MAOIs (Monoamine Oxidase Inhibitors) are drugs that are considered “first-generation” antidepressants. This class of drugs was originally developed for the treatment of tuberculosis, but were found to have antidepressant properties when given to depressed patients. In the 1950s, they became very popular as antidepressants. Scientists eventually developed more selective MAOI drugs to reduce side effects and improve upon existing treatments.

Monoamine oxidase inhibitors work by inhibiting activity of monoamine oxidase, which results in increased levels of various neurotransmitters (serotonin, norepinephrine, dopamine). These drugs have been proven effective for depression (specifically atypical subtypes) and are still commonly utilized to help treat Parkinson’s disease (some are considered first-line treatments). They may also be prescribed for panic disorders, social phobia, mixed anxiety with depression, PTSD, some eating disorders, and borderline personality disorder.

The major drawback associated with MAOIs is that the interactions that they have with certain foods can be lethal. Due to various lethal dietary interactions, they are considered a “last-line” treatment option for depression. In other words, people typically use MAOIs when they’ve already tried various SSRIs/SNRIs, new atypical antidepressants, and tricyclic antidepressants. Newer research suggests that the dietary interactions associated with MAOIs may not be as severe as initial claims.

MAOI List: Monoamine Oxidase Inhibitors

There are two common subtypes of monoamine oxidase inhibitors, MAO-A inhibitors and MAO-B inhibitors.

  • MAO-A: The MAO-A subtype specifically focuses on tyramine, serotonin, norepinephrine, and dopamine.
  • MAO-B: The MAO-B subtype focuses more on dopamine, phenylethylamine and trace amines.

It should be noted that some MAOIs consist of a mix of MAO-A and MAO-B targeting.  Additionally some are non-selective and irreversible, while others are selective and reversible.

Marplan (Isocarboxazid)

This is a MAOI that is of the hydrazine class with non-selective and irreversible properties. Marplan is among the oldest few MAOIs that is still sometimes utilized in psychiatric treatment throughout the world. In addition to treating depression, this drug tends to work well for anxiety disorders, and in some cases can help with neurodegenerative diseases like dementia.

Although this drug is considered very effective, it can produce many severe unwanted side effects including: headaches, weight gain, dizziness, fainting, and tremors. An MAOI like Marplan is seldom prescribed this day in age due to side effects as well as potentially dangerous interactions with food.

Moclobemide (Aurorix / Manerix)

This is a selective MAOI with reversible inhibition properties that is most often prescribed for major depression. It is approved in a variety of countries outside the United States including Australia and the United Kingdom. Mclobemide has been found significantly more effective than placebos and equally effective as SSRIs with arguably better tolerability and quicker onset of action.

It works as a selective, reversible inhibitor of MAO-A and increases neurotransmitters serotonin, norepinephrine, and dopamine. The drug inhibits approximately 4/5 of all MAO-A and slightly less than 1/3 of all MAO-B. Contrary to most modern antidepressants, this drug can actually increase libido and improve sexual performance. It also is documented as not being associated with any weight gain as a side effect.

Interestingly long-term use of this drug is associated with increases in neuroprotection and higher testosterone (as opposed to SSRIs which may lower testosterone). This is one of the safest antidepressants on the market and in many cases can be considered a first-line treatment option.

Nardil (Phenelzine)

This is an MAOI with non-selective and irreversible properties of the hydrazine class. It is regarded as one of the most effective non-selective MAOIs that is still clinically prescribed for depression and sometimes anxiety disorders. This drug has been documented as working particularly well among individuals diagnosed with atypical and neurotic depression.  Nardil is often used as a third-line treatment option for individuals with treatment-resistant depression.

The drug works by inhibiting both MAO-A and MAO-B to a similar extent (slightly more MAO-A). In addition to boosting serotonin, norepinephrine, and dopamine, this MAOI also increases concentrations of GABA, which may contribute to its overall efficacy. It should be noted that there are some disputes over the efficacy of the old Nardil vs. new Nardil in regards to changes in the inactive ingredients.

Parnate (Tranylcypromine)

This is an MAOI that has non-selective and irreversible inhibition properties. It is utilized mostly as an antidepressant and in some cases for certain types of anxiety disorders. It was initially synthesized in 1948 and created with similar structure to an amphetamine.  It has proved to be a very effective medication for treatment-resistant depression, but many people who take it cannot tolerate side effects at higher doses.

It works by inhibiting MAO-B slightly more than MAO-A, releasing norepinephrine and dopamine, and increasing trace amines. It is considered roughly 10% as stimulating as an amphetamine. Unlike other MAOIs, Parnate was not derived from hydrazine and upon being released was thought to have significant clinical potential.

Pirlindole (Pirazidol)

This drug is an MAOI with reverse inhibition properties used primarily in Russia to treat major depression. It is very similar to the drug Metralindole due to the fact that it acts primarily as a reverse inhibitor of MAO-A. This drug tends to have more of an activating profile as opposed to being sedating. It has also been found effective in treating some cases of fibromyalgia.

Selegiline (Deprenyl / Eldepryl / Emsam)

This is an MAOI drug that acts as an irreversible selective MAO-B inhibitor at standard doses. The initial use of this drug was to help treat Parkinson’s disease, but it has since been approved by the FDA to treat major depression (2006) in the form of transdermal patch. At increased doses, the drug becomes non-selective and inhibits both MAO-A and MAO-B. It is currently being investigated for smoking cessation and the treatment of ADHD.

Toloxatone (Humoryl)

This drug is an MAOI that acts as a reverse inhibitor on MAO-A. It was introduced to France in 1984 for depression. This drug tends to have activating properties and in many cases can increase levels of anxiety. Compared to the MAOI Moclobemide, this drug was found to have more side effects and be less effective. It has been suggested that individuals with low norepinephrine and/or anxiety-free depression may be ideal for this medication.

MAOIs: Non-Antidepressants

Additionally there are various drugs that function as MAOIs, but are utilized to treat conditions other than depression.  Listed below are drugs with MAOI properties that are not prescribed to treat depression.

Hydracarbazine: This is a compound with MAOI properties that is utilized primarily to lower blood pressure. There isn’t much formal research that has been conducted utilizing just this compound.

Isoniazid (Nydrazid): Isoniazid is significant and important to note because it lead researchers to investigate biological causes of major depression. This drug is commonly utilized as a first-line prevention option and treatment for tuberculosis. As it became widely utilized for tuberculosis in the 1950s, many people began to note mood elevating side effects. Due to significant reports of mood elevation, it lead researchers to create a new generation of antidepressants; the MAOIs.

Linezolid: This is an example of a medication that has very negligible effects as an MAOI. This drug is used as an antibiotic for infections that resist treatment with other antibiotics. It is used to treat pneumonia, various skin infections, and central nervous system infection.

Procarbazine (Matulane): This is a mild MAOI that is used to treat Hodgkin’s lymphoma and various types of brain cancer as an antineoplastic drug. It has been on the market since 1969 and belongs to a group of drugs called “alkylating agents.” Due to its mild MAO inhibition, it raises levels of neurotransmitters in the brain. It is considered an important drug and has been cited on the World Health Organization’s List of Essential Medicines.

Rasagiline (Azilect): This drug functions as an MAOI with irreversible inhibition properties. It is often used in treatment during the onset of Parkinson’s disease. It affects the inhibition of MAO-B up to 14x that of MAO-A. It has been documented as having neuroprotective effects and was created as a result of possible neurotoxicity resulting from the drug Selegiline.

MAOIs: Discontinued Antidepressants

There are other MAOI drugs that have been withdrawn from the market due to adverse side effects. The majority of discontinued and problematic MAOIs are classified as “hydrazines.” The hydrazines are a group of non-selective MAOIs with irreversible inhibition properties. Most hydrazines were marketed throughout the 1950s and 1960s, but were withdrawn due to causing liver damage.

  • Benmoxin: This was an irreversible non-selective MAOI that was created in 1967 and was utilized as an antidepressant throughout Europe. It belonged in the hydrazine class of drugs and was eventually discontinued from the market.
  • Caroxazone (Surodil / Timostenil): This is a non-hydrazine MAOI drug that acted on both MAO-A and MAO-B as a reversible inhibitor. When this drug came out, some research suggested that it may be safer than other MAOIs on the market. It affected MAO-B up to 5x that of MAO-A. It would eventually get removed from the pharmaceutical market.
  • Iproclozide (Sursum): This was another hydrazine class MAOI with selective, irreversible properties. It was eventually withdrawn from the market prior to 1980 due to the fact that it resulted in three deaths. Upon investigation it was discovered that this drug lead to symptoms of jaundice followed by acute liver failure.
  • Iproniazid: This MAOI carries irreversible and non-selective properties and is classified as a hydrazine. It was considered the first antidepressant to ever be marketed, but has since been discontinued worldwide. This drug was developed specifically for tuberculosis, but was found to produce antidepressant effects among patients being treated. The drug was approved in the late 1950s, but was removed from the market as a result of causing liver damage.
  • Mebanazine (Actomol): This is a MAOI drug that was utilized throughout the 1960s as a treatment for depression, but has since been removed from the market. It was of the hydrazine class and due to being removed from the market, there isn’t much published research regarding its usage.
  • Minaprine (Cantor): This is an MAOI antidepressant that had been used throughout France until 1996. The drug worked on MAO-A as a reverse inhibitor. It was eventually discontinued as a result of causing seizures.
  • Niamid (Nialamide): This MAOI of the hydrazine class functioned as an antidepressant with non-selective and irreversible properties. Chemically this drug was similar to Iproniazide as a derivative of isonicotinic acid. It was withdrawn by Pfizer from United States, UK, and Canada in 1963 as a result of causing liver damage.
  • Octamoxin (Ximaol / Nimaol): This is an MAOI drug classified as a “hydrazine” that contains irreversible and non-selective inhibition properties. It was used as a treatment for depression but was removed from markets in 1960s.
  • Pheniprazine (Catron): This is another MAOI of the hydrazine class that has irreversible and non-selective inhibition properties. It was used to treat depression throughout the 1960s and in some cases was prescribed for schizophrenia. Various adverse effects associated with this drug included: eye damage and jaundice. As a result, it was deemed unsafe and taken off the market.
  • Phenoxypropazine (Drazine): This drug was marketed in 1961 for the treatment of depression. It worked as an irreversible MAOI and was classified as a hydrazine. It was eventually discontinued five years after its release as a result of possible cases of liver damage.
  • Pivalylbenzhydrazine (Tersavid): This drug worked as an MAOI with non-selective and irreversible properties, classified as a hydrazine. Throughout the 1960s it was commonly used to treat depression, but it has since been removed from the market.
  • Safrazine (Safra): This MAOI has been largely withdrawn from the global market. Like most problematic MAOIs, it resulted in non-selective, irreversible inhibitory effects and was classified as a hydrazine. It was a drug mostly used in the heyday of hydrazine MAOIs in the 1960s.

MAOI Drugs: Should They Be Used More Often?

In many cases MAOIs can be very effective drugs for treating major depression. Although many carry unwanted side effects and dietary interactions, there a few that stand out from the crowd, namely Parnate, Nardil, and Moclobemide. The best MAOI drugs are often under-utilized as antidepressants and yield very good results in treatment-resistant individuals. Unfortunately the class of MAOIs tends to harbor a reputation of being old, outdated, and having dangerous dietary interactions.

Based on what is known about MAOIs, I think that they should be used more often in certain individuals. People who aren’t responding well to the newer classes of medications may want to try a proven MAOI drug. A valid argument could even be made for a person trying certain MAOIs prior to various tricyclics, especially those with a minimal side effect profile like Moclobemide. For a majority of depressed individuals, making dietary compromises to avoid MAOI interactions is a small price to pay for depression relief.

The MAOI class is completely unique in function from other antidepressants in that they don’t inhibit reuptake of neurotransmitters. Instead, these drugs work to inhibit monoamine oxidase which results in increased levels of all neurotransmitters. Some MAOIs inhibit MAO-A more than MAO-B and vice versa.  Inhibition of MAO-A is associated with increases in tyramine, norepinephrine, serotonin, and dopamine, while inhibition of MAO-B is associated with increases in just dopamine; hence being used more often in cases of Parkinson’s disease.

If you have tried various MAOIs and/or have an opinion on them, feel free to share your thoughts in the comments section below. Many people are afraid to use them simply because they tend to carry dietary interactions and are essentially “older” drugs. That being said, many MAOIs have proven to be just as effective as other classes of drugs.