reducing MAOA Activity

1) Cognitive-Behavioral Therapy

One of the most common forms of therapy used by mental health professionals for mood and anxiety disorders is cognitive-behavioral therapy (CBT). Evidence suggests that CBT works by reducing the activity of brain regions involved in emotional and cognitive processing [236, 237, 238, 239].

Two clinical trials of people with OCD associated this condition with reduced methylation of the MAOA gene, resulting in increased MAOA activity. In both of them, CBT reduced MAOA activity and improved the condition [107, 105].

Moreover, carriers of high-activity variants may be more responsive to this type of therapy. This was the case in 2 clinical trials of people with panic disorder [132, 240].

2) Exercise

Exercise has multiple proven health benefits, including:

Physical activity plays a complex regulatory role in the activity of dopamine, norepinephrine, and serotonin. Moderate exercise causes an overall increase in monoamine transmission that improves brain function, motivation, and adaptation to exercise [248, 189]. Research in animals shows that physical exercise may enhance monoamine levels by reducing MAOA activity [249, 250].

Although people with MAOA-increasing variants such as 3.5R and 4R may have a harder time getting motivated to exercise (due to their lower dopamine levels), they may benefit the most from the MAOA-lowering effects of physical activity [251].

3) Reducing Alcohol Intake

Carriers of MAOA-increasing variants (such as 4R) showed increased tendency to commit violent aggressions after drinking alcohol, especially at younger ages [252, 253].

In a clinical trial of heavy-drinking men arrested for domestic violence, those with these variants benefited more from programs that included a motivationally-based alcohol intervention [254].

Studies in humans and mice found that heavy alcohol consumption increases MAOA levels and activity in a brain region involved in complex cognitive processes, possibly contributing to the effects of high-activity MAOA variants [255, 256].

4) Moderate Sun Exposure

Active vitamin D (calcitriol) reduced MAOA levels and increased dopamine and serotonin production in studies on brain cells. Similarly, supplementation with this vitamin reduced MAOA to normal levels in diabetic rats [257, 258, 259].

Based on these preliminary findings, increasing blood vitamin D levels may help counteract the negative effects of MAOA variants that increase the levels of this enzyme.

Low blood levels of this vitamin have been associated with conditions such as depression, schizophrenia, and alcoholism, as well as with worse mood and cognitive performance in people with Alzheimer’s disease [260, 261, 262].

A moderate exposure to sunlight is the best way of raising blood vitamin D levels. It improves mood and reduces anxiety by increasing the production of serotonin, dopamine, and endorphins [263, 264, 265, 266].

Additionally, you can increase your intake of dietary sources of this vitamin (such as fatty fish, cod liver oil, beef liver, egg yolks, cheese, and mushrooms) or take supplements.

5) Blue Light Therapy

Light therapy typically involves placing a “light box” nearby for 30 minutes each morning shortly after waking up. This therapy has been reported to be especially effective for seasonal affective disorder (SAD), as the bright artificial light offsets the lack of sunlight that people often experience during the winter months [267, 268].

In a small clinical trial, MAOA activity decreased from fall/winter to spring/summer in healthy participants but not in those with SAD. Blue light therapy greatly reduced MAOA activity in both groups of participants when compared to placebo (low-intensity light) [269].

6) Cold Exposure

According to several animal studies, cold exposure and subsequent adaptation to cold temperatures reduces MAOA activity [270, 271, 272]. In a more recent animal study, cold exposure increased the levels of serotonin and dopamine in the brain [273].

Exposure to cold, such as from cold showers or cryotherapy, has several potential health benefits, including:

  • Improving mood in people with anxiety or depression [274, 275, 276]
  • Reducing fatigue [277, 278]
  • Alleviating migraine pain [279]

Importantly, the rapid immersion into cold water is highly unrecommended! It may cause dangerous (or even fatal) changes in breathing and heart rates, known as the cold shock response. People suffering from heart disease or any other chronic conditions should be especially cautious with any form of sudden temperature change [280].

7) Tryptophan & 5-HTP

The essential amino acid tryptophan is converted first to 5-HTP and finally to serotonin in the brain. Foods rich in tryptophan—such as oats, bananas, dried prunes, milk, tuna, cheese, bread, chicken, turkey, peanuts, and chocolate—may help restore normal serotonin levels in people with high MAOA activity [281, 281, 282].

Alternatively, both tryptophan and 5-HTP supplements are available and mainly used to improve depression [283, 284]. 5-HTP shows some advantages over tryptophan:

  • Its conversion to serotonin is faster [285].
  • While part of the tryptophan is used to make proteins and vitamin B3 (niacin), all of 5-HTP is converted to serotonin [286].
  • While tryptophan competes with branched-chain amino acids for entering the brain, all of 5-HTP crosses the blood-brain barrier [287].
  • Tryptophan (but not 5-HTP) can also be converted to compounds involved in psychiatric disorders such as schizophrenia, anxiety, depression, and ADHD [288].

A supplement with tryptophan, tyrosine, and blueberry juice designed to counteract negative effects of high MAOA activity (increased monoamine breakdown and oxidative stress) helped prevent postpartum depression in a clinical trial [289]. However, this supplement failed to prevent depression caused by cigarette withdrawal in smokers [290].

Importantly, tryptophan and 5-HTP supplements must not be combined with MAOA inhibitors because this may raise serotonin to dangerous levels and cause serotonin syndrome. The symptoms of this condition include agitation, delirium, fever, tremor, and hypertension [291].

8) Dietary Flavonoids

Flavonoids are antioxidant plant compounds widely investigated for their potential to prevent chronic health conditions. Importantly, the following ones inhibited MAOA in test tubes and animal studies:

  • Quercetin: found in foods such as capers, onions, eggplants, asparagus, buckwheat, berries, apples, oranges, honey, nuts, and tea; also found in supplements such as St John’s wort, Ginkgo biloba, and heather [292, 293, 294, 295, 294, 296].
  • Resveratrol: found in red wine and foods such as grapes, dark chocolate, berries, peanuts, soy, and “Itadori tea” [297, 298, 299, 300, 301].
  • Apigenin: found in foods such as parsley, celery, onions, artichokes, oranges, tea, and wheat sprouts; also found in supplements such as Ginkgo biloba, propolis, and chamomile [302, 303, 304, 296, 305].
  • Luteolin: found in foods such as celery, parsley, onion, citrus fruits, broccoli, cabbage, rosemary, and oregano; also found in supplements such as dandelion, olive leaf extract, and chamomile [302, 306, 304, 296, 307].
  • Kaempferol: found in foods such as kale, beans, tea, spinach, and broccoli; also found in supplements such as Ginkgo biloba, St. John’s wort, and witch hazel [303, 308, 300]
  • Chrysin: found in foods such as honey and oyster mushroom, and in supplements such as propolis, blue passionflower, and mint plant [303, 309].
  • Fisetin: found in foods such as strawberries, apples, persimmons, onions, grapes, kiwis, and lotus root [310, 311].
  • Acacetin: found in supplements such as black locust, damiana, silver birch, and Korean mint [312, 313].
  • Myricetin: found in foods such as oranges, peppers, garlic, broccoli, cabbage, tomatoes, apples, and tea; also found in supplements such as grape seed extract and Japanese raisin tree [314].
  • Naringenin: found in foods such as grapefruit, sour orange, tart cherries, tomatoes, dark chocolate, and beans; also found in supplements such as water mint [293].

These flavonoids may counteract the negative effects of high-activity MAO variants by increasing serotonin, dopamine, and norepinephrine levels, and reducing the oxidative stress caused by their byproducts. This may, in part, explain why many of them reduced anxiety, depression, schizophrenia, and brain degeneration in animal- and cell-based studies [315, 316, 317, 318, 319, 320, 321, 322, 323].

9) Ginkgo Biloba

Ginkgo biloba extract inhibited MAOA activity in test tubes, mainly due to the presence of the flavonoid kaempferol [324, 303]. In rats, Ginkgo biloba extract prevented the increases in MAOA levels caused by aging and chronic stress [325].

Multiple clinical trials suggest that Ginkgo biloba extract may help improve the symptoms of:

10) Curcumin

Curcumin and derived chemicals inhibited MAOA in multiple studies in test tubes and rats [342, 343, 344, 345, 346]. Possibly as a result of the reduced MAOA activity, brain dopamine and serotonin levels increased in rats given curcumin [347]

In part due to this mechanism, cucumin improved depression and cognitive function when used both alone and as an add-on to conventional treatments in several clinical trials [348, 349, 350].

11) Fenugreek

Fenugreek is used in folk medicine for anxiety and depression. Although the clinical research to back this use is scarce, supplementation with this herb reduced:

  • Depression in older women [351]
  • Aging-related anxiety in men [352]
  • Occupational stress-related anxiety in women and men [353].

The extract of its seeds had antidepressant effects and reduced MAOA activity in the brain in mice studies [354, 355, 356].

12) Kava

Kava extract is traditionally prepared from a combination of kava root and water, and used as a mind-altering beverage in the South Pacific. More recently, it has received attention for its anti-anxiety potential [357].

Several meta-analyses of clinical trials concluded that kava extract may reduce anxiety from generalized anxiety disorder and other conditions [358, 359, 360]. More limited clinical evidence suggests it may also help with depression [361, 362], cognitive performance [363, 364], and drug addiction [365].

Compounds isolated from kava (such as kavain and yagonin) inhibited MAOA in test tubes. In mice, kava extract had anti-anxiety effects and reduced MAOA activity in the brain [366, 367].

Note, however, that kava has been reported to cause several cases of liver damage and even death (possibly due to the presence of the toxic root and stem peelings in the kava product, instead of only the peeled root). For this reason and its potential for abuse, kava is banned in Europe, the UK, and Canada [357, 361].



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