fact, moclobemide causes a reduction in alcohol-related impairments. moclobemide also interacts with pethidine/meperidine, and dextropropoxyphene. ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects. moclobemide is also likely to interact with warfarin. the combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions. serotonin syndrome has been reported when moclobemide has been taken in combination with other serotonin enhancing drugs; however, due to moclobemide's reversible mao inhibition, serotonin syndrome is significantly less likely to occur with moclobemide than with older irreversible maois. serotonin syndrome has been reported when trazodone was abruptly replaced with moclobemide. taking at the same time or starting moclobemide too soon after discontinuing clomipramine or serotonin reuptake inhibitors such as ssris may result in the development of a serotonin syndrome. snris such as venlafaxine in combination with moclobemide have also been associated with serotonin syndrome. cimetidine causes a doubling of the blood plasma levels of moclobemide. blood plasma levels of trimipramine and maprotiline and possibly other tricyclic antidepressants increase when used in combination with moclobemide and may require dosage adjustments if the combination is used for treatment resistant depression. the elimination of zolmitriptan is reduced by moclobemide and if the combination is used, a dosage reduction of zolmitriptan is recommended. moclobemide reduces the metabolism of dextromethorphan. moclobemide may decrease metabolism of diazepam, omeprazole, proguanil, propranolol and others due to inhibition of cyp2c19. dietary irreversible maois can cause unpleasant and occasionally dangerous side effects such as a hypertensive crises after intake of food or drink containing indirectly acting sympathomimetic amines such as tyramine. this is sometimes referred to as the 'cheese effect'. these side effects are due to irreversible inhibition of mao in the gut and vasomotor neurones. however, the reversible maoi antidepressants such as moclobemide have a very different side effect profile in this regard. the reversible binding to mao-a by moclobemide allows amines such as tyramine to displace moclobemide from mao-a allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible mao inhibition. of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated hypertensive reaction. as the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible maois. however, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution. the potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible maois. in order to minimize this potentiation, postprandial administration (taken after meals) of moclobemide is recommended. the combined use of moclobemide and selegiline requires dietary restrictions as the combination can lead to increased sensitivity to the pressor effect of foods containing tyramine. while moclobemide or the irreversible mao-b selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietary restriction, the combination of selegiline with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of tyramine. the combination of moclobemide and a reversible mao-b inhibitor requires tyramine dietary restrictions. overdose moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and the irreversible and non-selective maois, making it a safer antidepressant in the elderly or people with physical disorders. of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for inpatient as well as outpatient use. intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or ssri antidepressants the overdose is much more toxic and potentially fatal. moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose. patients with mixed intoxications (e.g. with other cns active drugs) may show severe or life-threatening symptoms and should be hospitalized. treatment is largely symptomatic and should be aimed at maintenance of the vital functions. withdrawal and tolerance withdrawal symptoms appear to be very rare with moclobemide compared to other antidepressants; a single report of relatively mild flu-like symptoms persisting for 7 days after rapid reduction of high dose moclobemide therapy has been reported in one patient. withdrawal of moclobemide causes a rebound in rem sleep. moclobemide does not seem to prevent withdrawal symptoms from serotonin reuptake inhibitors. discontinuation of moclobemide is recommended to be done gradually to minimise side effects (e.g. rapid return of condition being treated and/or the appearance of withdrawal symptoms). tolerance to the therapeutic effects has been reported in a small number of users of maois including moclobemide. pharmacology a picture of 150 mg tablets of the reversible maoi drug moclobemide, brand name aurorix. moclobemide is a benzamide, derivative of morpholine, which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase-a (rima), a type of monoamine oxidase inhibitor (maoi), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of rem sleep, down regulation of beta-3 adrenergic receptors. moclobemide's primary action is to disable mao-a enzymes from decomposing norepinephrine, serotonin, and dopamine which results in a rising level of these neurotransmitters. although it has been estimated that a single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase-a (mao-a) and 20-30% of mao-b, studies evaluating brain occupancy of mao-a enzymes have shown dosages of 600 mg to only inhibit 74% of mao-a enzymes and dosages in the 900-1200 mg range to inhibit slightly less mao-a than phenelzine (nardil) at 45-60 mg; subsequently, it is highly plausible that reports of lower efficacy could be largely or entirely the consequence of conservative dosage guidelines rather than the pharmacological properties of the drug. previously, it was widely reported that both mao-a and mao-b enzymes were responsible for the metabolism of dopamine; however, new research suggests that mao-b enzymes are involved in the generation of gaba and not the degradation of dopamine. there is also some evidence of moclobemide possessing neuroprotective properties in rodent models. there is no cumulative effect of moclobemide centrally when taken long-term. with long-term use of moclobemide, there is a significant down-regulation of b-adrenoceptors. single or repeated dosing with 100–300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-hiaa. excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. there is also a temporary increase in prolactin during initial intake of 100–300 mg of moclobemide. l-dihydroxyphenylalanine is also reduced. inhibition of the serotonin metabolite is less pronounced than the norepinephrine metabolite which suggests there are other major metabolic pathways for serotonin other than mao-a. it has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to mao-a slowly form a more tightly bound complex, resulting in the non-competitive mao inhibition by moclobemide. with three times daily dosing the inhibition on mao-a was relatively constant with moclobemide. the mao inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing. the inhibition of mao-a by moclobemide is 10 times more potent than the irreversible maoi phenelzine and approximately equivalent to tranylcypromine and isocarboxazid. moclobemide increases levels of extracellular monoamines and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. moclobemide lacks anticholinergic effects and cognitive impairments can be improved by moclobemide. moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines. long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (camp) binding to camp-dependent protein kinase (pka). moclobemide is chemically unrelated to irreversible maoi antidepressants and only has a very weak pressor effect of orally administered tyramine. in humans, the n-oxide metabolites of moclobemide and moclobemide itself are the compounds that produce most of the inhibition of mao-a; other metabolites are significantly less potent than the parent compound. in healthy people moclobemide has a relatively small suppressing effect on rem sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (nrem) sleep and rapid eye movement (rem) sleep. there have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels. testosterone levels increase significantly with long-term use of moclobemide in depressed males. moclobemide also has neuroprotective properties in its demonstrated anti-hypoxia or anti-ischemia effects; there is a possibility that moclobemide may possess similar neuro-rescuing properties, similar to selegiline, however, research is required to determine this. moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties. platelet mao is of the mao-b and this is inhibited only to a small degree in humans; the inhibition is due to low levels of metabolites of moclobemide that have mao-b inhibiting properties. moclobemide has been reported to be a mixed mao-a/mao-b inhibitor in rats but in man, it has been reported to be a pure mao-a inhibitor, blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. no reuptake inhibition of any of the neurotransmitters occurs. the pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. the duration and quality of sleep may be improved. in the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with tcas/ssris). mao inhibition returns completely back to normal after 24 hours, which allows for changing to another antidepressant within 24 hours of the last dose taken of moclobemide. pharmacokinetics in humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver. peak plasma levels occur 0.3 to 2 hours after oral administration. the bioavailability increases during the first week of therapy from 60% to 80% and more. the elimination half-life is around 2 hours. it is moderately bound to plasma proteins, especially albumin. however, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution. despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours. the drug is almost completely metabolized in the liver; it is a substrate of cyp2c19 and an inhibitor of cyp2c19, cyp2d6 and cyp1a2. less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours. the main metabolites are the n-oxide ro 12-5637 formed via morpholine n-oxidation and lactam derivative ro 12-8095 formed via morpholine c-oxidation; active metabolites are found only in trace amounts. the unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). the main degradation pathway of moclobemide is oxidation. about 44 percent of the drug is lost due to the first pass effect through the liver. age and renal function do not affect the pharmacokinetics of moclobemide. however, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide. food slows the absorption but does not affect the bioavailability of moclobemide. steady state concentrations are established after one week. it has been suggested that changes in dose should not be made with a gap of less than a week. moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration. animal toxicology acute toxicity: the oral ld50 values in mouse and rat are quite high, indicating a wide therapeutic index. ld50 for mice is 730 mg/kg and for rats 1,300 mg/kg. in dogs doses in excess of 300 mg/kg led to vomiting, salivation, ataxia, and drowsiness. chronic toxicity: in an 18-months-study in rats with 10 mg/kg no signs of chronic toxicity were noted, with 50 mg/kg and 250 mg/kg only a slight loss of