Monoamine Oxidase Inhibitors (MAOI)

Summary

drug class: MAO (Monoamine Oxidase) Inhibitors

drugs and trade names:
• Furazolidone: Furoxone
• Isocarboxazid: Marplan®
• Isoniazid: Laniazid®, Nydrazid®
• Isoniazid rifampin: Rifamate®, Rimactane®/INH
• Moclobemide
• Pargyline: Eutonyl®
• Phenelzine: Nardil®
• Procarbazine: Matulane®
• Selegiline: Atapryl®, Deprenyl®, Eldepryl®
• Tranylcypromine: Parnate®

type of drug:
Two groups:
• Hydrazine derivatives: phenelzine, isocarboxazid
• Non-hydrazine derivatives: tranylcypromine, pargyline

mechanism: Agents that inhibit monoamine oxidase and alter catecholamine metabolism (down-regulating noradrenergic synpases and upregulating serotogenic synapses); includes other agents with secondary MAOI action, e.g., phenelzine.

used to treat: Depression (refractory to tricyclic antidepressants); antineoplastic (procarbazine), antibiotic (furoxone); adjunctive treatment in Parkinson's (selegine) and hypertension (pargyline).

overview of interactions:
• nutrient affected by drug: Vitamin B6 (Pyridoxine)

• nutrient affecting drug performance: Tryptophan

• foods interacting with drug: Tyramine-containing Foods

• herb affecting drug performance: Cytisus scoparius (Scotch Broom)

• herbal constituents affecting drug performance: MAO-inhibiting herbal constituents

Harmane alkaloids: Passiflora incarnata (Passion Flower); Peganum harmala (Syrian Rue)
Hypericin: Hypericum perforatum (St. John's Wort)
Isoliquiritigenin: Glycyrrhiza glabra (Licorice Root)
Mescaline: Lophophora williamsii (Peyote)
Myristicin: Myristica fragrans (Nutmeg)
Yohimbine: Pausinistalia yohimbe (Yohimbe)

• herb affecting drug performance: Hypericum perforatum (St. John's Wort)

• herbal constituent affecting drug performance: Yohimbine, as in Pausinystalia yohimbe (Yohimbe)

• herbs affecting drug performance: Physiological Interactions with Neuroendocrine and Cardiovascular Herbs.




Interactions

nutrient affected by drug: Vitamin B6 (Pyridoxine)

• research: Anecdotal evidence indicates that MAO Inhibitors, especially Nardil®, can cause vitamin B6 deficiencies. As of yet, there has been no definitive confirmation of this interaction.

• nutritional support: Given that several related drugs, such as Nardil®, hydralazine and isoniazid, can induce vitamin B6 deficiencies, some nutritionally-trained physicians advise patients taking these or similar drugs to supplement with vitamin B6, usually at moderate levels such as 50 mg per day.

• nutrient affecting drug performance: Tryptophan
Caution should be used when taking tryptophan while using monoamine oxidase inhibitors since its effects could be amplified. Tyrosine, phenylalanine, valine, leucine and isoleucine all compete with tryptophan for transport into the brain.
(Goff DC. Am J Psychiatry 1985 Dec;142(12):1487-1488; Pope HG Jr, et al. Am J Psychiatry 1985 Apr;142(4):491-492.)

foods interacting with drug: Tyramine-containing Foods

• mechanism: Since gastrointestinal MAO is essential for adequate breakdown of tyramine, anyone using MAO inhibitors should also avoid these foods. Absorption of intact tyramine leads to competition at adrenoreceptors and can cause potentially toxic elevation of catecholamine levels, resulting in pallor, headaches, nausea and hypertension.

Only a very limited number of foods, those with dangerously high concentrations of tyramine appear to require absolute restriction. These include aged cheese; aged or cured meats (e.g., air-dried sausage); any potentially spoiled meat, poultry, or fish; broad (fava) bean pods; Marmite concentrated yeast extract; sauerkraut; soy sauce and soy bean condiments; and tap beer. Wine and domestic bottled or canned beer are considered safe when consumed in moderation.
(Shulman KI, et al. J Clin Psychopharmacol 1989 Dec;9(6):397-402; Walker SE, et al. J Clin Psychopharmacol 1996 Oct;16(5):383-388; Gardner DM, et al. J Clin Psychiatry 1996 Mar;57(3):99-104.)

herb affecting drug performance: Cytisus scoparius (Scotch Broom)

• mechanism: Scotch broom is rich in tyramine. As discussed above, tyramine catabolism requires MAO; tyramine sources such as Scotch Broom combined with monoamine oxidase-inhibiting drugs can theoretically result in hypertension and other adverse effects through adrenoreceptor-tyramine interaction. However, Cytisus also contains the alkaloid sparteine which has cardiodepressant activity. In the unlikely event of patients with cardiovascular conditions on MAOI therapy consuming excessive doses of Scotch Broom, the effects of sparteine are actually anti-adrenergic, antiarrhythmic, and bradycardic which would, at least theoretically, counter any tyramine induced effects.

herbal constituents affecting drug performance: MAO-inhibiting herbal constituents – a speculative interaction.

• research: Numerous herbal constituents have been shown to have mild in vitro MAOI activity, including the following:

Harmane alkaloids: Passiflora incarnata (Passion Flower); Peganum harmala (Syrian Rue)
Hypericin: Hypericum perforatum (St. John's Wort)
Isoliquiritigenin: Glycyrrhiza glabra (Licorice Root)
Mescaline: Lophophora williamsii (Peyote)
Myristicin: Myristica fragrans (Nutmeg)
Yohimbine: Pausinistalia yohimbe (Yohimbe)

There have been no cases in which significant direct MAOI drug agonism has been reported and confirmed. In fact, several of the herbs containing MAOI active constituents have pronounced physiological actions that are more prominent than any catecholamine elevation. In some cases these physiological interactions would be significant in the case of MAOI therapy. However, the direct MAOI activity interactions are appropriately described as speculative. See herbal concerns below. The case of Hypericum (St. Johns Wort) is often quoted in textbook sources.

herb theoretically affecting drug performance: Hypericum perforatum (St. Johns Wort)

• mechanism: In vitro the phloroglucinol derivative hyperforin inhibits uptake of serotonin (5HT), dopamine (DA), noradrenaline (NA), GABA, and glutamate according to Chatterjee et al. Research by Cott and Misra demonstrated that, in vitro, the crude extract of Hypericum has weak receptor affinity for MAO-A and MAO B receptors. Isolated hypericin does not display this activity, but does have affinity for NMDA receptors. Muller and Rossol found that, in vitro, the crude extract of Hypericum inhibits serotonin receptor expression.
(Chatterjee SS, et al. Pharmacopsychiatry. 1998 Jun;31 Suppl 1:7-15; Cott and Misra, 1997; Muller WE, Rossol R. et al. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S63-634.)

Although St. John's Wort has been regarded as a MAOI, the MAOI effect of Hypericum is not large enough to account for an antidepressant action based on this effect. Current research indicates inhibition of reuptake of dopamine, serotonin, and norepinephrine to be the acute effects that lead to receptor adaptive changes that produce the antidepressant effect. This presents the theoretical possibility of Hypericum interacting adversely with some antidepressants, albeit through a mechanism different than MAOI. At this point any concern regarding an interaction between Hypericum and MAO-inhibitors is merely theoretical and no cases have been reported in the scientific literature. The reported pharmacological effects of many herbs are based on assays that may have little if any clinical relevance.
(Dentali)

herbal constituent affecting drug performance: Yohimbine, as in Pausinystalia yohimbe (Yohimbe)

• mechanism: Yohimbine, the principal alkaloid of Yohimbe, may block the enzyme monoamine oxidase. However its primary action is established as a central alpha-2a adrenergic antagonist, and by increasing central epinephrine and norepinephrine turnover, general sympathetic outflow is increased resulting in elevated catecholamine levels and autonomic activity. Adverse effects of excessive Yohimbe consumption in humans include a variety of cardiovascular, psychological and other effects. (Reviewed, De Smet, 1997).

• herbal concerns: Individuals taking an MAO Inhibitor should consult with their prescribing physician before consuming Yohimbe or derivative products.

herbs affecting drug performance: Physiological Interactions with Neuroendocrine and Cardiovascular Herbs.

• herbal concerns: The primary interactions most likely to be encountered in practice between common herbs and MAO inhibiting drugs are with those herbs that have actions directly affecting sympathetic function such as Ephedra spp.; or those that have physiological effects on the cardiovascular system whether directly (see Cytisus above) or indirectly, e.g., Licorice root and pseudoaldosterone induced hypertension. In addition, where MAO inhibiting drugs are being used as antidepressants or anxiolytics, it is not unreasonable to speculate that herbal sedatives may potentiate the drug action, and caution should be observed in any proposed concurrent use of sedative or opioid herbs with MAOI's.

References

Abdel-Fattah AF, Matsumoto K, Murakami Y, Adel-Khalek Gammaz H, Mohamed MF, Watanabe H. Central serotonin level-dependent changes in body temperature following administration of tryptophan to pargyline- and harmaline-pretreated rats. Gen Pharmacol. 1997 Mar;28(3):405-409.

Bhattacharya SK, Mitra SK. Anxiolytic activity of Panax ginseng roots: an experimental study. J Ethnopharmacol 1991 Aug;34(1):87-92.
Abstract: The putative anxiolytic activity of the white and red varieties of ginseng, the root of Panax ginseng, was investigated in rats and mice using a number of experimental paradigms of anxiety and compared with that of diazepam. Pilot studies indicated that -dose administration of ginseng had little to no acute behavioural effects, hence the two varieties of ginseng were administered orally at two dose levels twice daily for 5 days, while diazepam (1 mg/kg, i.p.) was administered acutely. White and red varieties of ginseng (20 and 50 mg/kg) showed positive results when tested against several paradigms of experimental anxiety. Both were effective in the open-field and elevated plus-maze tests and reduced conflict behaviour in thirsty rats and footshock-induced fighting in paired mice. Ginseng also attenuated pentylenetetrazole-induced decrease in rat brain MAO activity, confirming its anxiolytic activity since this has been proposed to be an endogenous marker for anxiety. The effects induced by white and red ginseng (50 mg/kg x 5 days) were comparable to those induced by diazepam (1 mg/kg).

Bhattacharya SK, Chakrabarti A, Chatterjee SS. Activity profiles of two hyperforin-containing hypericum extracts in behavioral models. Pharmacopsychiatry 1998 Jun;31 Suppl 1:22-29.
Abstract: The behavioral activity profile of a therapeutically used alcoholic hypericum extract containing hyperforin (4.5%) in rodent models was compared with that of an experimental CO2 extract devoid of hypericines but highly enriched in hyperforin (38.8%). The antidepressant activities of 50, 150 and 300 mg/ kg/day of the alcoholic extract were similar to those of 5, 15 and 30 mg/kg/day respectively of the CO2 extract. The ethanol extract in the same dose range potentiated dopaminergic behavioral responses, whereas these effects were either absent or less pronounced in the CO2 extract treated groups. By contrast, serotoninergic effects of the CO2 extract were more pronounced than those of the alcoholic extract. These and various other observations made during the study confirm that although the antidepressant action of hypericum extracts depends on their hyperforin contents, their spectrums of central activity are due to other component(s). Our working hypothesis that hyperforin and serotoninergic mechanisms are involved in the therapeutically observed antidepressant activities of hypericum extracts is in agreement with these observations.

Biber A, Fischer H, Romer A, Chatterjee SS. Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Pharmacopsychiatry. 1998 Jun;31 Suppl 1:36-43.
Abstract: Validated analytical methods suitable for determining hyperforin in plasma after administration of alcoholic Hypericum perforatum extracts containing hyperforin are described. After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 h, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 h in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 h after administration. Half-life and mean residence time were 9 and 12 h respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

Brinker F. Interactions of pharmaceutical and botanical medicines. J Naturopathic Med 1997;7(2):14-20.

Brown C, Taniguchi G, Yip K. The monoamine oxidase inhibitor-tyramine interaction. J Clin Pharmacol 1989 Jun;29(6):529-532.
Abstract: Reports of hypertensive reactions from monoamine oxidase inhibitors (MAOI) began to proliferate in the early 1960s. Asatoor did extensive research and found that the combination of an MAOI and a food containing tyramine resulted in the hypertensive interaction ("the cheese reaction"). Because of the risk of intracerebral hemorrhage and death, clinicians were hesitant to use the MAOIs. Although progress on the metabolic effects of MAOIs has been slow, use of clinical information in addition to analysis of bioactive amine content of foods has allowed the formulation of dietary recommendations, which are thought to be useful clinically in the administration of MAOIs. This has resulted in the gradual return to use of these psychotropic compounds.

Chatterjee SS, Noldner M, Koch E, Erdelmeier C. Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry. 1998 Jun;31 Suppl 1:7-15.
Abstract: Efforts leading to the identification of hyperforin as an antidepressive component of therapeutically used alcoholic hypericum extracts are described and discussed. Initially, the effects of this unique and major constituent of the herb were detected in peripheral organs using in vitro models and an extract was obtained by supercritical extraction of the herb by carbon dioxide. These extracts are highly enriched in hyperforin (38.8%) and are devoid of hypericines and numerous other components of alcoholic extracts. Studies with such an extract and with isolated hyperforin indicated that this acylphloroglucinol derivative can inhibit serotonin-induced responses and uptake of this neurotransmitter in peritoneal cells. Assuming that the effects of hyperforin were due to its actions on serotoninergic 5-HT3/5-HT4 receptors, further studies were conducted to investigate its effects on the CNS. These efforts revealed its antidepressant activity in the behavioral despair test and led to the working hypothesis that hyperforin and serotoninergic mechanisms are involved in the antidepressant activities of alcoholic hypericum extracts. The observations made during this study also indicate that hyperforin is the major, but not the only antidepressive component of alcoholic extracts.

Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci. 1998;63(6):499-510.
Abstract: We demonstrate that the phloroglucinol derivative hyperforin is not only the major lipophilic chemical constituent of the medicinal plant Hypericum perforatum (St. John's wort) but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and L-Glutamate with IC50 values of about 0.05-0.10 microg/ml (5-HT, NA, DA, GABA) and about 0.5 microg/ml (L-glutamate) in synaptosomal preparations. Furthermore, potencies of two different hypericum extracts in two conventional pharmacological paradigms useful for the detection of antidepressants (behavioral despair, learned helplessness), closely correlate with their hyperforin contents. In addition, most till now known neuropharmacological properties of the clinically used hypericum extracts can also be demonstrated with pure hyperforin. It appears, therefore, that this non-nitrogenous constituent is a possible major active principle responsible for the observed clinical efficacies of the extract as an antidepressant and that it could also be a starting point for drug discovery projects engaged in the search of psychoactive drugs with novel mode of action.

Cole AF, et al. Pharmacokinetic and metabolic aspects of the moclobemide-food interaction. Psychopharmacology (Berl). 1992;106 Suppl:S37-39.

Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry. 1997 Sep;30 Suppl 2:108-112.
Abstract: Hypericum perforatum L. Hypericaceae (St. John's wort), has been used since the time of ancient Greece for its many medicinal properties. Modern usage is still quite diverse and includes wound healing, kidney and lung ailments, insomnia and depression. This plant has been known to contain a red pigment, hypericin, and similar compounds, which have been assumed to be the primary active constituent(s) in this plant genus. A crude Hypericum extract was tested in a battery of 39 in vitro receptor assays, and two enzyme assays. A sample of pure hypericin was also tested. Hypericin had affinity only for NMDA receptors while the crude extract had significant receptor affinity for adenosine (nonspecific), GABAA, GABAB, benzodiazepine, inositol triphosphate, and monoamine oxidase (MAO) A and B. With the exception of GABAA and GABAB, the concentrations of Hypericum exact required for these in vitro activities are unlikely to be attained after oral administration in whole animals or humans. These data are consistent with recent pharmacologic evidence suggesting that other constituents of this plant may be of greater importance for the reported psychotherapeutic activity. Alternative pharmacologic mechanisms for Hypericum's antidepressant activity are critically reviewed and the possible importance of GABA receptor binding in the pharmacology of Hypericum is highlighted. Some of these results have been previously reported.

Cott JM, Fugh-Berman A. Is St. John's wort (Hypericum perforatum) an effective antidepressant? J Nerv Ment Dis. 1998 Aug;186(8):500-501.
Abstract: SJW is a remarkably safe antidepressant with an apparently unique mode of action. Although it has demonstrated efficacy in mild and moderate depression when compared with placebo or tricyclic antidepressants, several research areas beg to be explored. Its effects should be compared with serotonin reuptake inhibitors. Studies in severely depressed patients are lacking, as are studies on its utility as a therapeutic adjunct to standard antidepressants.

Cott J, Misra R, Medicinal Plants: potential source for new psychotheraputic drugs, in New Drug Developments from Herbal medicines in Neuropsychopharmacology, eds Kanba S, Richelson E, NY 1997.

Da Prada M, Zurcher G, Wuthrich I, Haefely WE. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl 1988;26:31-56.
Abstract: The pathways for the biosynthesis and metabolism of tyramine are described as a basis for the discussion of the interaction between MAO inhibitors and tyramine. While a role of endogenous tyramine in the antidepressant action of MAO inhibitors remains purely hypothetical at this time, the mechanisms leading to the potentiation of the tyramine pressor effect ("cheese effect") are well known. Experiments in animals and man have provided concordant quantitative information on the effect of irreversible and some novel reversible MAO inhibitors on the presystemic disposition of orally ingested tyramine and on the noradrenaline-releasing action of tyramine in noradrenergic nerve terminals. There is a profound difference in the magnitude of tyramine potentiation between the irreversible inhibitor tranylcypromine and the reversible inhibitor moclobemide. A systematic analysis of the tyramine content of current European food and beverage is reported and serves as a rational basis for providing advice to patients on moclobemide. Most of the food and beverages analyzed contain less tyramine than previously reported and a few rules concerning rare cheeses with high tyramine content are sufficient to eliminate the risk of hypertensive crises.

Dentali, Steven, Dentali Associates: Natural Products Consulting Services, Troutdale, Oregon.

De Smet, PAGM, Adverse Effects of Herbal Drugs, Volume 3. Springer, 1997.

el-Ganzouri AR, Ivankovich AD, Braverman B, McCarthy R. Monoamine oxidase inhibitors: should they be discontinued preoperatively? Anesth Analg. 1985 Jun;64(6):592-596.
Abstract: Adverse cardiovascular responses to anesthesia during either electroconvulsive therapy (ECT) or elective surgical procedures were evaluated in 27 patients maintained on chronic (3 months-3 yr) monoamine oxidase inhibitor (MAOI) therapy. Changes in blood pressure and heart rate in study patients (n = 22 ECTs in 13 patients) undergoing ECT were not significantly different from those observed in patients having ECT without prior treatment with MAOIs (n = 45 ECTs in 45 patients). In both groups, blood pressure and heart rate increased significantly after ECT, but returned to baseline levels within 15 min. No complications attributable to MAOIs were observed in study patients (n = 14) undergoing elective surgical procedures. We conclude that discontinuing chronic MAOI therapy prior to anesthesia and surgery is not necessary.

Faulhaber HD, Gawellek F, Singer P. [Treatment of hypertension. 3. Antihypertensive agents affecting catecholamine metabolism]. Dtsch Gesundheitsw 1968 Oct 24;23(43):2017-2024. [Article in German]

Fugh-Berman A, Cott JM. Dietary supplements and natural products as psychotherapeutic agents. Psychosom Med. 1999 Sep-Oct;61(5):712-728.
Abstract: Alternative therapies are widely used by consumers. A number of herbs and dietary supplements have demonstrable effects on mood, memory, and insomnia. There is a significant amount of evidence supporting the use of Hypericum perforatum (St. John's wort) for depression and Ginkgo biloba for dementia. Results of randomized, controlled trials also support the use of kava for anxiety and valerian for insomnia. Although evidence for the use of vitamins and amino acids as sole agents for psychiatric symptoms is not strong, there is intriguing preliminary evidence for the use of folate, tryptophan, and phenylalanine as adjuncts to enhance the effectiveness of conventional antidepressants. S-adenosylmethionine seems to have antidepressant effects, and omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid, may have mood-stabilizing effects. More research should be conducted on these and other natural products for the prevention and treatment of various psychiatric disorders.

Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI diet. J Clin Psychiatry 1996 Mar;57(3):99-104. (Review)
Abstract: BACKGROUND: Many monoamine oxidase inhibitor (MAOI) diets are considered to be excessively restrictive and founded on poor scientific evidence. We present a safe and practical MAOI diet based on the related clinical and analytic data. METHOD: We used a critical review of the literature and our own tyramine assay results to categorize foods to be restricted absolutely, taken in moderation only, or unrestricted. RESULTS: We recommend that users avoid aged cheese; aged or cured meats (e.g., air-dried sausage); any potentially spoiled meat, poultry, or fish; broad (fava) bean pods; Marmite concentrated yeast extract; sauerkraut; soy sauce and soy bean condiments; and tap beer. Wine and domestic bottled or canned beer are considered safe when consumed in moderation. Other foods not mentioned are considered unrestricted. CONCLUSION: The concerns about perpetuating an overly restrictive MAOI diet include the avoidance by prescribers of a potentially useful treatment option, excessive limitations on lifestyle for patients, and increased risk to patients secondary to noncompliance with the diet. We propose an MAOI diet that has a solid scientific and clinical basis and that is, above all, practical.

Goff DC. Two cases of hypomania following the addition of L-tryptophan to a monoamine oxidase inhibitor. Am J Psychiatry 1985 Dec;142(12):1487-1488.
Abstract: The combination of L-tryptophan and a monoamine oxidase inhibitor (MAOI) has been reported to be an effective antidepressant regimen. Neurotoxicity has previously been associated with this combination. The author presents two cases of hypomania following the addition of L-tryptophan to an MAOI.

Heller CA, Friedman PA. Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy. Am J Med 1983 Nov;75(5):887-888.
Abstract: A 51-year-old, nonalcoholic, nondiabetic woman with sensorimotor peripheral neuropathy and pyridoxine deficiency associated with long-term phenelzine therapy is described. Since phenelzine, like hydralazine and isoniazid, is a hydrazine capable of reducing pyridoxine levels in the rat, it is suggested that phenelzine, like hydralazine and isoniazid, may cause a pyridoxine-responsive peripheral neuropathy in humans.

Hölzl J, Demisch L, Gollnik B. Investigations about antidepressive and mood changing effects of Hypericum perforatum. Planta Med 1989;55:643.

Kaehler ST, Sinner C, Chatterjee SS, Philippu A. Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus. Neurosci Lett. 1999 Mar 12;262(3):199-202.
Abstract: Hyperforin is the main antidepressant component of hypericum perforatum (St. John's Wort). Using the push-pull superfusion technique we tested whether hyperforin influences extracellular concentrations of neurotransmitters in the rat locus coeruleus. Hyperforin (10 mg/kg, i.p.) not only enhanced the extracellular levels of the monoamines dopamine, noradrenaline and serotonin, but also that of the excitatory amino acid glutamate. The levels of the main serotonin metabolite 5-hydroxyindolacetic acid, as well as those of the amino acids GABA, taurine, aspartate, serine and arginine, were not influenced. Together with in vitro studies, our findings suggest that the antidepressant property of hyperforin is due to enhanced concentrations of monoamines and glutamate in the synaptic cleft, probably as a consequence of uptake inhibition.

Korn A, Da Prada M, Raffesberg W, Gasic S, Eichler HG. Effect of moclobemide, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine. J Cardiovasc Pharmacol 1988 Jan;11(1):17-23.
Abstract: We determined in healthy subjects the pressor effect and the plasma level of free tyramine in response to intravenous and oral tyramine doses before and after therapeutic doses (3 X 100 mg/day) of moclobemide, a new reversible, preferential type A monoamine oxidase (MAO) inhibitor. In fasting subjects moclobemide increased the pressor effect of intravenously and orally administered tyramine; the tyramine dose-pressor curve was shifted to the left by factors of 2.4 and 4.1, respectively. No increase in systolic blood pressure occurred at free plasma tyramine concentrations lower than 70 ng/ml before, and 20 ng/ml after, moclobemide. Peak plasma tyramine concentrations increased dose-dependently after oral tyramine; after moclobemide similar peak plasma concentrations of tyramine were obtained with 2.6 times smaller doses of tyramine. Thus, the potentiation by moclobemide of the pressor effect of oral tyramine appears to be due to inhibition of tyramine first-pass metabolism, as well as to inhibition of tyramine catabolism by MAO within adrenergic nerve terminals. The peak concentrations of free tyramine in plasma and the concomitant increase of systolic blood pressure were significantly (p less than 0.01) smaller when tyramine was administered with a meal (before or after moclobemide) than when given with tap water. We conclude that at doses of 3 X 100 mg/day moclobemide induces only a mild potentiation of the pressor effect of tyramine. This potentiation is virtually absent under natural conditions when tyramine is given with a meal.

Livingston MG, et al. Monoamine oxidase inhibitors. An update on drug interactions. Drug Saf. 1996 Apr;14(4):219-27. (Review)
Abstract: After initial enthusiasm, the use of monoamine oxidase inhibitors (MAOIs) has been limited by the wide range of MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine-containing foods, resulting in hypertensive reactions. Despite their clinical benefits, this has led to a reduction in use of such medications. Discovery of the 2 main subgroups of monoamine oxidase, types A and B, led to the synthesis of MAOIs selective for one or other of these isoenzymes. Consequently, selegiline (deprenyl), a selective MAO-B inhibitor, was developed for the treatment of idiopathic Parkinson's disease. This drug is useful in the treatment of the early stages of the disease and later on as an adjunct to other drug therapies. Although the selective MAO-A inhibitor, clorgiline (clorgyline), was found to be effective in the treatment of depression, it still retained the potential to cause hypertensive reactions. Recently, agents that are not only selective, but reversible in their inhibition of MAO-A (RIMAs) have been synthesised (e.g. moclobemide and toloxatone), and have proven antidepressant efficacy. While they are less likely to induce hypertensive reactions with the concomitant administration of sympathomimetic drugs or with tyramine-rich foodstuffs, it still seems wise to advocate care in co-prescribing potentially interacting medications and to advise a degree of caution with regard to the dietary intake of foodstuffs likely to contain a high tyramine content. Although these newer drugs represent an advance in safety, their use has, as yet, only been established in the treatment of depression. RIMAs also retain a potential for adverse interaction with other drugs. Concomitant prescription of serotonin-enhancing drugs should only be undertaken with caution for patients on moclobemide, toloxatone or selegiline. Coprescription of sympathomimetic drugs should also be avoided with these newer MAOIs and patients should be advised against purchasing over-the-counter preparations that may contain sympathomimetic drugs.

Muller T, Gieschke R, Ziegler WH. Blood pressure response to tyramine-enriched meal before and during MAO-inhibition in man: influence of dosage regimen. J Neural Transm Suppl 1988;26:105-114.
Abstract: In an open study oral tyramine in variable doses was administered to six healthy volunteers under three different conditions: 1) without moclobemide, 2) under moclobemide steady-state conditions (3 X 200 mg moclobemide daily) one hour after moclobemide intake and 3) under moclobemide steady-state conditions simultaneously with moclobemide. It was shown that the amount of tyramine effecting 30-50 mmHg systolic blood pressure increase was roughly doubled when moclobemide was administered together with tyramine instead of one hour before tyramine intake. The time interval between tyramine ingestion and maximal blood pressure increase did not differ significantly between conditions 2) and 3). The conclusion of this study is that moclobemide should always be taken at the end of a meal, which is anyway the usual time for drug intake.

Muller WE, Rossol R. Effects of hypericum extract on the expression of serotonin receptors. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S63-64.
Abstract: The influence of hypericum extract LI 160 on the expression of serotonin receptors was investigated using a neuroblastoma cell line to establish a model for the regulation of neurotransmitters by immunologically active compounds such as cytokines. The cells were incubated with hypericum extract LI 160 in kinetic form for 2, 4, 6, 8, and 10 hours, then washed. The serotonin receptor expression analysis was compared to that of a placebo control solution. The neuroblastoma cells showed a clearly reduced expression of the serotonin receptors under treatment with hypericum extract. First stimulation experiments with interleukin-1 (IL-1) and hypericum extract suggest that a further reduction of the serotonin receptors is possible when IL-1 is added.

Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry 1998 Jun;31 Suppl 1:16-21.
Abstract: Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.

Pohl R, Balon R, Berchou R. Reaction to chicken nuggets in a patient taking an MAOI. Am J Psychiatry 1988 May;145(5):651. (Letter)

Pope HG Jr, Jonas JM, Hudson JI, Kafka MP. Toxic reactions to the combination of monoamine oxidase inhibitors and tryptophan. Am J Psychiatry 1985 Apr;142(4):491-492.
Abstract: The combination of monoamine oxidase inhibitors and tryptophan--a recognized antidepressant regimen--has been reported to cause behavioral or neurologic toxicity. The authors present eight cases of delirious syndromes apparently attributable to this combination of agents.

Pope HG Jr, Jonas JM, Hudson JI, Kafka MP. Toxic reactions to the combination of monoamine oxidase inhibitors and tryptophan. Am J Psychiatry 1985 Apr;142(4):491-492.
Abstract: The combination of monoamine oxidase inhibitors and tryptophan--a recognized antidepressant regimen--has been reported to cause behavioral or neurologic toxicity. The authors present eight cases of delirious syndromes apparently attributable to this combination of agents.

Rafaelsen OJ. Cheese effects and new reversible MAO A inhibitors: summary. J Neural Transm Suppl 1988;26:123-124.

Shulman KI, Walker SE, MacKenzie S, Knowles S. Dietary restriction, tyramine, and the use of monoamine oxidase inhibitors. J Clin Psychopharmacol 1989 Dec;9(6):397-402.
Abstract: The aim of this study is to provide clearer guidelines for rational, safe, and practical dietary restriction for use with monoamine oxidase inhibitors. Tyramine levels were assayed in over 100 of the controversial foods that have been associated with hypertensive reactions or reported to contain high levels of tyramine. Only a very limited number of foods appear to require absolute restriction. These include all aged cheeses, concentrated yeast extracts (e.g., Marmite), sauerkraut, and broad bean pods. Alcoholic beverages, including Chianti wine consumed in moderation, appear to be safe. Some aged meats contain relatively high levels of tyramine and require closer investigation.

Shulman KI, Tailor SA, Walker SE, Gardner DM. Tap (draft) beer and monoamine oxidase inhibitor dietary restrictions. Can J Psychiatry 1997 Apr;42(3):310-312.
Abstract: OBJECTIVE: Traditional monoamine oxidase inhibitors (MAOIs) continue to play an important role in the management of a wide variety of clinical conditions. Accordingly, a practical and safe approach to MAOI dietary restrictions remains an essential component of patient management. METHOD: In an effort to refine MAOI dietary recommendations, we report a case of hypertensive crisis following the consumption of a modest amount of tap beer. RESULTS: A well-documented case report involving tap (draft) beer consumed while on an MAOI supports an earlier study, which recommended that all tap beers be restricted on MAOI diets. The 2 cases were remarkably similar in terms of the offending substance, quantity consumed, and subsequent reaction. CONCLUSIONS: As a result of recent tyramine analyses and 2 well-documented case reports, all tap (draft) beers should now be absolutely restricted on MAOI diets because they represent a very significant risk at modest levels of consumption.

Sullivan EA, Shulman KI. Diet and monoamine oxidase inhibitors: a re-examination. Can J Psychiatry 1984 Dec;29(8):707-711. (Review)
Abstract: Monoamine oxidase inhibitors (MAOIs) are attracting renewed attention as effective antidepressants for refractory depressions, particularly among the elderly. However, widespread fears concerning the interactions of MAOIs with tyramine-containing foods have led to the development of long and complicated diets. These diets have served as an obstacle to the ready use of MAOIs, yet very little systematic or critical review of the basis for food restriction has been undertaken. An international survey of MAOI diets was conducted and from the diets collected, foods were categorized according to frequency of restriction on the diet lists. On the basis of this survey and a critical review of the literature it was determined that only four foods clearly warrant absolute prohibition: aged cheese, pickled fish (herring), concentrated yeast extracts and broad bean pods. While there is insufficient evidence to prohibit alcohol completely (even chianti wine) true moderation must apply. It is suggested that a radically simplified diet should be investigated on a prospective basis.

Thom, Dickson. Surviving the Nineties: Coping With Food Intolerances. Portland, OR, 1992.

Uebelhack R, Franke L, Schewe HJ. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). Pharmacopsychiatry 1998 Sep;31(5):187-192.
Abstract: Kava-kava, a psychoactive beverage, induces relaxation, improves social interaction, promotes sleep and plays an important role in the sociocultural life in the islands of the South Pacific. On the other hand, standardized extracts of kava-kava roots are used for the therapy of anxiety, tension and restlessness. Kava pyrones, the major constituents of kava kava, are generally considered to be responsible for the pharmacological activity in humans and animals. To obtain more information on the mechanisms by which kava-kava exerts psychotropic properties we investigated the in vitro effects of kava-kava extract and pure synthetic kava pyrones on human platelet MAO-B, in comparison to amitriptyline, imipramine and brofaromine. Kava-kava extract was found to be a reversible inhibitor of MAO-B in intact platelets (IC50 24 microM) and disrupted platelet homogenates (IC50 1.2 microM). Structural differences of kava pyrones resulted in a different potency of MAO-B inhibition. The order of potency was desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-) dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain. The two most potent kava pyrones, desmethoxyyangonin and (+/-)-methysticin displayed a competetive inhibition pattern with mean Ki 0.28 microM and 1.14 microM respectively. The inhibition of MAO-B by kava pyrone-enriched extracts might be an important mechanism for their psychotropic activity.

Upton, R, ed. St. John’s wort, Hypericum perforatum. In American Herbal Pharmacopoeia and Therapeutic Compendium. Santa Cruz, CA: AHP, 1997.

Walker SE, Shulman KI, Tailor SA, Gardner D. Tyramine content of previously restricted foods in monoamine oxidase inhibitor diets. J Clin Psychopharmacol 1996 Oct;16(5):383-388.
Abstract: Traditional monoamine oxidase inhibitors (MAOIs) remain an important class of drugs for a variety of psychiatric conditions, including depressive illnesses, anxiety, and eating disorders. It was the objective of this study to refine the MAOI diet by determining the tyramine content of a variety of untested and "controversial" foods that continue to appear on MAOI diet-restricted food lists. A secondary objective of the study was to evaluate the effect of freshness on the tyramine content of some foods. Fifty-one food samples were evaluated for tyramine content by liquid chromatography. Food samples included a selection of sausages, beverages, sliced meat products, including chicken liver, and some fruits, including raspberries, bananas, and banana peels. Foods that were found to have dangerously high concentrations of tyramine (> or = 6 mg/serving) included chicken liver aged 9 days (63.84 mg/30 g), air-dried sausage (7.56 g/30 g), soy sauce (0.941 mg/ml), and sauerkraut (7.75 mg/250 g). Of the foods analyzed in this study, only those with high tyramine content per serving should continue to be absolutely restricted. All other foods are either safe for consumption or safe in moderation. The data provided should be combined with the data from other similar analytical studies to develop a list of foods that should be absolutely restricted. A more accurate list of restricted foods may enhance patient dietary compliance.