Substances that inhibits the cytochrome P450 system’s ability to metabolize certain drugs, leading to an overall increase in processing times.
Monoamine oxidase inhibitors (also known as MAOIs) are a class of drugs which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression and are particularly effective in treating atypical depression. They are also used in the treatment of social anxiety, Parkinson's disease and several other disorders.
Mechanism of action
MAOIs act by inhibiting the activity of monoamine oxidase, preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B.
MAOA preferentially deaminates norepinephrine (NE), serotonin (5-HT) and epinephrine (E), while MAOB preferentially deaminates benzylamine and phenylethylamine (PEA). Dopamine (DA) and tyramine are equally catabolized by both forms of MAO.
The early MAOIs inhibit monoamine oxidase irreversibly, meaning they permanently deactivate it and the enzyme cannot function until it has been replaced by the body, which can take about two weeks.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, known as reversible inhibitors of monoamine oxidase A (RIMAs), are reversible. This means that they are able to detach from the enzyme to facilitate usual catabolism of the substrate.
Consumption planning for MAOIs
Not only avoid the consumption but also the handling of substances with dangerous MAOI interactions (in case they are absorbed unintentionally, e.g. via breathing, skin absorption, or contaminated fingers to mouth, nose, eyes, etc).
Before MAOI consumption
- Substances with slow elimination
- Methamphetamine: Because of its slow elimination, low concentrations of Methamphetamine can be detected in urine for up to 7 days after a single oral dose of 30 mg (Valentine et al., 1995) or up to 60 h after a single 15-mg smoked or intravenous dose (Cook et al., 1993). A chronic meth user might still test positive seven to 10 days after consuming the drug.
- Pharmacotherapy examples
- Cannabinoids: Cannabinoids are lipophilic. For example, THC has been detected in heavy cannabis users after 77 days of drug abstinence (Ellis et al., 1985).
- SSRIs: Because of the extended half-life of norfluoxetine, a minimum of 5 weeks should lapse between stopping fluoxetine (20 mg/day) and starting an MAOI. With higher doses the interval should be longer. For example, a serotonin syndrome was reported following a 6-weeks washout in a patient who had been given fluoxetine (80 mg/day).
- Tolerance from heavy substance use or therapy may cause post-acute-withdrawal syndrome (PAWS). The condition gradually improves over a period of time which can range from six months to several years in more severe cases.
After MAOI consumption
MAOIs cause dangerous interactions with many substances, they must be avoided during or within 14 days of administration of monoamine oxidase inhibitors.
Poly drug use
When the CYP450 system is impacted in this way, it leads to higher levels of certain drugs in your system at one time. This can cause unwanted side effects, and sometimes, an overdose.
Tyramine causes hypertensive crises after MAO inhibition aka the "cheese effect" or "cheese crisis". Using a MAO inhibitor (MAOI), the intake of approximately 10 to 25 mg of tyramine is required for a severe reaction compared to 6 to 10 mg for a mild reaction. Tyramine rich food should also be avoided by people prone to headache and migraine.
Naturally occurring sources with tyramine.
- Psychedelic cacti. The cacti contain contain a bunch of phenethylamines, not just tyramine (but also 3-Methoxytyramine, methyltyramine, hordenine (aka dimethyltyramine), mescaline, etc) and should thus be avoided with MAOIs. However, tyramine has been identified in these species:
|Specie||Tyramine (mg/gram of alive plant)|
|L. williamsii||0.5 - 1|
- Aged cheese (gouda, camembert, cheddar) -- Few cheeses (even. 'mature' cheeses) contain more than 25 mg of tyramine in 100 grams. However, Stilton (a blue cheese) contains up to 217 mg tyramine per 100 grams.
- Aged, smoked or pickled meats
- Aged or fermented soy and yeast products (soy sauce, teriyaki sauce, home baked yeast bread, sourdough bread)
- Overripe fruits
- High amounts of nuts
Candy, and dried fruit:
- Chocolate, especially dark chocolate
- Dried and/or candied fruit rolled in cocoa powder
- Licorice (isoliquiritigenin and liquiritigenin are non-selective MAOIs).
- Licorice candy
- Dried and/or candied fruit rolled in licorice powder
Tyramine formation has been associated with bacterial contamination of foods or temperature abuse conditions, but can also occur as a side effect of generally desired ripening processes. Tyramine is a breakdown product of the amino acid L-tyrosine.
The MAOIs are well-known 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, noradrenaline, or dopamine activity as too much of any of these neurotransmitters can result in severe acute consequences including serotonin syndrome, hypertensive crisis, and psychosis.
- Lysergamides: LSA (morning glory: (Argyreia nervosa, Ipomoea tricolor, etc)
- Monoaminergics (MA)
- Cholinergics (see also MAOIs that act as acetylcholinesterase inhibitors (AChEIs)), certain substances, examples: alpha-GPC (suspected monoaminergic), centrophenoxine, citicoline (suspected monoaminergic)
- MAOIs, avoid mixing pure MAOIs. Plants with multiple MAOIs like Peganum harmala are fine since they have been evaluated.
- Norepinephrine and dopamine disinhibitors (NDDIs): Fluoxetine
- Neurotransmitter precursors
- Opioids: Some opioid analgesics are associated with a risk of serotonin syndrome in combination with MAOIs due to their serotonergic properties. Other combinations may result in opioid toxicity due to CYP450 enzyme inhibition by the MAOI. Given the widespread availability of several suitable alternative drugs, the combination of dextromethorphan, methadone, pethidine, tramadol, fentanyl or tapentadol with an MAOI should usually be avoided, including in the 14 day period following the withdrawal of an irreversible MAOI. Morphine, codeine, oxycodone and buprenorphine are alternative opioids for patients receiving MAOIs, though starting at a low dose and titrating cautiously against clinical response is advised.
- Racetams: Aniracetam, piracetam
- Receptor agonists
- Releasing agents and monoamine releasing agent (MRA) (or monoamine releaser)
- Dopamine releasing agent (DRA)
- Norepinephrine releasing agent (NRA) (or adrenergic releasing agent), examples: Adrenaline, ephedrine, pseudoephedrine
- Norepinephrine-dopamine releasing agents (NDRAs), examples: Amphetamine, cathinone, phenethylamine, tyramine, methamphetamine
- Serotonin releasing agent (SRA)
- Serotonin–norepinephrine-dopamine releasing agent (SNDRA) (also known as a triple releasing agent (TRA)), examples:
- Reuptake inhibitors and monoamine reuptake inhibitors (MRIs)
- Dopamine reuptake inhibitors (DRI), examples: Armodafinil, ethylphenidate, methylphenidate, modafinil
- Norepinephrine reuptake inhibitor (NRI, NERI) (or adrenergic reuptake inhibitor (ARI)), example: Tapentadol
- Norepinephrine-dopamine reuptake inhibitors (NDRI), examples: Ethylphenidate, methylphenidate, prolintane. Suspected: A-PVP, desoxypipradrol, MDPV
- Serotonin reuptake inhibitor (SRA)
- Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), examples:
- Serotonin modulator and stimulator (SMS)
- Substituted cathinones, examples: a-PVP, MDPV, methylone, mephedrone
- Substituted phenethylamines
- Substituted tryptamines, examples:
- Tetracyclic antidepressants (TeCA), example: Mirtazapine
- Tricyclic antidepressants (TCA), example: Tianeptine
- Tropane alkaloids
- Xanthines: Caffeine
- Hyoscine, also known as scopolamine: The transdermal patch (e.g., Transderm Scōp) for prevention of nausea and motion sickness employs hyoscine base, and is effective for up to three days.
- Antihistamines (allergy medicines), example but not limited to:
- Desloratadine -- hay fever medicine.
- Loratadine -- hay fever medicine.
- Cold medicine
- Decongestants, example but not limited to:
- Naphazoline (brand name Clear Eyes, Cleari) -- eye drops relieve dry, red, itchy eyes.
- Essential nutrients
- Certain cholinergics (see "Cholinergics")
- Local and general anesthetic
Over-the-counter (OTC) medicines
Although many psychoactive substances are reasonably safe to use on their own, they can suddenly become dangerous or even life-threatening when combined with other substances. The following list includes some known dangerous combinations (although it is not guaranteed to include all of them). Independent research (e.g. Google, DuckDuckGo) should always be conducted to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
- 2c-t-x - MAO-B inhibitors can increase the potency and duration of phenethylamines unpredictably, which could be dangerous given the unpredictability of the 2C-T-x series
- 2c-x - MAO-B inhibitors can increase the potency and duration of phenethylamines unpredictably
- dox - MAO-B inhibitors can increase the potency and duration of phenethylamines unpredictably
- ketamine - MAO-B inhibitors appear to increase the potency of Ketamine. MAO-A inhbitors have some negative reports associated with the combination but there isn't much information available
- nbomes - MAO-B inhibitors can increase the potency and duration of phenethylamines unpredictably
- opioids - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe and fatal adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
- alcohol - Tyramine found in many alcoholic beverages can have dangerous reactions with MAOIs, causing an increase in blood pressure.
- mxe - MAO-B inhibitors appear to increase the potency of MXE. MAO-A inhbitors have some negative reports associated with the combination but there isn't much information available
- amphetamines - MAO-B inhibitors can increase the potency and duration of phenethylamines unpredictably. MAO-A inhibitors with amphetamine can lead to hypertensive crises.
- amt - aMT is an MAOI on its own. Using enzyme inhibitors can greatly reduce predictability of effects.
- cocaine - This combination is poorly explored
- dxm - High risk of serotonin syndrome
- mdma - MAO-B inhibitors can increase the potency and duration of phenethylamines unpredictably. MAO-A inhibitors with MDMA will lead to hypertensive crises.
- pcp - This combination is very poorly explored
Essential vitamins and minerals
- Vitamin B6: MAOIs may reduce blood levels of vitamin B6.
List of MAOIs
Nonselective MAO-A and MAO-B inhibitors
- Naturally occurring sources
|Natural occuring source||Chemical||MAOI|
|Yangonin (ayahuasca, caapi or yagé)||(−)-epicatechin||MAO-B|
|Banisteriopsis caapi (ayahuasca, caapi or yagé)||(−)-epicatechin||MAO-B|
|Banisteriopsis caapi (ayahuasca, caapi or yagé)||(−)-procyanidins||MAO-B|
|Banisteriopsis caapi (ayahuasca, caapi or yagé)||Harmaline||RIMA|
|Banisteriopsis caapi (ayahuasca, caapi or yagé)||Harmine||MAO-A, MAO-B|
|Black pepper (Piper nigrum)||Piperine||MAO-A, MAO-B|
|Cannabis, Cannabis extract||MAO-A, MAO-B|
|Cocoa bean (from Theobroma cacao)||Caffeine||MAO-A, MAO-B|
|Cocoa bean (from Theobroma cacao)||Catechin||MAO-B|
|Cocoa bean (from Theobroma cacao)||Epicatechin||MAO-B|
|Cocoa bean (from Theobroma cacao)||Tetrahydro-beta-carbolines|
|Coffee (Coffea arabica, Coffea canephora)||Caffeine||MAO-A, MAO-B|
|Coffee (Coffea arabica, Coffea canephora)||Harman||MAO-A|
|Coffee (Coffea arabica, Coffea canephora)||Norharman||MAO-A|
|Liquorice/licorice (Glycyrrhiza Glabra)||Isoliquiritigenin||MAO-A, MAO-B|
|Liquorice/licorice (Glycyrrhiza Glabra)||Liquiritigenin||MAO-A, MAO-B|
|Long pepper (Piper longum)||Piperine||MAO-A, MAO-B|
|Nutmeg (Myristica fragrans)||Kaempferol||MAO-A|
|Nutmeg (Myristica fragrans)||Myristicin||MAO-A, MAO-B?|
|Nutmeg (Myristica fragrans)||Quercetin||MAO-A|
|Passionflower (Passiflora incarnata), weak MAOI||Apigenin||MAO-A|
|Passionflower (Passiflora incarnata), weak MAOI||Harmine||MAO-A, MAO-B|
|Passionflower (Passiflora incarnata), weak MAOI||Kaempferol||MAO-A|
|Passionflower (Passiflora incarnata), weak MAOI||Quercetin||MAO-A|
|Rhodiola rosea||MAO-A, MAO-B|
|Syrian rue (Peganum harmala)||Desoxypeganine||MAO-A|
|Syrian rue (Peganum harmala)||Harmaline||RIMA|
|Syrian rue (Peganum harmala)||Harman||MAO-A|
|Syrian rue (Peganum harmala)||Harmine||MAO-A, MAO-B|
|Tobacco||1,2,3,4-tetrahydro-b-carboline (THbC)||MAO-A, MAO-B|
- Hydrazine (antidepressant)
- Isocarboxazid (Marplan)
- Nialamide (Niamid)
- Phenelzine (Nardil, Nardelzine)
- Tranylcypromine (Parnate, Jatrosom)
- Hydrazine (antidepressant)
Selective MAO-A inhibitors
- Naturally occurring sources
- Bifemelane (Alnert, Celeport) (available in Japan)
- Isocarboxazid (common brand name Marplan)
- Phenelzine (common brand name Nardil)
- Pirlindole (Pirazidol) (available in Russia)
- Tranylcypromine (common brand name Parnate)
Selective MAO-B inhibitors
- Naturally occurring sources
- Betel nut (Areca catechu): MAO-A inhibitor.
- Kava (Piper methysticum): Yangonin. Kava pyrones: The order of potency was desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-)-dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain.
- Olives (Olea europaea), fresh, olive leaf extract: The selective MAO-B inhibitor hydroxytyrosol.
- Rasagiline (Azilect)
- Selegiline (Deprenyl, Eldepryl, Emsam, Zelapar)
- Safinamide (Xadago)
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