MAOIs: Overview & History

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MAOIs: Overview & History

The old irreversible monoamine oxidase inhibitors (MAOIs) like tranylcypromine (Parnate) andphenelzine (Nardil) are extremely effective antidepressant and anti-anxiety drugs that have much less by way of problems, side effects and interactions than most doctors imagine. Indeed many experienced psycho-pharmacologists would regard them as the most potent antidepressants available, and as being effective often when electroconvulsive therapy (ECT) is not.

MAOIs can be effective in all forms of biological depression, especially severe major or endogenous depression, that includes melancholic and psychotic depression (1). Not only that, but also, MAOIs treat or improve: hypertension, migraine, narcolepsy, epilepsy, Parkinson’s disease and dementia. Details about this are given in the other sections, but it is useful to briefly note here that depression, Parkinson’s disease, dementia and hypertension often occur together andtranylcypromine (TCP) improves all of those conditions; furthermore, there is reason to suppose that it also has some of the neuroprotective action that is a part of the benefit of newer MAOI drugs like Rasagiline (2, 3).

TCP is often better tolerated than SSRIs or other newer ADs. If it was a newly discovered drug that would be headline news.

The explanation for the chronic underuse of MAOIs over several decades tells us a lot about how profits, advertising and ideology contaminate the processes of good clinical science.

I have now completed my four major reviews relating to MAOIs: the pharmacology of MAOIs which has been published in the prestigious Journal of Clinical Psychopharmacology (4), my contribution to a book “Pharmacology of MAO-B inhibitors and the cheese reaction” (5), the most extensive and thorough review of dietary restrictions and the tyramine content of foods that has ever been done (6) and my MB review (7).

These MAOI commentaries will discuss various practical and theoretical aspects of the use of these drugs including their clinical pharmacology, side effects and interactions (actually only a few). The dietary review (and extensive 1st hand experience) indicates how few foods need to be restricted, and that almost no foods have to be completely avoided. The review sets out in detail the evidence for limiting the intake of, or avoiding, the small number of things which contain significantly elevated tyramine and can therefore occasionally precipitate blood pressure increases.

These commentaries overlap, they will be extend and re-organised in due course.


The current evidence indicates that old monoamine oxidase inhibitors, tranylcypromine and phenelzine, justify retaining a more prominent position in our treatment armamentarium than they now occupy. As a scientist I recognise the potentially misleading nature of anecdotal evidence. Nevertheless, many people may be heartened to read the story below of the man who, after 20 years of unsuccessful treatment, consulted me and got better on tranylcypromine (TCP) in six weeks (see ‘Anecdotes 1’ below).

Doctors’ lack of MAOI knowledge and familiarity leads to apprehension and avoidance of MAOIs; this is a major factor influencing their low usage. It is undoubtedly the case that withdrawal of all advertising and promotion about them, contrasted with the immense sums spent on the promotion of newer drugs (frequently misleading or false), exacerbates the disparity (see ‘Anecdotes 2’ for a revealing ‘inside story’ about that).

Psychiatry does not have a good track record for using science and the scientific method, especially in relation to pharmacology. The state of many psychiatrists’ knowledge about serotonin toxicity/syndrome and MAOIs exemplifies that. It is unscientific and sad that one sees frequent references, even in specialist texts, about MAOIs being “dangerous” drugs, and also much incorrect information about their properties and interactions (see section on Interactions). The activities of the advertising spin doctors have been so successful that most doctors, including specialists, now believe that the old drugs should not be used at all because they are dangerous and less effective. It is a continual source of amazement to me how far away from the truth spin can take you (see my commentary “Science and Scientific Information” which reveals more details about that). It is common for me to hear of doctors who tell patients they should not be on dangerous drugs like MAOIs, and when patients have asked for MAOI treatment they have been told, “we don’t use those drugs any more”, or dismissive comments to that effect. Such attitudes are a powerful testimony to the effect of advertising and ideology. As is so often the case, statements like that tell you more about the person making the statement than they do about the subject under discussion.

I have been asked many times how to open up discussion with such doctors. Unfortunately, I do not have a magic solution to this significant problem. I suppose it is helpful to understand that there are some doctors who are scientists and are therefore open to evidence and logical argument. Unfortunately there are also doctors who operate more on a belief system, akin to other belief systems, and therefore are much less open to logical argument but are more likely to be persuaded by personal revelation and anecdote. How to achieve personal revelation with such persons is not something I claim any great insight into. For those who have a choice, when faced with such a dilemma, the obvious course of action is to seek a doctor who is open to evidence and discussion.

As a contribution to breaking the ice, I have in the past written letters to doctors on behalf of people, such a letter may be download from the menu on the left of this screen.

A Little History

A little history goes a long way:

“Progress, far from consisting in change, depends on retentiveness. … Those who cannot remember the past are condemned to repeat it.” Santayana (8).

The monoamine oxidase inhibitors can be considered as the first real and effective antidepressants. I discovered the earliest report of serotonin syndrome which occurred in a doctor being treated for tuberculosis in 1955 with the then ‘experimental’ MAOI drug iproniazid (9). During the 1950s the antidepressant properties of drugs with this type of chemical structure were recognised (hydrazine rocket fuel- there was a bit of a stockpile around 1945, thankfully the manufacturers failed to successfully export their full production) and it was discovered that they acted by blocking (antagonizing) the enzyme MAO (3, 10-12).

As early as 1952 doctors were experimenting with hydrazines in mental disorders (13-17).

By 1959 iproniazid was on the market as an ‘antidepressant’, that term was first used about then (18, 19). It was closely followed (1960) by tranylcypromine (Parnate) (19-21). The Lopez-Munoz history of these events is informative reading (22, 23). See also (24-27).

This is also an appropriate point at which to relate how some useful psychotropic drugs did not make it into the modern era, or only just made it. That was because of the struggles involving the power and ideology of the nascent “Federal Drugs Administration” (FDA). This is an important story to be aware of, and for those interested in learning from history I recommend Shorter’s book “Before Prozac: the troubled history of mood disorders in psychiatry”; Ed Shorter is the professor in medical history at Toronto, and is an eminent medical historian (28, 29). Understanding the machinations and politics behind all of this FDA related stuff is instructive. It helps one to appreciate that whether most drugs do, or do not, get on the market sometimes has little to do with science. It often has to do with vested interests in society, business and politics. Another text that I highly recommend for those wishing to understand the (two-way) interactions between science and society is the short and pithy book by Professor Richard Lewontin entitled “Biology as Ideology” (30), and see also my commentary “Science and Scientific Information”.

Early Influence of FDA

As part of a power struggle in the early years of the expansion of the FDA in the 1960s there was an initiative called ‘DESI’. This stands for “drug efficacy study implementation”. It was part of a retrospective evaluation of the effectiveness of drugs that existed in America and had been approved prior to 1962. As part of this many psychotropic drugs required new evidence of effectiveness to be to submitted. Some were removed from the market, even Parnate was removed for short time in 1964. It was only because SKF (now GSK) did a few further studies that Parnate is now on the market at all.

This coincided with the recognition of the morbidity and mortality caused by the cheese effect. At that time, early 1960s, the presence of tyramine in some foods, and its effect on elevating blood pressure, was not appreciated. It is not difficult to understand how, with this background, many doctors were apprehensive about these drugs. However, it was obvious to many experienced specialists that they produced a spectacular effect in serious cases of depression which had previously been untreatable, except by ECT. One of the great ironies is, at that time, Parnate was considered especially effective for psychotic depression (I agree, see (31)). However, the new labeling, post-DESI, specifically excluded its use for that indication and relegated it to the treatment of so-called atypical depression. At this time the tricyclic antidepressants were also coming into use and had none of these perceived problematic effects. Perhaps the final death-blow was a drug trial done by the Medical Research Council (MRC) in 1965 comparing imipramine with phenelzine (32). In my opinion the dose of phenelzine was rather low, but the result was that phenelzine (and hence by association other MAOIs) came out badly, that is as less effective than imipramine, and from then on MAOIs were pretty much history in general psychiatry. However, it is striking that most psycho-pharmacologists who specialized in treating serious depression went on using them extensively. This is a prominent example of a phenomenon that is frequently encountered. Double-blind trials that are supposed to be better and more objective science than clinical observation frequently produce results which experience show to be clearly wrong. This trial was the death knell of MAOIs and yet after 30 years experience using them I would stake both my own life and my pension fund on the fact that they work very well.

By the mid-1980s in USA, tranylcypromine and phenelzine together accounted for more than 90% of the market in MAOIs (24).


1.Wimbiscus, M, Kostenko, O, and Malone, D, MAO inhibitors: risks, benefits, and lore. Cleve. Clin. J. Med., 2010. 77(12): p. 859-82.

2.Rascol, O, Fitzer-Attas, CJ, Hauser, R, Jankovic, J, et al., A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol, 2011. 10(5): p. 415-23.

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4.Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol, 2011. 31(1): p. 66-74.

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6.Gillman, PK, Monoamine oxidase inhibitors, dietary tyramine and drug interactions (V2.2.1).

7.Gillman, PK, CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol (Oxf), 2011. 25(3): p. 429-3.

8.Santayana, G, The Life of Reason. 1905:

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15.Smith, JA, The use of the isopropyl derivative of isonicotinylhydrazine (marsilid) in the treatment of mental disease; a preliminary report. Am Pract Dig Treat, 1953. 4(8): p. 519-20.

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21.Petersen, MC and Brayer, JW, Treatment of affective depression with trans-dl-phenylcyclopropylamine hydrochloride; a preliminary report. Am J Psychiatry, 1959. 116(1): p. 67-8.

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25.Ban, TA, Pharmacotherapy of depression: a historical analysis. J Neural Transm, 2001. 108(6): p. 707-16.

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27.Healy, D, The history of psychopharmacology and the CINP as told in autobiography

28.Shorter, E, Before prozac: the troubled history of mood disorders in psychiatry. 2009: Oxford University Press.

29.Tyrer, P, Twisted science, regulation, and molecules. Lancet, 2009. 373: p. 1513-1514.

30.Lewontin, RC, Biology as Ideology. The Doctrine of DNA. 1991: HarperCollins.

31.Gillman, PK, Psychotic depression and ‘multi-aminergic’ treatment strategies. Br J Psychiatry, 2006: p.

32.Thiery, M, Clinical Trial of the Treatment of Depressive Illness. Report to the Medical Research Council by Its Clinical Psychiatry Committee. Br. Med. J., 1965. 1(5439): p. 881-6.

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