Use of MAO inhibitors. MAO inhibitors - what are they? Irreversible selective MAO-B inhibitors

Monoamine oxidase inhibitors (MAOIs)- biologically active substances that can inhibit the enzyme monoamine oxidase contained in nerve endings, preventing this enzyme from destroying various monoamines (serotonin, norepinephrine, dopamine, phenylethylamine, tryptamines, octopamine) and thereby helping to increase their concentration in the synaptic cleft.

Monoamine oxidase inhibitors include some antidepressants, as well as a number of natural substances.

MAOI classification

According to their pharmacological properties, monoamine oxidase inhibitors are divided into reversible and irreversible, selective and non-selective.

Selective MAOIs inhibit primarily one type of MAO, while non-selective MAOIs inhibit both types (MAO-A and MAO-B).

Irreversible MAOIs interact with monoamine oxidase, forming chemical bonds with it. The enzyme then becomes unable to perform its functions and is metabolized, and instead the body synthesizes a new one, which usually takes about two weeks.

Reversible MAOIs bind to the active site of the enzyme and form a relatively stable complex with it. This complex gradually dissociates, releasing the MAOI, which then enters the blood and is excreted from the body, leaving the enzyme intact.

Non-selective irreversible MAOIs

Iproniazid
Nialamid
Isocarboxazid
Phenelzine
Tranylcypromine

Strictly speaking, it is not entirely correct to classify tranylcypromine into this group, since it is a reversible inhibitor, however, it may take up to 30 days to dissociate its complex with the enzyme and completely eliminate it from the body. In addition, it exhibits some selectivity towards MAO-A.

Currently, non-selective MAO inhibitors are rarely used. This is due to their high toxicity. Unlike most other non-selective MAOIs, iproniazid, which is now widely discontinued due to high hepatotoxicity, is not used at all; In many countries, isocarboxazid has also been discontinued for the same reason.

Isoniazid, an anti-tuberculosis drug, historically the first MAOI, also has clinically significant activity: it was the euphoric effect of isoniazid, observed in tuberculosis patients, that led to the discovery of monoamine oxidase inhibitors. Because of its significant hepatotoxicity and potential to cause pyridoxine-deficiency polyneuropathies, isoniazid has ceased to be used as an MAOI, except for its off-label use at high doses in combination with high doses of vitamin B6 in countries where other hydrazine MAOIs are not available.

Reversible selective MAO-A inhibitors

Moclobemide
Pirlindol (pyrazidol)
Bethol
Metrolindole
Garmaline
Beta-carboline derivatives

Irreversible selective MAO-B inhibitors

Selegilin
Rasagiline
Pargilin

The division into MAO-A and MAO-B is partly arbitrary, since in high doses MAO-B lose selectivity and also begin to block MAO-A, and MAO-A in high doses (exceeding the maximum doses recommended in the instructions) also significantly block MAO-B . The division into irreversible and reversible MAOIs is also somewhat arbitrary: only hydrazine derivatives - nialamide, phenelzine, isocarboxazid, iproniazid - are completely irreversible MAOIs. Tranylcypromine and selegiline are partly reversible: after stopping their use, monoamine oxidase is restored not after 2 weeks, as after stopping taking hydrazine MAOIs, but after 5-7 days.

Selegiline and rasagiline are officially registered in Russia only for the treatment of Parkinson's disease. The antidepressant effect of selegiline in monotherapy is observed only in high doses, when it loses its selective effect. However, as potentiators, selegiline and rasagiline can be used in selective MAO-B dosages, in which they act as dopaminergic agents.

Tranylcypromine and selegiline are slightly metabolized in the body into amphetamine, which is partly due to their strong stimulating activity.

Therapeutic effect

MAOIs, by blocking the destruction of monoamines by monoamine oxidase, increase the content of one or more mediator monoamines (norepinephrine, serotonin, dopamine, phenylethylamine, etc.) in the synaptic cleft and enhance monoaminergic (monoamine-mediated) transmission of nerve impulses (neurotransmission). For this reason, for medical purposes, these substances are used mainly as antidepressants. MAO-Bs are also used in the treatment of parkinsonism and narcolepsy.

Side effects

Non-selective inhibitors

The main adverse effect is orthostatic hypotension, which occurs in almost all patients taking these drugs, while a hypertensive reaction due to the interaction of MAO inhibitors with foods or drugs that can provoke a hypertensive crisis is rare.

Non-selective MAO inhibitors have a large number of side effects. These include dizziness, headache, urinary retention, constipation, fatigue, dry mouth, blurred vision, skin rashes, anorexia, paresthesia, swelling of the legs, convulsive epileptiform seizures, hepatitis. In addition, due to the pronounced psychostimulating effect, these drugs can cause euphoria, insomnia, tremor, and hypomanic agitation; due to the accumulation of dopamine - delusions, hallucinations and other mental disorders. The development of Korsakov's syndrome is possible. Taking non-selective MAO inhibitors often leads to sexual side effects such as decreased libido, erectile dysfunction, delayed or absent orgasm, delayed or absent ejaculation.

Like other antidepressants, MAOIs may precipitate a manic episode in predisposed patients. MAOIs are more likely to cause manic episodes than some other antidepressants, and for this reason they are not the drugs of choice for the treatment of depressive episodes with preexisting manic episodes.

Iproniazid has a pronounced hepatotoxic effect, which makes it unsuitable for widespread use in psychiatry. Phenelzine is less toxic to the liver than iproniazid, but its common side effects are hypotension and sleep disturbances, and isocarboxazid may be used in cases where patients respond well to phenelzine but suffer from these side effects.

Tranylcypromine differs from other MAOIs in its combination of MAO inhibitory properties and amphetamine-like stimulant effects; this drug is partially metabolized to amphetamine. Some patients become dependent on the stimulant effect of tranylcypromine. Compared to phenelzine, it can more often provoke hypertensive crises, but affects the liver less. For these reasons, tranylcypromine should be prescribed with great caution.

Selective inhibitors

They are used more widely because they have significantly fewer side effects. Possible side effects include mild dry mouth, urinary retention, tachycardia, dyspeptic symptoms; in rare cases, dizziness, headache, anxiety, restlessness, and hand tremors are possible. Allergic skin reactions may also occur.

Interactions

The combination of monoamine oxidase inhibitors with substances that affect monoamine metabolism can lead to an unpredictable increase in their effect and be life-threatening.

Foods incompatible with MAOIs

There are significant risks when using MAOIs, especially non-selective irreversible MAOIs, represents the consumption of foods containing various monoamines and their metabolic precursors. First of all, it is tyramine and its metabolic precursor, the amino acid tyrosine, as well as tryptophan. Tyramine, like amphetamine psychostimulants, causes the release of catecholamines from nerve endings. Its combined use with MAOIs is fraught with a hypertensive crisis (see tyramine syndrome).

Tryptophan is used by the body to produce serotonin, and eating foods containing high amounts of tryptophan can result in serotonin syndrome.

Foods to avoid:

All cheeses, except fresh homemade cheese (cottage cheese), are especially sharp and aged; milk, cream, sour cream, kefir
Ice cream with syrup
Red wine, beer containing yeast (unrefined), ale, liqueurs, whiskey
Smoked meats, salami, chicken and beef liver, chicken pate, meat broths, marinades, any stale meat products, fried poultry and fried game
Caviar, smoked fish, herring (dried or salted), dried fish, shrimp paste, marinated fish (fresh fish is relatively safe)
Yeast extracts and brewer's yeast (regular baker's yeast is safe)
Protein supplements
Legumes (beans, lentils, beans, soybeans), soy juice
Sauerkraut
Overripe fruits, canned figs, bananas, avocados, raisins
Spices
All types of cookies

Products to be careful with:

White wine, port
Strong alcoholic drinks (risk of respiratory depression)
Some fruits such as figs, prunes, raspberries, pineapple, coconut
Fermented milk products (yogurt, yoghurt, etc.)
Chocolate
Soy sauce
Peanut
Caffeine, theobromine, theophylline (coffee, tea, mate, Coca-Cola)
Spinach

Irreversible, non-selective MAOIs require avoidance of these products and the medications and drugs mentioned below while taking them and for two weeks after you stop taking them. In the case of reversible MAOIs, dietary restrictions are usually less stringent and apply to the time the substance remains in the body (no more than a day). You should also refrain from using drugs and surfactants listed in the list together with reversible MAOIs until they are completely eliminated.

Interaction with drugs and narcotics

To prevent tyramine syndrome and serotonin syndrome, the following drugs should be avoided during MAOI therapy:

Psychostimulants of the amphetamine group and related ones - increasing the levels of catecholamines in the synaptic cleft (amphetamine, methamphetamine, sydnocarb, etc.)
Any empathogens (entactogens)
Cold remedies containing sympathomimetics (ephedrine, pseudoephedrine, phenylpropanolamine, phenylephrine, chlorpheniramine, oxymetazoline, etc.): Coldrex, Theraflu, Rinza, etc., nasal sprays and drops (naphthyzine, etc.)
Weight loss products
Oral hypoglycemic agents
Neuronal monoamine reuptake inhibitors:
- Cocaine
- Cyclic antidepressants, including clomipramine, imipramine
- Selective serotonin reuptake inhibitors (SSRIs), eg paroxetine, citalopram, fluoxetine
- Venlafaxine
- Trazodone, nefazodone
Herbal antidepressants containing St. John's wort
5-hydroxytryptophan, tryptophan
Lithium preparations
Dextromethorphan (DXM)
Metabolic precursors of monoamines: levodopa, methyldopa, 5-hydroxytryptophan
Antihypertensive drugs (guanethidine, reserpine, pargyline)
Adrenaline and local anesthetics containing adrenaline (lidocaine and novocaine are harmless)
Anti-asthma drugs
Diuretics
Beta blockers
Antihistamines
Barbiturates
Anticholinergic drugs
Narcotic analgesics.
Alcohol.

After discontinuation of fluoxetine, a period of at least five weeks should be maintained before initiating an irreversible MAOI to prevent serotonin syndrome. In older patients, this period should be at least eight weeks. After stopping short-acting SSRIs, there should be a break of at least two weeks before prescribing an MAOI.

When switching from irreversible MAOIs to SSRIs, a break of four weeks should be maintained; When switching from moclobemide to SSRIs, 24 hours is sufficient.

The likelihood of developing serotonin syndrome when an SSRI interacts with selegiline or moclobemide is significantly lower compared to the risk of its occurrence when combining an SSRI with a non-selective irreversible MAOI, but such an interaction is still possible. Serotonin syndrome was also observed during monotherapy with moclobemide.

Irreversible MAOIs should not be combined with antihypertensive drugs due to the risk of severe orthostatic hypotension, or the dose of the antihypertensive drug should be reduced.

MAOIs enhance the effect of alcohol, sedatives and anxiolytics, as well as painkillers, sometimes bringing the effect of these drugs beyond the safety line.

MAOIs can complicate procedures involving anesthesia or analgesia, as they interact with narcotic substances, causing a syndrome manifested by agitation, fever, headaches, convulsions, coma with the possibility of death. They can cause respiratory depression. Fatal outcomes have been reported with the use of meperidine. Patients undergoing surgery should have their dose of MAO inhibitors reduced in advance to avoid adverse drug reactions.

Diabetic patients taking insulin may experience a more dramatic decrease in blood sugar levels. In this case, the insulin dose can be reduced.

Restrictions on use

The presence of a hypotensive effect and the ability of irreversible MAOIs to provoke orthostatic hypotension complicates their use in patients with initial hypotension and a tendency to faint, in elderly patients with severe cerebral atherosclerosis, in severe arterial hypertension, when a sharp decrease in blood pressure is dangerous.

Precautionary measures

If you suddenly change your body position, you may feel unsteady. This can be avoided by rising slowly from a horizontal position. If the tablets are taken with meals, this and other side effects are much less pronounced.

Caution should be exercised when servicing machinery or operating machinery, as many patients are prone to increased drowsiness during the initial period of MAOI treatment.

Non-medical use

There are a number of reports of abuse of MAO inhibitors. The mechanism of abuse may be due to the similarity of the chemical structure of MAOIs to the chemical structure of amphetamine; however, the mechanism of action of MAOIs and amphetamines differs significantly. Individuals who abuse MAOIs may be particularly prone to developing hypertensive crises because they use high doses of MAOIs and/or may be unaware of the recommended diet.

Interactions with phenylethylamine and tryptamine psychedelics

Most tryptamines are good substrates for MAO-A. DMT and 5-MeO-DMT, when taken orally, are metabolized by it in the gastrointestinal tract and liver, without having time to enter the blood, so they are inactive when taken orally. 4-Hydroxy-DMT (psilocin) is less susceptible to degradation by MAO because its hydroxyl group at the 4th position makes it difficult to bind to the active site of the enzyme, making it orally active. Alkyl substituents on the amino group, more voluminous than methyl (ethyl, propyl, cyclopropyl, isopropyl, allyl, etc.), also complicate the metabolism of tryptamines with such substituents through MAO, therefore all such tryptamines are active when taken orally. The alpha-methyl in tryptamine molecules like AMT and 5-MeO-AMT significantly impedes their metabolism by MAO and turns them de facto from substrates into weak inhibitors of this enzyme.

Inhibition of peripheral MAO-A in the GI tract and liver by potent MAOIs allows tryptamines such as DMT and 5-MeO-DMT to be orally active and also enhances and prolongs the effects of other tryptamines such as psilocin and DET. On the other hand, long-term use of MAOIs as antidepressants significantly reduces the effects of psychedelics. This occurs, obviously, due to changes in the monoaminergic systems of the brain caused by increased levels of monoamines. The nature of this phenomenon currently remains unclear and is not explained by a simple loss of sensitivity of the serotonin receptors with which psychedelics interact.

Thus, taking MAOIs together with tryptamines or immediately before using tryptamines prolongs and in some cases enhances the effects of the latter, and in addition makes it possible to use tryptamines such as DMT orally. This is the basis of the principle of action of ayahuasca and similar mixtures, including the so-called pharmacohoasca, in which pure DMT is used instead of plant components, and traditional Banisteriopsis Caapi, and Peganum Harmala seeds, or their extracts, or even moclobemide (Aurorix). However, taking an irreversible MAOI a few days before taking a psychedelic will weaken its effects. The same thing will happen with long-term use of both irreversible and reversible MAOIs before taking a psychedelic drug.

Taking 5-MeO-DMT with an MAOI is not safe. Many people note strong and unpleasant side effects of this combination, including serotonin syndrome. In addition, many people find this experience extremely difficult psychologically and can be associated with serious mental health risks.

Tryptamines, which significantly increase monoamine levels in the synaptic cleft (AMT, 5-MeO-AMT, AET, etc.), can be lethal when combined with MAOIs. There is some concern about the safety of using MAOIs with tryptamines such as DPT.

The metabolism of LSD is currently not well understood, but MAO does not appear to be involved in any way. However, according to some authors, when used in conjunction with harmala, its effects are enhanced and prolonged. The same applies to other ergolines.

MAO plays a minor role or even practically does not participate in the metabolism of phenylethylamine psychedelics. Therefore, taking MAOIs together with them has no practical meaning. Although, according to some users, both harmala and moclobemide enhance the effects of some PEAs, such as 2C-B.

In most cases, taking MAOIs with phenylethylamine psychedelics does not pose any serious health risks. However, the use of MAOIs with sulfur-containing phenylethylamines such as 2C-T-7 and Aleph-7 should be avoided due to their controversial and poorly studied effects on brain monoamine levels and high toxicity. Combinations of MAOIs with TMA-6 and TMA-2 may also be unsafe.

Overdose

MAOI antidepressants are extremely toxic in overdose, and symptoms of intoxication do not necessarily appear immediately. In acute poisoning with large doses of MAOIs, general weakness, dizziness, ataxia, slurred speech, and clonic muscle twitching are observed; this is followed by the development of comatose states or convulsive seizures (such as generalized epileptiform seizures) followed by coma. After emerging from a coma, the stunned state may persist for some time. In some cases, coma does not occur, and the initial symptoms of overdose are replaced by delirious syndrome. Impaired consciousness in case of MAOI overdose is not always observed; in cases where they are absent, the depression that caused the prescription of MAOIs very quickly, paroxysmally, gives way to euphoria.

Manifestations of overdose may also include anxiety, confusion, hypertensive crisis, cardiac arrhythmias, rhabdomyolysis, and coagulopathies.

Due to the high toxicity of MAOIs, they should be prescribed to patients with suicidal tendencies in quantities sufficient for only a few days of use.

MAOI classification

According to their pharmacological properties, monoamine oxidase inhibitors are divided into reversible and irreversible, selective and non-selective.

Selective MAOIs inhibit primarily one type of MAO, while non-selective MAOIs inhibit both types.

Non-selective irreversible MAOIs

Strictly speaking, it is not entirely correct to classify tranylcypramine in this group, since it is a reversible inhibitor, however, it may take up to 30 days to dissociate its complex with the enzyme and completely remove it from the body. In addition, it exhibits some selectivity towards MAO-A.

Reversible selective MAO A inhibitors

Beta-carboline derivatives

There is no need to follow a diet when taking reversible MAOIs.

Irreversible selective MAO B inhibitors

Pharmacology MAOI

General information

Interaction with drugs and some surfactants

The combination of monoamine oxidase inhibitors with substances that affect monoamine metabolism can lead to an unpredictable increase in their effect and be life-threatening.

List of drugs to avoid:

Foods incompatible with MAOIs

A significant danger when using MAOIs is the consumption of foods containing various monoamines and their metabolic precursors. Primarily tyramine and its metabolic precursor amino acid tyrosine, as well as tryptophan. Tyramine, like amphetamine psychostimulants, causes the release of catecholamines from nerve endings. Taking it together with MAOIs is fraught with hypertensive crisis. Tryptophan is used by the body to produce serotonin, and eating foods containing large amounts of it can lead to serotonin syndrome.

Foods to avoid:

Cheeses, especially aged ones
Red wine, beer, especially dark (including non-alcoholic), ale, liqueurs, whiskey.
Smoked meats, sausages and any products made from stale meat
Marinated, smoked and dried fish (fresh fish is relatively safe)
Yeast extracts and brewer's yeast (regular baker's yeast is safe)
Protein supplements
Legumes (beans, lentils, beans, soybeans)

Products to be careful with:

Strong alcoholic drinks (risk of respiratory depression)
Some fruits, such as bananas, avocados, figs, raisins, prunes, raspberries, pineapple, coconut
Fermented milk products (yogurt, kefir, yogurt, sour cream)
Caffeine, theobromine, theophylline (coffee, tea, mate, Coca-Cola)

Irreversible, non-selective MAOIs require avoidance of the above-mentioned substances and products during use and for two weeks after use. In the case of reversible MAOIs, dietary restrictions are usually less stringent and apply to the time the substance remains in the body (no more than a day). You should also refrain from using drugs and surfactants listed in the list together with reversible MAOIs until they are completely eliminated.

Interactions with phenylethylamine and tryptamine psychedelics

Most tryptamines are good substrates for MAO-A. DMT and 5-MeO-DMT, when taken orally, are metabolized by it in the gastrointestinal tract and liver, without having time to enter the blood, so they are inactive when taken orally. 4-Hydroxy-DMT (psilocin) is less susceptible to degradation by MAO because its hydroxyl group at the 4th position makes it difficult to bind to the active site of the enzyme, making it orally active. Alkyl substituents on the amino group that are larger than methyl (ethyl, propyl, cyclopropyl, isopropyl, allyl, etc.) also hinder the metabolism of tryptamines with such substituents through MAO, therefore all such tryptamines are active when taken orally. Alpha-methyl in the molecules of tryptamines such as AMT and 5-MeO-AMT significantly impedes their metabolism by MAO, and turns them, de facto, from substrates into weak inhibitors of this enzyme.

Inhibition of peripheral MAO-A - in the gastrointestinal tract and liver by strong MAOIs allows tryptamines such as DMT and 5-MeO-DMT to be orally active, as well as enhance and prolong the effects of other tryptamines such as psilocin and DET. On the other hand, long-term use of MAOIs as antidepressants significantly reduces the effects of psychedelics. This occurs, obviously, due to changes in the monoaminergic systems of the brain caused by increased levels of monoamines. The nature of this phenomenon currently remains unclear, and is not explained by a simple loss of sensitivity of the serotonin receptors with which psychedelics interact.

Thus, taking MAOIs with tryptamines or immediately before using tryptamines prolongs, and in some cases enhances, the effects of the latter, and also makes it possible to use tryptamines such as DMT orally. This is the basis of the principle of action of ayahuasca, and similar mixtures, including the so-called pharmacohoasca, in which pure DMT is used instead of plant components, and both traditional Banisteriopsis Caapi and Peganum Harmala seeds, or their extracts, can be used as MAOIs. or even moclobemide (Aurorix). At the same time, taking an irreversible MAOI a few days before taking a psychedelic will weaken its effect. The same thing will happen with long-term use of both irreversible and reversible MAOIs before taking a psychedelic.

Taking 5-MeO-DMT with an MAOI is not safe. Many people note strong and unpleasant side effects of this combination, including serotonin syndrome. In addition, such an experience is psychologically extremely difficult for many people, and can pose serious risks to mental health.

Tryptamines that significantly increase monoamine levels in the synaptic cleft, such as AMT, 5-MeO-AMT and AET, can be lethal when combined with MAOIs. There is some concern about the safety of using MAOIs with tryptamines such as DPT.

The metabolism of LSD is currently not well understood, but MAO does not appear to be involved in any way. However, according to some participants, when used in conjunction with harmala, its effects are enhanced and prolonged. The same applies to other ergolines.

MAO plays a minor role, or even practically does not participate in the metabolism of phenylethylamine psychedelics. Therefore, taking MAOIs together with them is devoid of practical meaning. Although, according to some users, both harmala and moclobemide enhance the effect of some PEAs, such as 2C-B. In most cases, there are no serious health risks associated with taking MAOIs with phenylethylamine psychedelics. However, the use of MAOIs with sulfur-containing phenylethylamines, such as 2C-T-7 and Aleph-7, should be avoided due to their controversial and poorly studied effects on brain monoamine levels and high toxicity. Combinations of MAOIs with TMA-6 and TMA-2 may also be unsafe.

Other MAOIs

Amphetamines and alpha-methyltryptamines

Nicotiana Rustica

Notes

Indications

In the past, MAO inhibitors were prescribed to patients resistant to tricyclic antidepressants. Newer MAO inhibitors, such as selegiline (commonly used to treat Parkinson's disease) and the reversible MAO inhibitor moclobemide, provide safer alternatives to these drugs and are now sometimes used as first-line treatment. However, these substances do not always act as effectively as their predecessors. MAOIs have been found effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia and post-traumatic stress disorder, and borderline personality disorder. There is evidence of the effectiveness of MAOIs in the treatment of obsessive-compulsive disorder (OCD), trichotillomania, body dysmorphic disorder, and avoidant personality disorder, but these data are from uncontrolled clinical sources. MAOIs may also be used in the treatment of Parkinson's disease, acting in particular on MAO-B (thus affecting dopaminergic neurons), as well as providing an alternative for migraine prevention. Inhibition of MAO-A and MAO-B is used to treat depression and anxiety. MAO inhibitors are particularly often prescribed to outpatients with “neurotic depression” complicated by panic disorder or hysterical dysphoria, which involves repeated episodes of depressed mood in response to feelings of rejection.

Mechanism of action

MAOIs work by inhibiting monoamine oxidase activity, preventing the breakdown of monoamine neurotransmitters, thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A predominantly deaminates serotonin, melatonin, adrenaline and norepinephrine. MAO-B preferentially deaminates phenylethylamine and residual amines. Dopamine is deaminated equally by both types of isoforms.

Reversibility

First-generation MAOIs irreversibly inhibit monoamine oxidase. When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it is replaced in the body with a new one, which can take about two weeks. Some newer MAO inhibitors, the most notable of which is moclobemide, are reversible, meaning they can be dissociated from the enzyme to facilitate normal catabolism of the substrate. The level of inhibition is thus controlled by the concentration of the substrate and the MAOI. Harmaline, found in the plants harmala vulgaris, ayahuasca, spirit vine, and red stratum, is a reversible MAO-A inhibitor (RIMA).

Selectivity

In addition to reversibility, MAO inhibitors vary in MAO receptor selectivity. Some MAO inhibitors can inhibit MAO-A and MAO-B equally, while other MAO inhibitors have been developed for specific purposes. Inhibition of MAO-A reduces the breakdown primarily of serotonin, norepinephrine and dopamine; Selective inhibition of MAO-A allows metabolism via MAO-B. Taking drugs that affect serotonin when taken with another drug that increases serotonin levels can result in a potentially fatal interaction called serotonin syndrome. When taking MAOIs with irreversible and non-selective inhibitors (for example, older generation MAOIs), as a result of interaction with tyramine in the diet, the development of a hypertensive crisis can be provoked. Tyramine is broken down by MAO-A and MAO-B, so inhibition of this action may lead to excessive accumulation, so the patient should carefully monitor his tyramine intake. MAO-B inhibition primarily reduces the breakdown of dopamine and phenylethylamine, so there are no dietary restrictions associated with this. MAO-B will also metabolize since the only differences between dopamine, phenylethylamine and tyramine are the two phenylhydroxyl groups on carbons 3 and 4. 4-OH does not sterically hinder MAO-B on tyramine. Two MAO-B drugs, selegiline and rasagiline, have been approved by the FDA without dietary restrictions except for high-dose treatment, in which case they lose their selectivity.

Dangers

When administered orally, MAO inhibitors inhibit the catabolism of dietary amines. When consuming foods containing tyramine (the so-called “cheese effect”), a person may experience a hypertensive crisis. Hyperserotonemia may develop when consuming foods containing tryptophan. The amount of substance required to produce a response varies greatly among individuals and depends on the degree of inhibition, which in turn depends on dose and selectivity. The exact mechanism by which tyramine causes the hypertensive response is not well understood, but it is thought that tyramine displaces norepinephrine from the vesicles in which it is stored. This can cause a cascade of effects in which excessive amounts of norepinephrine can lead to the development of a hypertensive crisis. Another theory suggests that a hypertensive crisis causes the proliferation and accumulation of catecholamines. It is tyrosine, and not tyramine, that is the precursor of catecholamines. Tyramine is a breakdown product. In the intestine and during fermentation, the amino acid tyrosine is decarboxylated into tyramine. Under normal circumstances, tyramine is deaminated in the liver to inactive metabolites, but when hepatic MAO (primarily MAO-A) is suppressed, the "first pass" of tyramine is blocked, which can lead to increased circulating levels of tyramine. Increased amounts of tyramine compete with for transport across the blood-brain barrier (via aromatic amino acids), where it can penetrate adrenergic nerve endings. After penetration into the cytoplasmic space, tyramine is transported by the vesicular monoamine transporter into synaptic vesicles, thereby displacing norepinephrine. The massive movement of norepinephrine from its vesicular storage into the intercellular space can accelerate the development of a hypertensive crisis. Untreated hypertensive crises can cause stroke or cardiac arrhythmia. Both types of intestinal MAO inhibition can lead to the development of hyperthermia, nausea and psychosis when consuming substances high in . Foods and drinks with potentially high levels of tyramine include: liver and fermented substances such as alcoholic beverages and aged cheeses. found in foods such as beans. These dietary restrictions are not necessary for individuals taking selective MAO-B inhibitors at normal or low doses. Of particular note is the fact that some meat and yeast extracts (Bovril, Marmite, Vegemite) contain extremely high levels and should not be consumed while taking such medications.

When an MAOI is first introduced to the market, be aware of these risks.

nothing was known, and over the next four decades fewer than 100 people died from hypertensive crisis. Presumably due to the sudden onset and violent nature of the reaction, MAOIs gained a reputation for being so dangerous that for a time they were completely discontinued in America. However, it is now believed that when MAOIs are used under the supervision of a qualified psychiatrist, this class of drugs is a viable alternative even for long-term use. The most significant risk associated with the use of MAO inhibitors is the potential for interactions with medications, both over-the-counter and prescription-only, illicit drugs or drugs, and some supplements (eg, St. John's wort). It is very important that a doctor monitors such combinations to avoid possible adverse reactions. For this reason, many users have an MAOI card, which gives all the emergency medical information about the drugs that the patient should avoid (for example, the dose of adrenaline in this case should be reduced by 75% and the duration of exposure increased). The risk of MAOI drugs interacting with other drugs or certain products is especially dangerous because patients taking such drugs often take the attitude that they "don't care if they live or not." MAO inhibitors should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants and illicit substances) except under expert advice. Certain combinations can be fatal, including combinations with SSRIs, TCAs, MDMA, meperidine, tramadol, and dextromethorphan. Drugs that affect epinephrine, norepinephrine or dopamine should be administered in much lower doses due to potentiation and long-lasting effects. Nicotine, a common substance in tobacco addiction, has a “relatively weak” addictive potential when used alone. When administered concomitantly with MAOIs, the addictive potential increases dramatically, resulting in an allergenic musculoskeletal response in rats, which is a measure of the addictive potential of a substance. This may result in difficulty quitting smoking, since tobacco contains natural compounds in addition to nicotine.

Conclusion

Antidepressants, including MAO inhibitors, have addictive properties, the most notable result of which is withdrawal syndrome, which can be severe, especially if MAOIs are stopped suddenly or too quickly. However, the dependence potential of MAO inhibitors or antidepressants in general is not as significant as that of benzodiazepines. To minimize or prevent withdrawal symptoms, the dose may be gradually reduced over several weeks, months, or years. MAO inhibitors, like any other antidepressants, cannot change the course of the disease, so it is possible that when stopping treatment, the patient may return to the state he had before starting treatment. This circumstance significantly complicates the patient’s switching from MAOIs to SSRIs, since after taking one drug and before starting another, a complete cleansing of the body system is necessary. With a gradual dose reduction, the patient will face the fact that for several weeks he will have to deal with depression without pharmacological support during the drug-free interval. This may be preferable to the risk of developing interaction effects between the two drugs, but often this trial is not easy for the patient.

Interactions

MAO inhibitors are known to have numerous drug interactions, including with the following types of substances: 1. Substances that are metabolized by monoamine oxidase, as they can increase their exposure several times. 2. Substances that increase the activity of serotonin, norepinephrine or dopamine, since excess of any of these neurochemicals can lead to serious acute consequences, including the development of serotonin syndrome, hypertensive crisis and psychosis, respectively. Such substances include: - Phenethylamines: 2C-B, mescaline, phenethylamines, etc. - Amphetamines: amphetamine, MDMA, dextroamphetamine, methamphetamine, DOM, etc. - Tryptamines: DMT, psilocin/psilocybin (“magic mushrooms”), etc. - Lysergamides: ergolines/LSA, LSD (“acid”), etc. - Serotonin, norepinephrine and/or dopamine reuptake inhibitors: - Serotonin reuptake inhibitors (SSRIs): citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, . - Serotonin-norepinephrine reuptake inhibitors: desvenlafaxine, duloxetine, milnacipran, . - Norepinephrine-dopamine reuptake inhibitors: amineptine, bupropion, methylphenidate, nomifensine. - Norepinephrine reuptake inhibitors: atomoxetine, mazindol, reboxetine. - Tricyclic antidepressants (TCAs): butriptyline, clomipramine, dozulepine, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine. - Tetracyclic antidepressants: amoxapine, maprotiline. - Phenylpiperidine opioid derivatives: meperidine/pethidine, tramadol, methadone, dextropropoxyphene, propoxyphene. - Others: brompheniramine, chlorpheniramine, cocaine, cyclobenzaprine, dextromethorphan (DXM), ketamine, MDPV, nefazodone, phencyclidine (PCP), pheniramine, sibutramine, trazodone. - Substances that release serotonin, norepinephrine and/or dopamine: 4-methylaminorex (4-MAR), amphetamine, benzphetamine, cathine, cathinone, diethylcathinone, levmethamphetamine, lisdexamfetamine, MDMA (“ecstasy”), methamphetamine, pemoline, phendimetrazine, phenethylamine ( PEA), phentermine, propylhexedrine, pseudoephedrine, phenylephrine, . - Precursors of serotonin, norepinephrine and/or dopamine: 5-HTP, L-phenylalanine, L-tyrosine. - Anesthetics used in surgery and dentistry for local and general action, in particular those containing adrenaline. There is no universal practice in dentistry regarding the use of MAO inhibitors such as phenelzine, which is why it is important to inform all clinicians, especially dentists, about the potential effect of MAO inhibitors in local anesthesia. It is advisable to stop taking phenelzine in preparation for dental procedures, however, because it takes two weeks to stop taking it, this option is not always desirable or practical. Dentists using local anesthesia are advised to use a non-epinephrine based anesthetic such as 3% carbocaine. Particular attention should be paid to blood pressure during the procedure. The anesthetic level should be regularly and correctly replenished, since non-epinephrine anesthetics begin to act later and wear off more quickly. Patients taking phenelzine should notify their psychiatrists before undergoing any dental treatment. - Some other supplements: Hypericum perforatum (St. John's wort), inositol, Rhodiola rosea, S-adenosyl-L-methionine (SAME), . - Other monoamine oxidase inhibitors.

Story

The heyday of MAOI popularity occurred for the most part from 1957 to 1970. The initial popularity of “classical” non-selective irreversible MAO inhibitors has waned due to the presence of dangerous interactions of these drugs with sympathomimetic drugs and products containing tyramine, which can lead to the development of a hypertensive crisis. As a result, physician use of previous generation MAOIs has decreased. When scientists discovered that there were two different MAO enzymes (MAO-A and MAO-B), they developed MAO-B selective compounds (such as selegiline, which is used to treat Parkinson's disease) to reduce side effects and serious drug interactions. . Further improvement has occurred with the development of compounds (moclobemide and toloxatone) that are not only selective, but also cause reversible MAO-A inhibition and have a reduced rate of dietary and drug interactions. Irreversible MAO inhibitors were the first open antidepressants, but their popularity has declined with the advent of safe antidepressants; This new class of antidepressants has fewer side effects, especially the dangerous irreversible interaction of MAOIs with tyramine-containing foods, sometimes called “cheese syndrome,” which leads to severe hypertension. However, reversible MAO inhibitors do not have these adverse hypertensive consequences. Moclobemide was the first reversible MAO-A inhibitor introduced into widespread clinical practice. Its features as a reversible inhibitor give it a number of advantages over previous generation irreversible MAO inhibitors. On February 28, 2006, the US FDA approved a transdermal form of the MAOI selegiline, called Emsam, for the treatment of depression.

List of MAOIs

Mentions in culture

In the episode "The Late Shaft" of the detective TV drama Castle, Bobby Mann was taking MAO inhibitors. His killer used this fact to cause a negative interaction with the drug, which led to Bobby's death, which looked like a normal heart attack.

In the episode "Cut" of Law & Order, a surgeon puts a patient on painkillers that interact with the MAO inhibitors she is taking, causing her death.

The pilot episode of Law & Order was based on true events. Journalist Sidney Zion questioned the sudden death of his daughter Libby Zion in a Manhattan emergency room on October 4, 1984. The cause of death was listed as "mysterious infection." The father convinced the authorities to open a criminal case. This was done after it was discovered that his daughter had taken certain medications before her death, including Demerol, which reacted with the drug Nardil, which the victim was taking. The district attorney filed a murder charge against the doctor who approved the use of drugs on Libby. This case led to many reforms in medical education and restrictions on the number of working hours for medical employees. In the end, it turned out that the main cause of death was drug abuse.

Monoamine oxidase inhibitors (MAO) are biological substances that, by reducing the rate of chemical reactions of the enzyme monoamine oxidase, prevent the destruction of various monoamines (this group includes serotonin, norepinephrine, dopamine, phenylethylamine, tryptamine and octamine). This increases the concentration of the active element between two neurons or between a neuron and an effector molecule (a particle that binds to proteins to increase biological activity).

For medical purposes, MAOIs are used as antidepressants, and sometimes to treat Parkinson's disease and narcolepsy attacks - a pathological condition of the nervous system that causes drowsiness and a sudden "attack" of sleep.
Based on their pharmacological properties, MAOIs are divided into:
non-selective irreversible;

reversible selective;

irreversible selective.

So, let's take a brief look at each group and learn about the active ingredients, properties and trade names.

№	Non-selective irreversible MAOIs – inhibit MAO-A and MAO-B	Table 1	Active substance
1.	Short description	Has a pronounced hepatotoxic effect. In this regard, it is used and prescribed very rarely. Can be used for no more than 2 weeks.	"Iprazide"
2.	Nialamid	The chemical structure is similar to iproniazid, but has a more gentle toxic effect. Improves general condition and helps recover from depression. The appearance of the therapeutic effect is observed after 1-2 weeks.	"Nialamide"
3.	Isocarboxazid	Activates certain natural components in the brain to maintain mental balance.	"Marplan"
4.	Phenelzine	Prescribed to reduce depressive syndrome. Reduces restlessness and anxiety.	"Nardil"
5.	Tranylcypromine	Recommended in the treatment of mental illnesses that develop against the background of depression. Has a stimulating effect. Can be metabolized to amphetamine.	"Parnat"

Reversible selective MAO-A inhibitors

table 2

№	Non-selective irreversible MAOIs – inhibit MAO-A and MAO-B	Table 1	Active substance
1.	Moclobemide	Prescribed for depression and social phobia. Blocks the destruction of norepinephrine and serotonin.	"Aurorix"
2.	Pyrazidol	Shows therapeutic effects in patients with apathetic attacks and depressive disorders. It is also prescribed for agitation – strong emotional arousal, which is manifested by feelings of anxiety and fear. The drug is widely used in psychiatric practice.	"Pirlindol"
3.	Bethol	Indications: depressive syndrome, anxiety and delusional disorders, hallucinations. For alcoholism: asthenosubdepressive syndrome.	"Befol"
4.	Incazan	Pharmacological properties are similar to pyrazidol. Activates norepinephrine and serotonin in the central nervous system. Widely used for mental disorders: schizophrenia, manic-depressive psychosis, sudden mood swings, and also to improve blood circulation in the brain. When treating alcoholism, the drug is recommended to be taken during the period of remission.	"Metralindole"
5.	Beta-carboline derivatives	The β-Carboline backbone is the main structure for many alkaloids that are isolated from plant components. Medicines containing this substance can be used in the fight against alcoholism and depression. Derivatives are also used in antiviral, antibacterial and antitumor therapy. In addition, active compounds help in the fight against rheumatoid arthritis, osteoarthritis, and bronchial asthma.	"Garman", "Garmin"

Irreversible selective MAO-B

Table 3

№	Non-selective irreversible MAOIs – inhibit MAO-A and MAO-B	Table 1	Active substance
1.	Selegilin	Pharmacological group: antiparkinsonian drug. Selegin is involved in dopamine metabolism (inhibits). Thus, there is an increase in neurotransmitter in various parts of the brain. The time it takes for the enzyme to recover is 2 weeks.	"Yumex", "Stillin"
2.	Rasagiline	Antiparkinsonian drug. Recommended for the treatment of true Parkinson's disease, as well as in the presence of symptoms that indicate this pathology. The product has an effect due to the accumulation of special natural compounds in the brain. The drug is taken according to the schedule; sudden withdrawal or sharp increase in dose can lead to serious consequences.	"Azilect"
3.	Pargilin	Antidepressant, recommended for mental and nervous disorders. When combined with the drug Methyclothiazide, it may lower blood pressure.	"Pargilin"

Surely each of us has been exposed. Thanks to sudden life changes, the human body seems to develop “mental immunity”, thereby increasing its regenerative abilities. Thus, before using psychotropic drugs (monoamine oxidase inhibitors), you should find out whether they are really necessary to survive depression or stress.

Use of MAO inhibitors. MAO inhibitors - what are they? Irreversible selective MAO-B inhibitors

MAOI classification

Non-selective irreversible MAOIs

Reversible selective MAO-A inhibitors

Irreversible selective MAO-B inhibitors

Therapeutic effect

Side effects

Non-selective inhibitors

Selective inhibitors

Interactions

Foods incompatible with MAOIs

Interaction with drugs and narcotics

Restrictions on use

Precautionary measures

Non-medical use

Interactions with phenylethylamine and tryptamine psychedelics

Overdose

MAOI classification

Non-selective irreversible MAOIs

Reversible selective MAO A inhibitors

Irreversible selective MAO B inhibitors

Pharmacology MAOI

General information

Interaction with drugs and some surfactants

Foods incompatible with MAOIs

Interactions with phenylethylamine and tryptamine psychedelics

Other MAOIs

Amphetamines and alpha-methyltryptamines

Nicotiana Rustica

Notes

Links

see also

Group 2 - non-selective

Group 1 - electoral

Indications

Mechanism of action

Reversibility

Selectivity

Dangers

When an MAOI is first introduced to the market, be aware of these risks.

Conclusion

Interactions

Story

List of MAOIs

Mentions in culture

irreversible selective.

Reversible selective MAO-A inhibitors

Irreversible selective MAO-B