Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression. They are also used in the treatment of Parkinson's disease and several other disorders.
Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAOIs that selectively and reversibly inhibit the MAO-A enzyme. RIMAs are used clinically in the treatment of depression and dysthymia, though they have not gained widespread market share in the United States. Because of their reversibility and selectivity, RIMAs are safer than the older MAOIs like phenelzine and tranylcypromine.
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 indicates that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite the 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also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research. This research also notes that many practitioners have a poor understanding of drug interactions, however, and "drug interactions can be serious, and concomitant medication use must be stringently overseen" as they "can cause a dangerous or fatal serotonin syndrome/toxicity".
Medical uses
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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 have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety disorder and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder. MAOIs appear to be particularly effective in the management of bipolar depression according to a recent retrospective-analysis. There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.
MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety.
MAOIs appear to be particularly indicated for outpatients with dysthymia complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected.
Side effects
Hypertensive crisis
People taking MAOIs generally need to change their diets to limit or avoid foods and beverages containing tyramine. If large amounts of tyramine are consumed, they may suffer hypertensive crisis, which can be fatal. Examples of foods and beverages with potentially high levels of tyramine include animal liver and fermented substances, such as alcoholic beverages and aged cheeses. Excessive concentrations of tyramine in blood plasma can lead to hypertensive crisis by increasing the release of norepinephrine (NE), which causes blood vessels to constrict by activating alpha-1 adrenergic receptors. Ordinarily, MAO-A would destroy the excess NE; when MAO-A is inhibited, however, NE levels get too high, leading to dangerous increases in blood pressure.
RIMAs are displaced from MAO-A in the presence of tyramine, rather than inhibiting its breakdown in the liver as general MAOIs do. Additionally, MAO-B remains free and continues to metabolize tyramine in the stomach, although this is less significant than the liver action. Thus, RIMAs are unlikely to elicit tyramine-mediated hypertensive crisis; moreover, dietary modifications are not usually necessary when taking a reversible inhibitor of MAO-A (i.e., moclobemide) or low doses of selective MAO-B inhibitors (e.g., selegiline 6 mg/24 hours transdermal patch).
Drug interactions
The most significant risk associated with the use of MAOIs is the potential for drug interactions with over-the-counter and prescription medicines, illicit drugs or medications, and some dietary 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.)
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. Drugs that affect the release or reuptake of epinephrine, norepinephrine, or dopamine typically need to be administered at lower doses due to the resulting potentiated and prolonged effect. MAOIs also interact with tobacco-containing products (e.g., cigarettes) and may potentiate the effects of certain compounds in tobacco. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally occurring MAOI compounds in addition to the nicotine.
While safer than general MAOIs, RIMAs still possess significant and potentially serious drug interactions with many common drugs; in particular, they can cause serotonin syndrome or hypertensive crisis when combined with almost any antidepressant or stimulant, common migraine medications, certain herbs, or even most cold medicines (including decongestants, antihistamines, and cough syrup).
Withdrawal
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 too rapidly. The dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines, however. 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.
Interactions
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:
- Phenethylamines: 2C-B, mescaline, phenethylamine (PEA), etc.
- Amphetamines: amphetamine, MDMA, dextroamphetamine, methamphetamine, DOM, etc.
- Tryptamines: DMT (Prevents your body from digesting it, allowing one to experience effects by taking it orally i.e. by Ayahuasca), psilocin/psilocybin ("Magic Mushrooms"), etc.
- Lysergamides: ergolines/LSA, LSD ("Acid"), etc.
- Norepinephrine, and/or dopamine reuptake inhibitors:
- Serotonin-norepinephrine reuptake inhibitors (SNRIs): desvenlafaxine, duloxetine, milnacipran, venlafaxine.
- Norepinephrine-dopamine reuptake inhibitors (NDRIs): amineptine, bupropion, methylphenidate, nomifensine.
- Norepinephrine reuptake inhibitors (NRIs): atomoxetine, mazindol, reboxetine.
- Tricyclic antidepressants (TCAs): amitriptyline, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine.
- Tetracyclic antidepressants (TeCAs): amoxapine, maprotiline.
- Phenylpiperidine derivative opioids: meperidine/pethidine, tramadol, methadone, fentanyl, dextropropoxyphene, propoxyphene.
- Others: brompheniramine, chlorpheniramine, cocaine, cyclobenzaprine, dextromethorphan (DXM), ketamine, MDPV, nefazodone, phencyclidine (PCP), pheniramine, sibutramine, trazodone
- Serotonin, norepinephrine, and/or dopamine releasers: 4-methylaminorex (4-MAR), amphetamine, benzphetamine, cathine, cathinone, diethylcathinone, ephedrine, levmetamfetamine, lisdexamfetamine, MDMA ("Ecstasy"), methamphetamine, pemoline, phendimetrazine, phenethylamine (PEA), phentermine, propylhexedrine, pseudoephedrine, phenylephrine, tyramine.
- 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 therefore it is 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; since this takes two weeks, however, it is not always a desirable or practical option. Dentists using local anesthesia are advised to use a non-epinephrine anesthetic such as mepivacaine 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, for non-epinephrine anesthetics take longer to come into effect and wear off faster. Patients taking phenelzine are advised to notify their psychiatrist prior to any dental treatment.
- Certain other supplements: Hypericum perforatum ("St John's wort"), inositol, Rhodiola rosea, S-adenosyl-L-methionine (SAMe), L-theanine.
- Antibiotics such as Linezolid
- Other monoamine oxidase inhibitors.
Mechanism of action
MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.
Reversibility
The early MAOIs covalently bound 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.
Harmaline found in Peganum harmala, Banisteriopsis caapi, and Passiflora incarnata is a reversible inhibitor of monoamine oxidase A (RIMA).
Selectivity
In addition to reversibility, MAOIs differ by their selectivity of the MAO enzyme subtype. 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.
History
MAOIs started off due to the serendipitous discovery that iproniazid was a potent MAO inhibitor (MAOI). Originally intended for the treatment of tuberculosis, in 1952, iproniazid's antidepressant properties were discovered when researchers noted that the depressed patients given iproniazid experienced a relief of their depression. Subsequent in vitro work led to the discovery that it inhibited MAO and eventually to the monoamine theory of depression. MAOIs became widely used 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. Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice.
A transdermal patch form of the MAOI selegiline, called Emsam, was approved for use in depression by the Food and Drug Administration in the United States on 28 February 2006.
List of MAO inhibiting drugs
Marketed MAOIs
- Nonselective MAO-A/MAO-B inhibitors
- Hydrazines
- Isocarboxazid (Marplan)
- Nialamide (Niamid)
- Phenelzine (Nardil, Nardelzine)
- Hydracarbazine
- Non-hydrazines
- Tranylcypromine (Parnate, Jatrosom)
- Hydrazines
- Selective MAO-A inhibitors
- Bifemelane (Alnert, Celeport) (available in Japan)
- Moclobemide (Aurorix, Manerix)
- Pirlindole (Pirazidol) (available in Russia)
- Toloxatone (Humoryl) (available in France)
- Selective MAO-B inhibitors
- Rasagiline (Azilect)
- Selegiline (Deprenyl, Eldepryl, Emsam, Zelapar)
- Safinamide (Xadago)
Linezolid is an antibiotic drug with weak MAO-inhibiting activity.
Methylene blue, the antidote indicated for drug-induced methemoglobinemia, among a plethora of other off-label uses, is a highly potent, reversible MAO inhibitor.
MAOIs that have been withdrawn from the market
- Nonselective MAO-A/MAO-B inhibitors
- Hydrazines
- Benmoxin (Nerusil, Neuralex)
- Iproclozide (Sursum)
- Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida) (discontinued worldwide except for France)
- Mebanazine (Actomol)
- Octamoxin (Ximaol, Nimaol)
- Pheniprazine (Catron)
- Phenoxypropazine (Drazine)
- Pivalylbenzhydrazine (Tersavid)
- Safrazine (Safra) (discontinued worldwide except for Japan)
- Non-hydrazines
- Caroxazone (Surodil, Timostenil)
- Hydrazines
- Selective MAO-A inhibitors
- Minaprine (Cantor)
List of RIMAs
Marketed pharmaceuticals
Naturally occurring RIMAs in plants
- Curcumin (selectivity for MAO-A is disputed)
- Harmaline
- Harmine
Research compounds
References
