How MAO Inhibitors Fight Depression

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″  target=”_blank”>Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today,</a> Curr Pharm Des. 2009

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/”  target=”_blank”>Current place of monoamine oxidase inhibitors in the treatment of depression,</a> CNS Drugs. 2013

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”  target=”_blank”>Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases,</a> Biochemistry. 2009

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″  target=”_blank”>Monoamine oxidase (MAO) in human peripheral tissues,</a> Neurotoxicology. 2004

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″  target=”_blank”>The role of monoamine oxidase A in aggression: Current translational developments and future challenges,</a> Prog Neuropsychopharmacol Biol Psychiatry. 2016

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″  target=”_blank”>Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression,</a> Arch Gen Psychiatry. 2006 ⁷Godar SC, et al. The role of monoamine oxidase A in aggression: Current translational developments and future challenges, Prog Neuropsychopharmacol Biol Psychiatry. 2016

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″  target=”_blank”>MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology,</a> PLoS One. 2008

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”  target=”_blank”>
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″  target=”_blank”>Selective inhibitors of monoamine oxidase type B and the “cheese effect”,</a> Int Rev Neurobiol. 2011

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.¹¹Tiller JW, Maguire KP, Davies BM. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/3432450″  target=”_blank”>Tyramine pressor response with moclobemide–a reversible monoamine oxidase inhibitor,</a> Psychiatry Res. 1987

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″  target=”_blank”>Dietary restriction, tyramine, and the use of monoamine oxidase inhibitors,</a> J Clin Psychopharmacol. 1989

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″  target=”_blank”>Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity,</a> Br J Anaesth. 2005

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″  target=”_blank”>Dietary restrictions and drug interactions with monoamine oxidase inhibitors: the state of the art,</a> J Clin Psychiatry. 2007

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″  target=”_blank”>Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression,</a> Pharmacotherapy. 2015 ¹⁶Shulman KI, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/23934742/” target=”_blank”>Current place of monoamine oxidase inhibitors in the treatment of depressione,</a> CNS Drugs. 2013

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:¹⁷T. S. Sathyanarayana Rao, et al. <a href=”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738414/”  target=”_blank”>Hypertensive crisis and cheese,</a> Indian J Psychiatry. 2009

• 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.¹⁸Krishnan KR. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/17640156″  target=”_blank”>Revisiting monoamine oxidase inhibitors,</a> J Clin Psychiatry. 2007

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″  target=”_blank”>A placebo-controlled comparison of nortriptyline and phenelzine in maintenance therapy of elderly depressed patients,</a> Arch Gen Psychiatry. 1989

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″  target=”_blank”>Treatment of depression with atypical features: a meta-analytic approach,</a> Psychiatry Res. 2006

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”  target=”_blank”>PRACTICE GUIDELINE FOR THE
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”  target=”_blank”>PRACTICE GUIDELINE FOR THE
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″  target=”_blank”>Current prescription patterns and safety profile of irreversible monoamine oxidase inhibitors: a population-based cohort study of older adults,</a> J Clin Psychiatry. 2009

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″  target=”_blank”>Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial,</a> Prog Neuropsychopharmacol Biol Psychiatry. 2003

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″  target=”_blank”>Selegiline and methylphenidate in treatment of ADHD,</a> Psychiatr Danub. 2003 ²⁶Rubinstein S, et al. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/16958566″  target=”_blank”>Placebo-controlled study examining effects of selegiline in children with attention-deficit/hyperactivity disorder,</a> J Child Adolesc Psychopharmacol. 2006

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.²⁷Peter Riederer and Gerd Laux. <a href=”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213739/”  target=”_blank”>MAO-inhibitors in Parkinson’s Disease,</a> Exp Neurobiol. 2011

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″  target=”_blank”>Dawn simulation vs. bright light in seasonal affective disorder: Treatment effects and subjective preference,</a> J Affect Disord. 2015

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″  target=”_blank”>HPLC-based activity profiling of Salvia miltiorrhiza for MAO A and iNOS inhibitory activities,</a> Planta Med. 2004

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″  target=”_blank”>Antidepressant-like effects of sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae),</a> Biol Pharm Bull. 2006

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″  target=”_blank”>Antidepressant activity of curcumin: involvement of serotonin and dopamine system,</a> Psychopharmacology (Berl). 2008

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″  target=”_blank”>Inhibition of MAO A and B by some plant-derived alkaloids, phenols and anthraquinones,</a> J Ethnopharmacol. 2004

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″  target=”_blank”>Asparagus racemosus competitively inhibits in vitro the acetylcholine and monoamine metabolizing enzymes,</a> Neurosci Lett. 2011

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.³⁴Yamada M, Yasuhara H. <a href=”https://www.ncbi.nlm.nih.gov/pubmed/14697896″  target=”_blank”>Clinical pharmacology of MAO inhibitors: safety and future,</a> Neurotoxicology. 2004

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