A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths

Gillman, P. Ken

doi:10.1007/s00702-018-1932-y

Cited by 239 publications

(64 citation statements)

References 121 publications

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Section: Introductionmentioning

confidence: 99%

“…The biogenic amine tyramine is formed through decarboxylation of tyrosine by microbes, and is thus found in numerous fermented, aged, or ripened protein-rich food products (McCabe-Sellers et al, 2006; Ladero et al, 2010; Gillman, 2018). Tyramine functions as an indirect sympathomimetic by promoting the release of noradrenaline from synaptic vesicles, thereby having hypertensive effects (referred to as the tyramine pressor response; Gillman, 2018). In combination with monoamine oxidase (MAO) inhibitors, tyramine can cause a so-called hypertensive crisis that, beside symptoms like headache, migraine, nausea, or vomiting, may even cause end-organ damage, intracerebral haemorrhage, and death (Blackwell, 1963; Gillman, 2018; Salter and Kenney, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A

et al. 2019

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Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A

et al. 2019

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“…It should be cautioned that reversibility of MAO-A inhibition is an important consideration since irreversible inhibitors such as tranylcypromine and phenelzine may cause a severe hypertensive crisis when combined with food that contains the sympathomimetic amine, tyramine [10,11]. With the irreversible inhibition of MAO-A in the gastrointestinal tract and vascular endothelium, dietary tyramine gains access to the circulatory system which leads to the release of norepinephrine from the sympathetic neurons and subsequently a hypertensive reaction [5,12]. In some instances, this hypertensive reaction can be fatal.…”

Section: Introductionmentioning

confidence: 99%

The monoamine oxidase inhibition properties of C6- and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives

Marais

Petzer

2019

Mol Divers

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Quinazolinone compounds are of interest in medicinal chemistry since they display a wide range of biological properties. In the present study, a series of C6-and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO). Some of these quinazolinones are structurally related to a series of 3,4-dihydro-2(1H)-quinolinone derivatives, which have previously been reported to act as specific inhibitors of MAO-B. The results document that, among 37 compounds synthesised, seven displayed IC 50 values < 1 µM for the inhibition of MAO-B. The most potent MAO-A inhibitor exhibits an IC 50 value of 7.43 µM while the most potent MAO-B inhibitor possesses an IC 50 value of 0.269 µM. Good-potency MAO inhibition was only observed among C6-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives with N1-substitution yielding comparatively lowpotency inhibition. MAO-B-specific inhibitors such as some of the quinazolinone compounds investigated here may act as leads for the design of therapies for neurodegenerative disorders such as Parkinson's disease.

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“…Consequently, psychiatrists overestimate the risks of side effects, drug-drug interactions, and the difficulty of following a low-tyramine diet with MAOIs. 8,9 It has been pointed out that there is much misleading and incorrect information contained in standard texts, including the United States Physicians' Desk Reference (PDR), the European electronic Medicines Compendium (eMC), and the British National Formulary (BNF); these texts require urgent updating to remove errors and bring them into line with state-of-the-art knowledge. Texts with more up-todate information are available.…”

mentioning

confidence: 99%

“…Texts with more up-todate information are available. 8,10 These issues lead to a disproportionate "riskaversion" toward prescribing MAOIs. Other examples of commonly perpetuated but incorrect information include the ideas that changes to medication regimens or combinations of antidepressants are difficult when receiving an MAOI, that MAOIs must be stopped prior to anesthesia, and that opioid medications cannot be used.…”

mentioning

confidence: 99%

Revitalizing monoamine oxidase inhibitors: a call for action

Pk¹,

Feinberg

Fochtmann

2019

CNS Spectr.

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This statement represents the view of the "International MAOI Expert Group" which is a group of clinicians, academics, and researchers with a special interest in monoamine oxidase inhibitors (MAOIs). This group was formed in March 2018 to promote actions aimed at: improving education; stimulating research; increasing clinical usage; and assuring continued availability of MAOIs worldwide. Non-selective irreversible MAOIs, including tranylcypromine, phenelzine, isocarboxazid, and the Selegiline Transdermal System (STS), can be dramatically effective for patients with biological depressive illnesses (e.g., melancholia and bipolar depression). It has been established by more than 50 years of research, including randomized double-blind studies, and clinical experience, that these medications can induce full remission when other antidepressants, combinations, and augmentation strategies, and even electroconvulsive therapy (ECT), have failed. 1-4 Because of their unique pharmacological properties, the efficacy of non-selective irreversible MAOIs is superior, in a proportion of patients, to more recently developed medications, including moclobemide, a reversible inhibitor of MAO-A, or MAO-B-selective doses of selegiline. Patients may experience fewer side effects with MAOIs than with other antidepressants; for example, the low rates of weight gain, cognitive dysfunction and sexual side effects with tranylcypromine and selegiline (STS) are a major advantage for many patients. 5,6 Despite these valuable attributes these vital life-saving antidepressant drugs are becoming unaffordable (because the cost has inexplicably escalated by about 50-fold), less available, or even unavailable, in many countries around the world.

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A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths

Cited by 239 publications

References 121 publications

Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A

Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A

The monoamine oxidase inhibition properties of C6- and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives

Revitalizing monoamine oxidase inhibitors: a call for action

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