What are Monoamine Oxidase (MAO) Inhibitors?

This articles discusses what MAOIs are, who may benefit from them, and how they work.

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What is a MAOI?

Monoamine oxidase (MAO) inhibitors or MAOIs are a unique class of prescription antidepressants with anxiolytic and antihypertensive effects. MAOIs play an important role in treating a wide variety of psychiatric and mental health conditions.

MAO inhibitors were among the first antidepressants to be discovered in the 1950s. [1] Because they were noted to increase neurotransmitter or chemical messenger levels in the brain via inhibition of the MAO enzyme, their discovery led to an idea which ultimately grew into the monoamine hypothesis of depression, a belief among the medical and psychiatric academic communities that depression was caused or worsened by a depletion of one or more neurotransmitters in the brain. [2]

Despite remaining as a highly effective treatment for atypical and major depression, bipolar disorder, and a variety of anxiety disorders including generalized anxiety, social anxiety, phobias, obsessive compulsive disorder (OCD), and post traumatic stress disorder (PTSD), their use has dwindled over time largely of exaggerated concerns of dietary restrictions and reactivity with other serotonergic medications. With introduction of newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), MAO inhibitors gradually fell out of favor as despite the very limited dietary restrictions compared to the 1950s and 1960s, when tyramine content in foods was immensely higher than it is today, and despite the fact that numerous studies have shown that many “serotonergic” drugs can safely be combined with MAO inhibitors to augment treatment. [3, 4]

In the United States, there are four MAO inhibitors that are FDA-approved for treatment of major depressive disorder:

Read about the similarities and differences among all four MAOIs here. Moclobemide (also known under the brands Amira, Aurorix, Clobemix, Depnil and Manerix) is a reversible MAO inhibitor that is believed to be weaker than irreversible MAOIs. A further discussion of Moclobemide is not included here as this drug is not approved for use in the United States.

Secondary or Alternative MAOI Mechanisms of Action

In addition to irreversible inhibition of the MAO enzyme, some MAO inhibitors possess secondary mechanisms of action. possess additional activities in the body. At higher doses, Parnate and, to a lesser extent, Nardil may act as a direct norepinephrine reuptake inhibitor (NRI) [25]. High-dose Parnate may also act as a dopamine releasing agent (DRA) to a mild extent. [26] Additionally, Nardil is associated with significantly greater levels of GABA, a neurotransmitter or chemical messenger responsible for inhibiting activity in the brain. [27] Parnate and Selegiline also have amphetamine metabolites. [28, 29]

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How Long Do MAO Inhibitors Last?

The half-life or time until half of the drug has been metabolized (broken down) or excreted (removed from the body) of each of the MAO inhibitors is relatively short:

But unlike the effects of many other drugs, the effects of MAO inhibitors do not strictly correlate with the drugs’ serum level because their primary mechanism of action involves the irreversible inhibition of MAO which regenerates at approximately 3% of the total body’s baseline level of MAO per day. [23] As a result, although Selegiline, for example, is virtually entirely eliminated from the body 24 hours later, its effects linger for a much longer period. In fact, a study with Selegiline dosing found that it can be effectively used with larger doses given only twice per week. [34]
However, some of the secondary mechanism of actions of various MAO inhibitors discussed above correlate with drug serum level. Thus, the stimulating effects of Parnate, for example, which are believed to be due to its dopamine releasing effects, norepinephrine reuptake inhibition, and amphetamine metabolites, typical only last a few hours after consumption. [35]