Drugs & Medication

Monoamine oxidase inhibitors (MAOIs) are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression, and have also shown efficacy in helping smokers to quit. Due to potentially lethal dietary and drug interactions they had been reserved as a last line of defense, used only when other classes of antidepressant drugs (for example tricyclic antidepressants and selective serotonin reuptake inhibitors) had been tried unsuccessfully. Recently however, a patch form of the drug (known as Emsam) was invented. (Emsam was approved for use by the FDA on February 28, 2006.) When applied transdermally the drug does not enter the gastro-intestinal system as it does when taken orally, thereby decreasing the dangers of dietary interactions associated with MAOI pills.

Contents 1 Uses 1.1 Therapeutic use 1.2 Traditional and entheogenic use 2 Mode of action 2.1 Reversibility 2.2 Selectivity 3 Dangers 4 List of MAOIs

Uses

Therapeutic use

In the past they were prescribed for those resistant to tricyclic antidepressant therapy, but newer MAOIs are now sometimes used as first-line therapy. They are also used for treating agoraphobia and social anxiety. Currently, the availability of Selegiline and moclobemide provides a safer alternative, although not always as effective as the old types.

Traditional and entheogenic use

Monoamine oxidase inhibitors can be used to potentiate the effect of a number of hallucinogenic drugs, notably phenethylamines, tryptamines and several others.

Ayahuasca, an entheogenic brew traditionally used in strict ritual context by South American native tribes, is a mixture of Banisteriopsis caapi, a vine containing various harmala alkaloids, and another plant containing N,N-DMT or 5-MeO-DMT alkaloids, usually Psychotria viridis or Diplopterys cabrerana. Modern, western analogues to ayahuasca often substitute Syrian Rue for B. caapi and Mimosa hostilis as a DMT source. As DMT is inactive orally on its own, it must be combined with an MAOI when taken orally in order to cause psychedelic effects.

Mode of action

MAOIs act by inhibiting the activity of monoamine oxidase preventing the breakdown of monoamine neurotransmitters and so increasing the available stores. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, adrenaline and noradrenaline. MAO-B preferentially deaminates phenylethylamine and trace amines. Dopamine is equally deaminated by both types. Many formulations use forms of fluoride attached to assist getting past the blood-brain barrier and is suspected as a factor in pineal gland effects.

Reversibility

The early MAOIs inhibited monoamine oxidase irreversibly. When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about two weeks. A few newer MAOIs, notably moclobemide, are reversible, meaning that they can inhibit the enzyme for a time, but eventually detach, allowing the enzyme to function once more.

Selectivity

In addition to reversibility, MAOIs differ by their selectivity of the MAO receptor. Older MAOIs inhibit both MAO-A and MAO-B equally, but newer MAOIs have been developed that target one over the other. For example, a 300 mg dose of moclobemide (Manerix, Aurorix) causes 80% inhibition of MAO-A and 20-30% inhibition of MAO-B.

Dangers

When ingested orally, MAOIs inhibit the catabolism of dietary amines. Sufficient intestinal MAO-A inhibition can lead to hypertensive crisis, when foods containing tyramine are consumed (so-called "cheese reaction"), or hyperserotonemia if foods containing tryptophan are consumed. The amount required to cause a reaction exhibits great individual variation 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 proliferation and accumulation of catecholamines causes hypertensive crises. Because tyramine is the building block of catecholamines (including dopamine, norepinephrine, and epinephrine), intake promotes production of these neurotransmitters. Excessive accumulation can result when MAO is inhibited, producing SNS effects of increased heart rate and vasoconstriction that lead to hypertension. Hypertensive crises can sometimes result in stroke or cardiac arrhythmia if not treated. This risk is generally not present with RIMAs. Both kinds of intestinal MAO-inhbition 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 fermented substances, such as Chianti and other aged wines, and aged cheeses. Liver is also a well-known source. (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.

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 MAOI's were first introduced, these risks were not known, and over the following four decades, less than 100 people have died from hypertensive crisis. Presumably due to the sudden onset and violent appearance of the reaction, MAOI's gained a reputation for being so dangerous that, for a while, they were taken off the market in America entirely. It is now known that, used as directed under the care of a qualified psychiatrist, this class of drugs remains the safest alternative 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 and certain supplements (e.g. St. John's Wort). 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)

MAOIs should not be combined with other psychoactive substances (antidepressants, illicit drugs, painkillers, stimulants, etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, meperidine and tramadol. Agents with actions on epinephrine, norepinephrine or dopamine must be administered at much lower doses due to potentiation and prolonged effect. Purely opiate-acting analgesics, such as morphine and buprenorphine may be used safely with MAOIs, but may require a dosage adjustment.

List of MAOIs

Monoamine oxidase inhibitors include:

• Isocarboxazid (Marplan)
  Moclobemide (Aurorix, Manerix, Moclodura®)
  Phenelzine (Nardil)
  Tranylcypromine (Parnate)
  Selegiline (Selegiline, Eldepryl), and Emsam
  Nialamide
  Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida)
  Iproclozide
  Toloxatone
  Many tryptamines have MAOI properties. Harmine (present in Harmal, Banisteriopsis caapi, and tobacco) is a powerful MAOI, which is often used as one of the ingredients of ayahuasca. Certain others as AMT, 5-MeO-DMT or 5-MeO-AMT provide only minor MAO inhibition.