What Are MAO Inhibitors?
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.1López-Muñoz F1, Alamo C. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/19442174″
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.2Shulman KI, Herrmann N, Walker SE. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/23934742/”
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.3Dale E. Edmondson, et al. <a href=”https://pubs.acs.org/doi/10.1021/bi900413g”
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.4Billett EE. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/14697888″
MAO-A is the enzyme that catalyzes the degradation of brain serotonin, melatonin, noradrenaline, and adrenaline.5Godar SC, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/26776902″
High levels of MAO-A has been implicated in major depression, antisocial behavior, seasonal affective disorder and violence.6Meyer JH, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/17088501″
MAO-B increases with age and acts on the monoamines phenethylamine and benzylamine.8Mallajosyula JK, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/18286173″
Both MAO-A and B break down dopamine, tyramine, and tryptamine equally.9Amit S. Kalgutkar, et al. <a href=”http://pubs.acs.org/doi/abs/10.1021/tx010073b”
Interactions of Nitrogen-Containing Xenobiotics with Monoamine Oxidase (MAO) Isozymes A and B: SAR Studies on MAO Substrates and Inhibitors,</a> Chem. Res. Toxicol. 2001
What Is An Example Of An MAO Inhibitor Drug?
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 Finberg JP, Gillman K. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/21971008″
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.
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.11Tiller JW, Maguire KP, Davies BM. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/3432450″
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.12Shulman KI, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/2592589″
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.13Gillman PK. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/16051647″
Generally, you will need to discontinue any SSRI, SNRI, or tricyclic for at least two weeks before starting an MAOI.14Rapaport MH. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/17640157″
Are MAOIs Safe?
MAOIs are largely considered effective and safe for treating depression when they are administered under physician care.15Thomas SJ, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/25884531″
The main issues with MAOIs are due to interactions with certain foods and other medications.
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:17T. S. Sathyanarayana Rao, et al. <a href=”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738414/”
- Aged cheeses
- Aged meats
- Concentrated yeast extracts (marmite)
- Draft beer
- Soy sauces
- Spoiled meat
- 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.18Krishnan KR. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/17640156″
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.19Georgotas A, McCue RE, Cooper TB. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/2673129″
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.20Henkel V, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/16321446″
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.21Alan J. Gelenberg, et al. <a href=”https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf”
Treatment of Patients With
Major Depressive Disorder,</a> APA. 2010
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.22Alan J. Gelenberg, et al. <a href=”https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf”
Treatment of Patients With
Major Depressive Disorder,</a> APA. 2010
Overall, prescriptions of MAOIs have decreased over the years, even as antidepressant prescriptions in general have risen.23Shulman KI, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/19852903″
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.24Akhondzadeh S, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/12921918″
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.25Niederhofer H. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/19112366″
This points to MAOIs being a promising treatment for ADHD, but more large-scale research needs to be done.
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.27Peter Riederer and Gerd Laux. <a href=”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213739/”
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.28Danilenko KV, Ivanova IA. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/25885065″
DanShen: This extract of the Salvia miltiorrhiza plant, has a pronounced inhibitory effect on MAO A. This may give it some therapeutic effects.29Dittmann K, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/15490317″
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.30Ren LX, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/17077534″
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.31Kulkarni SK, Bhutani MK, Bishnoi M. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/18766332″
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.32Kong LD, Cheng CH, Tan RX. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/15120460″
Wild Asparagus: The extract from this plant can significantly inhibit MAO activities, although not to the degree of the pharmaceuticals it was compared to.33Meena J, Ojha R, Muruganandam AV, Krishnamurthy S. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/21843599″
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.34Yamada M, Yasuhara H. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/14697896″
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