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Comparing MAO Inhibitors

This article outlines differences between the four FDA-Approved MAO inhibitors including a comparison of benefits and side effects.

Comparing MAO Inhibitors
Hydrazine (left) is structurally similar to Nardil & Marplan; Amphetamine (right) is structurally similar to Parnate & Selegiline

We support our patients’ choices for which MAO inhibitor they want when it is reasonable and safe to do so. Our providers prescribe all four MAO inhibitor medications that FDA-approved for the treatment of major depressive disorder:

  • Parnate (Tranylcypromine)
  • Nardil (Phenelzine)
  • Marplan (Isocarboxazid)
  • Selegiline

All four of these drugs irreversibly bind to or destroy monoamine oxidase (MAO). [1]

MAO Subtypes

There are two subtypes of the MAO enzyme: MAO-A and MAO-B.  MAO-A is responsible for degrading serotonin, norepinephrine, and tyramine. MAO-B is responsible for degrading amine-based chemical messengers. Both MAO subtypes degrade dopamine. [2]

Parnate, Nardil, and Marplan are non-selective MAO inhibitors (i.e., they do not show a preference for inhibiting one subtype over the other). Selegiline, by contrast, is a selective MAO inhibitor that preferentially binds to and destroys MAO-B at lower doses. At higher doses (typically greater than 10-15 mg), however, Selegiline is non-selective and destroys both MAO subtypes equally. [3]

Chemical Structures: Amphetamine- vs Hydrazine-Based

The chemical structures of Parnate and Selegiline are similar to that of amphetamine, a powerful stimulant. Additionally, Parnate and Selegiline produce amphetamine and amphetamine-related metabolites. Some experts speculate that some of the characteristics observed with these drugs (e.g., tendency to cause weight loss instead of weight gain, stimulating effects that last hours or all day) may be attributed to their association with amphetamine. [4, 5]

By contrast, the chemical structures of Nardil and Marplan resemble that of hydrazine, a poorly understood drug. [6]

Amphetamine-Based MAO Inhibitors: Parnate & Selegiline

More commonly associated with weight loss than weight gain, [8, 9] although Parnate may cause more significant weight gain at very high doses [7], and may be associated with weight loss in some patients

✓ or  Commonly has a stimulating effect within an hour of consumption. [8, 10] Parnate commonly has two types of stimulating effects: one that starts within minutes of ingestion and typically lasts a few hours and one that lasts all day and may even cause people to wake up early the following morning. Selegiline’s effects commonly last all day hours. Parnate’s simulating effect tends to be more significant cause increase work productivity while Selegiline’s stimulant effect tends to feel more like natural energy and cause patients to stop taking daytime naps or driving coffee frequently.

May cause positive urine toxicology screens for amphetamine and methamphetamine, although higher doses of Parnate are typically needed [4, 5]

Parnate (Tranylcypromine)

 Highly effective in treating depressed mood and, from our experience, effective in treating low energy and motivation, apathy, and anhedonia

 Highly effective in treating anxiety disorders from our experience

 Possibly most likely among the mao inhibitors to cause a hypertensive crisis with tyramine consumption [11]

 Frequently requires twice daily dosing (with breakfast and lunch) if once daily dosing is not tolerated due to side effects

Selegiline

Effective in treating depressed mood, low energy and motivation, apathy, and anhedonia from our experience

Least likely of the MAO inhibitors to cause hypertensive crisis from tyramine consumption when used at lower doses and via the transdermal or sublingual routes [12]

 Typically limited side effects compared to Parnate and Nardil from our experience

Three possible routes of administration: sublingual, oral, and transdermal

 Likely the least effective mao inhibitor from our experience

 Infrequently helps with anxiety disorders from our experience

Selegiline Formulations

Sublingual
(brand typically not used)

Oral
Eldepryl (brand)
Transdermal (i.e., Patch)
Emsam (brand)

While already at a reduced risk of hypertensive crisis from tyramine consumption, sublingual formulation minimizes gut MAO exposure of the drug, further reducing risk of hypertension [13]

Lower levels of amphetamine metabolites are produced reducing the risk of a false positive urine toxicology [13-15]

 Possible day-to-day dosing variation with the imperfect splitting of the tablets or inadequate absorption of the tablet resulting in some oral consumption

Selegiline HCl tablets are approved for oral consumption only and thus sublingual use is off-label administration

Selegiline tablets commonly take up to 10 minutes to fully absorb sublingually and many patients report a slight bitter taste (fortunately, they are very small tablets and patients tend to not notice the slight bitter taste as much after a few days)

Given poor bioavailability (7-10%), tablets should be consumed with a high-fat snack or meal to increase absorption [16]

High doses needed given poor bioavailability (10 mg oral is similar to 1.25 mg sublingual) [14]

Should be taken twice daily (in the morning with breakfast and a second dose with lunch)

While already at a reduced risk of hypertensive crisis from tyramine consumption, transdermal formulation minimizes gut MAO exposure of the drug, further reducing risk of hypertension [17, 18]

Lower levels of amphetamine metabolites are produced reducing the risk of a false positive urine toxicology [17, 18]

Very costly and thus frequently not covered by insurance (although each patch may be used up to 3 days). [19] Additionally, may be made into a cheaper cream by some compound pharmacies.

Limited dosing options: 6 mg, 9 mg, and 12 mg and given that doses up to 24 mg per day may be needed, 2 prescriptions and 1-2 copays may be required

Forms a rash for some people although this is treatable with hydrocortisone and applying the patch to different areas of skin

Hydrazine-Based MAO Inhibitors: Nardil and Marplan

 Often associated with weight gain; [20] however, Marplan is sometimes associated with weight loss [21]

Nardil (Phenelzine)

 Particularly effective at treating anxiety disorders possibly due to its association with increased GABA levels [22-26] and effective at treating refractory OCD

Infrequently associated with water retention leading to edema or swelling of the extremities. New extremity swelling, however, warrants consideration of other, potentially serious causes including liver disease, which may be precipitated by Nardil use, and heart problems, not typically associated with Nardil use. [30]

Least predictable dose-dependent among the MAO inhibitors although it has been discovered that effective dosing frequently requires greater than 1 mg per kg [11]

Rarely causes liver damage but is likely the most common MAO inhibitor to cause liver damage [22]

Unlikely to have anticholinergic side effects (e.g., dry mouth, constipation, urinary retention), but most likely to have them among the MAO inhibitors [22]

May cause vitamin B6 deficiency and thus may require supplementation of the vitamin (typically, 100-200 mg per day). Oversupplementation of vitamin B6 may reduce the effectiveness of Nardil as Nardil binds to vitamin B6 to produce an inactive complex, however. [28, 29]

Highly likely to cause orthostatic hypotension or dizziness with standing during the first few weeks of taking the drug [22, 30]

 Associated with significant brain fog and fatigue for many patients which typically worsens with higher doses but improves with time and may be difficult to treat.

Marplan (Isocarboxazid)

“Clean drug” because it only has one known mechanism of action: MAO inhibition [31]

 Effective for anxiety, particularly social anxiety, in our experience

 Limited side effects compared to Parnate and Nardil

Has faced critical drug shortage issues recently and may face shortage issues in the future [32]

Frequently not covered by insurance and very costs to pay out-of-pocket [33]

 May cause vitamin B6 deficiency [34]

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4. Romberg RW, Needleman SB, Snyder JJ, Greedan A. Methamphetamine and amphetamine derived from the metabolism of selegiline. J Forensic Sci. 1995 Nov;40(6):1100-2. PMID: 8522918.

5. Akhgari M, Jokar F, Etemadi-Aleagha A, Ghasemi A. Discrimination Between Drug Abuse and Medical Therapy: Case report of a tranylcypromine overdose-related fatality. Sultan Qaboos Univ Med J. 2017;17(2):e213-e217. doi:10.18295/squmj.2016.17.02.013

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7. Nihalani N, Schwartz TL, Siddiqui UA, Megna JL. Weight gain, obesity, and psychotropic prescribing. J Obes. 2011;2011:893629. doi:10.1155/2011/893629

8. Parikh N, Yilanli M, Saadabadi A. Tranylcypromine. [Updated 2020 Jul 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459162/

9. Culpepper L, Kovalick LJ. A review of the literature on the selegiline transdermal system: an effective and well-tolerated monoamine oxidase inhibitor for the treatment of depression. Prim Care Companion J Clin Psychiatry. 2008;10(1):25-30. doi:10.4088/pcc.v10n0105

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11. Cole JO, Bodkin AJ. MAO inhibitors: An option worth trying in treatment-resistant cases. Current Psychiatry. 2002 June;1(6):40-47.

12. Heinonen EH, Myllylä V. Safety of selegiline (deprenyl) in the treatment of Parkinson’s disease. Drug Saf. 1998 Jul;19(1):11-22. doi: 10.2165/00002018-199819010-00002. PMID: 9673855.

13. Clarke A, Brewer F, Johnson ES, Mallard N, Hartig F, Taylor S, Corn TH. A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm (Vienna). 2003 Nov;110(11):1241-55. doi: 10.1007/s00702-003-0036-4. PMID: 14628189.

14. Clarke, A., Johnson, E., Mallard, N. et al. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm 110, 1257–1271 (2003). https://doi.org/10.1007/s00702-003-0042-6

15. Löhle M, Storch A. Orally disintegrating selegiline for the treatment of Parkinson’s disease. Expert Opin Pharmacother. 2008 Nov;9(16):2881-91. doi: 10.1517/14656566.9.16.2881. PMID: 18937619.

16. Magyar K. The pharmacology of selegiline. Int Rev Neurobiol. 2011;100:65-84. doi: 10.1016/B978-0-12-386467-3.00004-2. PMID: 21971003.

17. Azzaro AJ, Vandenberg CM, Blob LF, Kemper EM, Sharoky M, Oren DA et al (2006). Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects. J Clin Pharmacol 46: 933–944.

18. Azzaro AJ, Ziemniak J, Kemper E, Campbell BJ, VanDenBerg C (2007). Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules. J Clin Pharmacol 47: 1256–1267.

19. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021336s002lbl.pdf

20. Cantú TG, Korek JS. Monoamine oxidase inhibitors and weight gain. Drug Intell Clin Pharm. 1988 Oct;22(10):755-9. doi: 10.1177/106002808802201002. PMID: 3068037.

21. Davidson J, Turnbull C. Loss of appetite and weight associated with the monoamine oxidase inhibitor isocarboxazid. J Clin Psychopharmacol. 1982 Aug;2(4):263-6. PMID: 7119133.

22. Sidhu G, Marwaha R. Phenelzine. [Updated 2021 Feb 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554508/

23. Buigues J, Vallejo J. Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. J Clin Psychiatry. 1987 Feb;48(2):55-9. PMID: 3542985.

24. Mountjoy CQ, Roth M, Garside RF, Leitch IM. A clinical trial of phenelzine in anxiety depressive and phobic neuroses. Br J Psychiatry. 1977 Nov;131:486-92. doi: 10.1192/bjp.131.5.486. PMID: 338081.

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31. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Isocarboxazid. [Updated 2020 Apr 8]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548518/

32. https://www.fda.gov/media/130259/download

33. https://www.goodrx.com/marplan

34. Larsen, JK, Bendsen, BB, and Bech, P, Vitamin B6 treatment of oedema induced by mirtazapine and isocarboxazid. Acta Psychiatr. Scand., 2011. 124(1): p. 76-7; discussion 77.