How MAO Inhibitors Fight Depression

What Are MAO Inhibitors?

MAO enzymes are responsible for breaking down neurotransmitters

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that prevent the breakdown of monoamines, including vital neurotransmitters such as dopamine and serotonin. MAOs oxidize and remove these transmitters from the synaptic cleft.

By preventing this action, MAOIs can indirectly raise levels of certain chemicals in the brain. This could potentially help with a number of cognitive issues.

MAOI’s were discovered in the 1950s and are the original pharmaceutical antidepressants. They were originally used to lower depression symptoms in tuberculosis patients. By the end of the ’50s, more than 400,000 depressed patients were being treated with this drug.¹

This led to the formulation of the monoamine theory of mental illness and opened the door for other antidepressants that act on these neurotransmitters, such as SSRIs and tricyclics.²

MAOI popularity has diminished over the years mostly due to safety concerns about the tyramine reaction and hypertensive crisis known as the “Cheese effect.”

Essentially, there is the possibility that some foods, especially aged cheese, may cause a potentially fatal blood pressure reaction when combined with these drugs.

However, there is some debate in the medical community as to whether or not this should prevent prescribing this class of drug.

Monoamine Oxidase Enzyme

The enzyme MAO is found in the mitochondrial outer membrane and is expressed in most tissues of the body, especially the liver. Monoamine oxidase exists in two isoforms, MAO-A and MAO-B.³

Distribution of MAO-A and B varies throughout the body. MAO-A activity is found mostly in the body and peripheral tissues while MAO-B is found in the brain.⁴

MAO-A is the enzyme that catalyzes the degradation of brain serotonin, melatonin, noradrenaline, and adrenaline.⁵

High levels of MAO-A has been implicated in major depression, antisocial behavior, seasonal affective disorder and violence.⁶⁷

MAO-B increases with age and acts on the monoamines phenethylamine and benzylamine.⁸

Both MAO-A and B break down dopamine, tyramine, and tryptamine equally.⁹

What Is An Example Of An MAO Inhibitor Drug?

Pixabay — There are multiple drugs that can block MAO activity

Some MAO inhibitors selectivity inhibit MAO-A (moclobemide), others selectively inhibit MAO-B (pargyline and selegiline) and some are non-selective (phenelzine, tranylcypromine), inhibiting both A and B.

However, selectivity is often concentration-dependent. For example, selegiline is selective for MAO-B at low doses, but loses its selectivity at concentrations and will block MAO-A as well.¹⁰

There are also natural herbs that can have some MAOI effects, such as curcumin. In fact, using tobacco has this effect, which may be one of the reasons it is addictive.

MAOI Complications

Treating mental illness with MAOIs has fallen out of favor due to potentially fatal dietary interactions.

In particular, foods containing tyramine, a naturally occurring amino acid, can cause a hypertensive crisis in some people who are taking MAOIs.

This is known as the “cheese effect” as there are particularly high concentrations of tyramine in aged cheese. Other foods with high concentrations of tyramine include aged meats, fermented foods, and yeast.¹¹

Tyramine helps to regulate blood pressure and is also broken down by MAO. MAOIs prevent this breakdown, meaning excess tyramine can build up, potentially causing an out of control rise in blood pressure.

Non-selective MAOIs generally elicit a greater danger than selective MAOIs in this regard.¹²

There are also major interactions between SSRI/SNRI medications and MAOIs. Since serotonin is primarily broken down by MAO-A, any drug that works as a serotonin reuptake inhibitor can produce serotonin syndrome.

Serotonin syndrome is a dangerous and potentially fatal buildup of serotonin in the synapses.

So, any drug blocking serotonin reuptake could potentially be dangerous when combined with an MAOI.¹³

Generally, you will need to discontinue any SSRI, SNRI, or tricyclic for at least two weeks before starting an MAOI.¹⁴

Are MAOIs Safe?

MAOIs are largely considered effective and safe for treating depression when they are administered under physician care.¹⁵¹⁶

The main issues with MAOIs are due to interactions with certain foods and other medications.

MAOI Diet

Foods allowed while on MAOI’s include:

Dairy: Fresh cottage cheese, ricotta cheese, and processed cheese slices. All milk products that have been stored properly including sour cream, yogurt, ice cream, etc

Meats: All properly stored and refrigerated processed meats (ex Hot dogs, ham), fish, poultry.

Fruits and Veggies: All are allowed except fava or bean pods, and banana peel

Alcohol: No more than 2 bottled or canned beers per day and 4oz of red wine

Misc: Brewer’s yeast, soy milk, tofu are all ok

MAO Inhibitor Foods To Avoid AKA The Cheese Effect

You should avoid the following while on MAOIs:¹⁷

Aged cheeses
Aged meats
Concentrated yeast extracts (marmite)
Draft beer
Sauerkraut
Soy sauces
Spoiled meat
Poultry
Fish
Broad (fava) bean pods
Tap beer

The Effectiveness of Using MAOIs As An Antidepressant

There’s no doubt that MAOIs are an effective antidepressant. Recent reviews have shown that patients treated with MAOIs had a response rate between 50 and 70%, similar to that of tricyclic antidepressants (TCA).

Researchers concluded that MAOIs are probably the treatment of choice for treatment-resistant depression. They may also be helpful with specific subtypes of depression including atypical depression.¹⁸

One study found that elderly patients with depression treated with the MAOI phenelzine did significantly better in terms of recurrence of mood disorder compared to placebo or tricyclic antidepressants. This effect may be related to the increase in MAO observed in older adults.¹⁹

Serkan Göktay — Some trials have shown MAOIs to be an effective class of antidepressant

MAOIs have been shown to be more effective in treating atypical depression, which is defined by mood reactivity, weight gain, increased sleep, feelings of paralysis, and rejection hypersensitivity. Some 30 % of depressives may meet these criteria.²⁰

MAOI’s Current and Future Status

MAOIs continue to be listed as second or third line options for treatment resistant depression, atypical depression or bipolar depression in most of the major consensus guidelines including the American Psychiatric Association.²¹

In the American Psychiatric Association Practice Guidelines for major depression, MAOIs are not recommended as first-line agents but traditional MAOIs or the transdermal selegiline can be considered options for patients who have not responded to SSRIs.²²

Overall, prescriptions of MAOIs have decreased over the years, even as antidepressant prescriptions, in general, have risen.²³

MAOI Use For ADHD

MAOIs have been proposed as a treatment option for ADHD. However, clinical results on this use are mixed. Additionally, most of the studies have focused on children, which may be of limited use for adult ADHD.

In a placebo-controlled study of 11 children with ADHD, the MAOI selegiline significantly improved attention, but not impulsivity.²⁴

Other studies found that selegiline may target specific symptoms of childhood ADHD such as sustained attention, the learning of novel information, hyperactivity, and peer interactions.

Some of the trials saw that selegiline was about as effective as methylphenidate (Ritalin) in treating ADHD symptoms. However also noted that there was far less chance of negative side-effects when compared to traditional stimulants, which are notorious for some pretty severe drawbacks.²⁵²⁶

This points to MAOIs being a promising treatment for ADHD, but more large-scale research needs to be done.

Parkinson’s Disease

MAOIs may be successful in treating Parkinson’s symptoms. This is because MAO-B most likely plays a large role in this condition.

Research shows that patients with Parkinson’s disease have significantly lower levels of dopamine than normal. This is a hallmark of PD, and may be responsible for many of its symptoms.

This is most likely related to the increase in MAO-B levels, which rise naturally as you age. Inhibiting MAO-B may conserve dopamine, and delay the need for other treatment in patients with early-stage PD.

MAO-B inhibitors selegiline and rasagiline may treat many of the cognitive and motor dysfunctions associated with Parkinson’s. Researchers note that both selegiline and rasagiline have a neuroprotective and neurorestorative potential. They are safe and well-tolerated at the recommended daily doses.²⁷

Holistic MAOI Alternative Treatments

There are several alternatives to prescription MAOI that may have benefits for certain people.

Light Therapy: Many patients with seasonal affective disorder see their symptoms improve with dawn simulation and bright light therapy.²⁸

Marta Branco — Some herbs, like turmeric, may naturally have MAOI properties

DanShen: This extract of the Salvia miltiorrhiza plant, has a pronounced inhibitory effect on MAO A. This may give it some therapeutic effects.²⁹

Zhi Mu: This Chinese herb showed significant antidepressant effects in animal trials, with results comparable to the drug fluoxetine. It has significant MAOI properties, which are most likely the source of this effect.³⁰

Curcumin: This natural compound found in turmeric has been used for thousands of years in Ayurvedic medicine. Curcumin exhibits antidepressant properties by inhibiting MAO-A activity. It can also inhibit MAO-B at higher doses.

Supplementing curcumin enhanced brain levels of serotonin in mice. It also may be related to MAO-B inhibition resulting in higher central dopamine levels. Both these activities, by enhancing the availability of serotonin and dopamine in the brain, could be responsible for its antidepressant activity.³¹

Curcumin may work best when combined with piperine, an extract from black pepper. It is also an MAOI, and it may improve the efficacy of curcumin.³²

Wild Asparagus: The extract from this plant can significantly inhibit MAO activities, although not to the degree of the pharmaceuticals it was compared to.³³

Selective MAOIs

After MAOIs became associated with hypertensive crises, researchers and drug manufacturers sought to develop selective MAOIs. These selective inhibitors do not bind irreversibly to the MAO in the gut, meaning that when tyramine enters your system, it can displace these drugs.

This means that tyramine has much less ability to raise blood pressure and cause a hypertensive crisis, which is one of the main dangers of MAOIs.

Selegiline is a selective MAO-B inhibitor at low doses, but researchers eventually determined that it was only at higher doses, when selegiline inhibits both MAO-A and MAO-B, that it possessed antidepressant benefits.

They later developed selective reversible inhibitors of MAO-A. These include moclobemide, which has a much lower risk profile than other MAOIs but seems to be equally effective.³⁴

In spite of improved safety and fewer dietary restrictions, moclobemide and selegiline never reached the popularity of drugs like SSRIs or SNRIs. While this may be due to concerns about side effects and efficacy, it is also likely due to their place in clinical practice guidelines

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