Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed. New research into MAOIs indicate that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite proven effectiveness of this class of drugs, it is underutilized and misunderstood in the medical profession. New research also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research.
Newer MAOIs such as selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy.
MAOIs appear to be particularly indicated for outpatients with "neurotic depression" complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected.
The early MAOIs covalently bond to the monoamine oxidase enzymes, thus inhibiting them irreversibly; the bound enzyme could not function and thus enzyme activity was blocked until the cell made new enzymes. The enzymes turn over approximately every two weeks. A few newer MAOIs, a notable one being moclobemide, are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.
In addition to reversibility, MAOIs differ by their selectivity of the MAO receptor. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed to target one over the other.
MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B. Agents that act on serotonin if taken with another serotonin-enhancing agent may result in a potentially fatal interaction called serotonin syndrome or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. Tyramine is broken down by MAO-A and MAO-B, therefore inhibiting this action may result in its excessive build-up, so diet must be monitored for tyramine intake.
MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine so there are no dietary restrictions associated with this. MAO-B would also metabolize tyramine, as the only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine. Two MAO-Bi drugs, selegiline and rasagiline have been approved by the FDA without dietary restrictions, except in high-dosage treatment, wherein they lose their selectivity.
Diet and Drug Interactions
When ingested orally, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese effect"), the individual may suffer from hypertensive crisis. The amount required to cause a reaction varies greatly from individual to individual, and depends on the degree of inhibition, which in turn depends on dosage and selectivity.
The exact mechanism by which tyramine causes a hypertensive reaction is not well-understood, but it is assumed that tyramine displaces norepinephrine from the storage vesicles. This may trigger a cascade in which excessive amounts of norepinephrine can lead to a hypertensive crisis. Another theory suggests that proliferation and accumulation of catecholamines causes hypertensive crisis
Tyrosine, not tyramine, is the precursor to catecholamines. Tyramine is a breakdown product of tyrosine. In the gut and during fermentation, tyrosine, an amino acid, is decarboxylated to tyramine. Under ordinary circumstances, tyramine is deaminated in the liver to an inactive metabolite, but, when the hepatic MAO (primarily MAO-A) is inhibited, the "first-pass" clearance of tyramine is blocked and circulating tyramine levels can climb. Elevated tyramine competes with tyrosine for transport across the blood–brain barrier (via aromatic amino acid transport) where it can then enter adrenergic nerve terminals. Once in the cytoplasmic space, tyramine will be transported via the vesicular monoamine transporter (VMAT) into synaptic vesicles, thereby displacing norepinephrine. The mass transfer of norepinephrine from its vesicular storage space into the extracellular space via mass action can precipitate the hypertensive crisis. Hypertensive crises can sometimes result in stroke or cardiac arrhythmia if not treated. In general, this risk is not present with RIMAs. Both kinds of intestinal MAO inhibition can cause hyperpyrexia, nausea, and psychosis if foods high in levodopa are consumed.
Examples of foods and drinks with potentially high levels of tyramine include liver and fermented substances, such as alcoholic beverages and aged cheeses. (See a List of foods containing tyramine). Examples of levodopa-containing foods include broad beans. These diet restrictions are not necessary for those taking selective MAO-B inhibitors, unless these are being taken in high dosages, as mentioned above.
It deserves separate mention that some meat extracts and yeast extracts (Bovril, Marmite, Vegemite) contain extremely high levels of tyramine, and should not be used with these medications.
When MAOIs were first introduced, these risks were not known, and, over the following four decades, fewer than 100 people have died from hypertensive crisis. Presumedly due to the sudden onset and violent appearance of the reaction, MAOIs gained a reputation for being so dangerous that, for a while, they were taken off the market in America entirely. However, it is now believed that, used as directed under the care of a qualified psychiatrist, this class of drugs is a viable alternative treatment for intermediate- to long-term use.
The most significant risk associated with the use of MAOIs is the potential for interactions with over-the-counter and prescription medicines, illicit drugs or medications, and some supplements (e.g., St. John's Wort, tryptophan). It is vital that a doctor supervise such combinations to avoid adverse reactions. For this reason, many users carry an MAOI-card, which lets emergency medical personnel know what drugs to avoid. (E.g., adrenaline dosage should be reduced by 75%, and duration is extended.) The risk of the interaction of MAOI medications with other drugs or certain foods is particularly dangerous because those on the medication who would have to restrict their diets often are depressed patients who "don't care if they live or die."
Tryptophan supplements should not be consumed with MAOIs as the potentially fatal serotonin syndrome may result.
MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine,tramadol, and dextromethorphan. Agents with actions on epinephrine, norepinephrine, or dopamine must be administered at much lower doses due to potentiation and prolonged effect.
Nicotine, a substance frequently implicated in tobacco addiction, has been shown to have "relatively weak" addictive properties when administered alone. The addictive potential increases dramatically after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally-occurring MAOI compounds in addition to the nicotine.
Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a withdrawal syndrome, which may be severe especially if MAOIs are discontinued abruptly or over-rapidly. However, the dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. Withdrawal symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimize or prevent withdrawal symptoms.
MAOIs, as with any antidepressant medications, do not alter the course of the disorder, so it is possible that discontinuation can return the patient to the pre-treatment state.
This consideration greatly complicates switching a patient between a MAOI and a SSRI, because it is necessary to clear the system completely of one drug before starting another. If one also tapers dosage gradually, the result is that for weeks a depressed patient will have to bear the depression without chemical help during the drug-free interval. This may be preferable to risking the effects of an interaction between the two drugs, but it is often not easy for the patient.
Listing of Interactions
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The MAOIs are infamous for their numerous drug interactions, including the following kinds of substances:
Substances that are metabolized by monoamine oxidase, as they can be boosted by up to several-fold.
Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.
Such substances that can react with MAOIs include:
Local and General anesthetic in surgery and dentistry in particular those containing Epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as Phenelzine and it is, therefore, vital to inform all clinicians especially dentists of the potential effect of MAOIs and Local Anesthesia. In preparation for dental work, withdrawal from Phenelzine is specifically advised, however since this takes two weeks it is not always a desirable or practical option. Dentists using Local Anesthesia are advised to use a non-epinephrine anesthetic such as Carbocaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure and the level of the anesthetic should be regularly and appropriately topped up since non-epinephrine anestetics take longer to come into effect and wear off faster. Patients taking Phenelzine are advised to notify their Psychiatrist prior to any dental treatment.
MAOIs started off due to the serendipitous discovery that iproniazid was a weak MAO inhibitor (MAOI). Originally intended for the treatment of tuberculosis, in 1952, iproniazid antidepressant properties were discovered when researchers noted that the patients given iproniazid became "inappropriately happy" which led to the development and widespread use of MAOIs as antidepressants in the early 1950s. The discovery of the 2 isoenzymes of MAO has led to the development of selective MAOIs that may have a more favorable side-effect profile.
The older MAOIs' heyday was mostly between the years 1957 and 1970. The initial popularity of the 'classic' non-selective irreversible MAO inhibitors began to wane due to their serious interactions with sympathomimetic drugs and tyramine-containing foods that could lead to dangerous hypertensive emergencies. As a result, the use by medical practitioners of these older MAOIs declined. When scientists discovered that there are two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, (for example, selegiline, which is used for Parkinson's disease), to reduce the side-effects and serious interactions. Further improvement occurred with the development of compounds (moclobemide and toloxatone) that not only are selective but cause reversible MAO-A inhibition and a reduction in dietary and drug interactions.
Irreversible MAOIs were the first antidepressants to be discovered, but they fell out of favour with the advent of the discovery of safer antidepressants; these newer antidepressant drug classes have fewer adverse effects, especially the dangerous irreversible MAOI food interaction with tyramine, sometimes referred to as the 'cheese syndrome', which leads to dangerous hypertension. However, reversible MAOIs lack these hypertensive adverse effects.Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice; its reversible inhibitory features give it a number of advantages over the older irreversible MAO inhibitors.
In the episode "The Late Shaft" of the TV detective drama Castle, Bobby Mann was taking an MAO inhibitor. His killer used this fact to trigger a negative interaction with the drug, leading to Bobby's death through what seemed to be a normal heart attack.
In the episode "Cut" of Law & Order, a surgeon prescribes painkillers that interact with an MAOI a patient was taking, leading to her death.
The pilot episode of Law and Order was similar to an actual event. Journalist Sidney Zion questioned the sudden death of his daughter Libby Zion in an emergency department in Manhattan on Oct 4, 1984. The cause of death was attributed to "mysterious infection". The father convinced authorities to launch a criminal investigation when it was discovered that several medications, including Demerol, were administered to his daughter, reacting with her Nardil medications. The DA sought charges of murder against a doctor who had approved use of restraints and narcotics when Zion became increasingly agitated. The case prompted many reforms in graduate medical education and limiting number of hours staff can work. Drug abuse was successfully argued as a major factor leading to her death.
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