Below is an excerpt of the full MAOI toolkit, available for free download.

References are located at the bottom of the full toolkit PDF.


Monoamine oxidase inhibitors (MAOIs) were the first antidepressants found to be effective in clinical use. Their discovery was serendipitous; the anti-tuberculosis agent, iproniazid, was noted to improve depressive symptoms in patients with tuberculosis. It was found that the antidepressant effect was related to inhibition of monoamine oxidase (MAO) (1-3). Currently, four MAOIs are approved and marketed for treatment of depression in the United States: phenelzine, tranylcypromine, transdermal selegiline, and isocarboxazid. Rasagiline is an MAOI that is only approved for treatment of Parkinson’s disease. Iproniazid, while widely used initially, was removed from the market because of hepatotoxicity. An additional MAOI, moclobemide, is approved for the treatment of depression in Europe, Canada, and Australia.

Shortly after MAOIs were introduced, it was discovered that ingestion of dietary tyramine (TYR) or sympathomimetic drugs, such as orally ingested nasal decongestants, by patients taking MAOIs could result in hypertensive crisis and potential fatality. As a result, the need for tyramine-restricted diets was identified. Early versions of these diets were quite restrictive and resulted in poor adherence to MAOIs. MAOIs also are believed to be poorly tolerated and commonly cause adverse effects such as hypertension, weight gain, cognitive dysfunction, and sexual dysfunction. While these may occur with some MAOIs, they are not a universal problem (4).

With the introduction of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), bupropion, etc., use of MAOIs decreased dramatically. They are now used very infrequently, and, as a result, many clinicians are not familiar with them and how they can be applied to the treatment of depression and anxiety. This Toolkit is intended to provide clinicians (pharmacists, physicians, nurse practitioners, etc.) with evidence-based information necessary to allow them to safely and confidently manage patients who are candidates for treatment with MAOIs.

MAO Function in Neurotransmission

MAO occurs in two subtypes. MAO-A is found in brain, intestine, liver, placenta and skin and preferentially metabolizes serotonin (5HT) and norepinephrine (NE); it also metabolizes dopamine (DA) and TYR. MAO-B is found in brain, lymphocytes, and platelets and metabolizes DA, TYR, and phenylethylamine. Brain activity of MAO is the critical target for antidepressant efficacy. MAO resides in presynaptic neurons and glial cells where it breaks down and regulates the amounts of 5HT, NE and DA available for neurotransmission. According to one theory of depression, the monoamine theory, there is a deficiency of some or all of these neurotransmitters that results in the symptoms associated with depression. Reuptake transport pumps move these monoamines from the synaptic space into the presynaptic neuron where they are either catabolized by MAO or stored in synaptic vesicles for use in neurotransmission (1,2).

MAOI Pharmacology

The characteristics of MAOIs in clinical use are summarized in Table 1.

Table 1: Characteristics of MAOIs

MAOI Hydrazine Selective Reversible
Moclobemide   MAO-A X
Isocarboxazid X No  
Phenelzine X No  
Tranylcypromine   No  
Transdermal Selegiline   No  
Oral Selegiline   MAO-B (≤10 mg/day)  
Rasagiline   MAO-B  

All MAOIs currently available in the United States (tranylcypromine, phenelzine, isocarboxazid, selegiline and rasagiline) are irreversible inhibitors of MAO. They covalently bind to and inactivate the enzyme. As a result, MAO activity does not return to normal until approximately 2 – 3 weeks after these MAOIs are discontinued (the time required for synthesis of new enzymes) (1,2). Moclobemide is a selective reversible inhibitor of MAO-A (RIMA). Moclobemide, as a competitive inhibitor of MAO-A, can be displaced from the enzyme by high concentrations of other substrates such as NE (5). Therefore, it has a lower likelihood of significant interaction with dietary TYR and sympathomimetics. MAOIs prevent the catabolism of 5HT, NE, and DA and make more of these neurotransmitters available for release. Additionally, tranylcypromine inhibits NE reuptake at doses of 40 – 60 mg daily, and at high doses of 100 mg/day it may cause release of DA from neuron storage vesicles (6).

Tranylcypromine, phenelzine and isocarboxazid are non-selective and equally inhibit both MAO-A and MAO-B. Selegiline and rasagiline are selective inhibitors of MAO-B. The selective inhibition of MAO-B by selegiline is dose dependent; at oral doses greater than 10 mg/day, it begins to inhibit MAO-A as well as MAO-B. At oral selegiline doses above 20 mg/day, MAO-A and MAO-B are equally inhibited (3,7). Rasagiline’s selectivity is also dose-dependent, although doses far above those used in Parkinson’s disease (in excess of 6 mg daily) are needed to produce significant MAO-A inhibition (8). Oral selegiline and rasagiline are only FDA-approved for treatment of Parkinson’s disease either alone (rasagiline) or as an adjunct to levodopa (rasagiline and selegiline). They are believed to work in Parkinson’s disease by inhibiting the breakdown of DA in the brain. At oral doses recommended for Parkinson’s disease, neither selegiline nor rasagiline is effective as an antidepressant. There have been isolated case reports of antidepressant effectiveness of oral selegiline at doses of 10 mg daily or less (9,10). However, the strongest evidence indicates that 30 – 60 mg daily of oral selegiline is required for consistent antidepressant efficacy (11-13). A transdermal patch formulation of selegiline is available and is approved for the treatment of depression (see “MAOI Dosage Forms” below). Transdermal selegiline inhibits brain MAO-A and MAO-B equally (7). Unlike other antidepressants that increase 5HT and/or NE neurotransmission, non-selective MAOIs increase 5HT, NE, and DA; this broad effect on the neurotransmitters believed responsible for depression may explain the effectiveness of these MAOIs for a broad range of symptoms associated with depression (2). Non-selective MAOIs appear to be the strongest dopaminergic antidepressants. Moclobemide, despite being selective for MAO-A, does appear to increase the amount of DA available for neurotransmission (5).

MAOIs fall into two chemical categories: hydrazines and non-hydrazines. The hydrazine MAOIs are phenelzine and isocarboxazid. Tranylcypromine, moclobemide, rasagiline, and selegiline are non-hydrazines. The distinction between these chemical classes is important in that it helps predict potential therapeutic and adverse effects of these drugs (7,14).

Most available evidence-based information regarding hydrazine MAOIs relates to the effects of phenelzine, but one would expect isocarboxazid to affect patients in a similar way. Phenelzine increases brain concentrations of gamma-amino butyric acid (GABA) through a direct effect and also as a result of inhibition of glutamic acid decarboxylase and GABA transaminase (14). These effects may help explain phenelzine’s sedative and antianxiety properties. Phenelzine also inhibits gluconeogenesis and potentially increases the risk of hypoglycemia as well as inhibiting adipocyte lipid storage; these effects likely contribute to the weight gain seen with phenelzine (14). Hydrazine MAOIs may also cause depletion of pyridoxal phosphate (vitamin B6). This may result in neuropathy and neurotoxicity (rarely, seizures). While phenelzine is much less hepatotoxic than its predecessor, iproniazid, it has been associated with cases of liver damage/failure. These side effects are discussed more fully in the section “Potential Adverse Effects”.

Non-hydrazine MAOIs have a different side effect profile from the hydrazines. They tend to be stimulating rather than sedating. Selegiline is metabolized to l-amphetamine and l-methamphetamine (7); these compounds contribute to its tendency to stimulate and cause sleep disruption. Tranylcypromine is not converted to amphetamine, but it is chemically similar to amphetamine and may cause amphetamine-like effects at higher doses (15).

MAOI Dosage Forms

Tranylcypromine, phenelzine, moclobemide, and isocarboxazid are all administered orally. Oral administration results in significant inhibition of MAO in the intestine and liver because these are the organs first exposed to MAOIs as they are absorbed. This inhibition of intestinal and hepatic MAO is important from the standpoint of interactions with dietary TYR.

Selegiline is approved as a transdermal formulation for the treatment of depression. When selegiline is administered transdermally, its bioavailability is significantly increased because it bypasses first-pass metabolism by the liver. As a result, high concentrations of selegiline reach the brain as it is absorbed. These concentrations are high enough to inhibit both MAO-A and MAO-B in the brain resulting in significant antidepressant activity. After redistribution of selegiline occurs, the liver and intestine are exposed to lower concentrations of the drug. For this reason, there is less inhibition of MAO in these organs, and there is a reduced risk of dietary TYR inducing hypertensive reactions (2). The lower risk of hypertensive reactions has been established for the use of the lowest strength transdermal selegiline (6 mg/24 hours). When higher doses of transdermal selegiline are used, there may be increased inhibition of MAO in the intestine and liver.