African rue
Syrian rue/Drug Interactions:
GeneralGeneral: Avoid oral consumption in any patient.AlcoholAlcohol: In animal research, ethanol was found to inhibit harmaline-induced tremors at doses as low as 0.1g/kg; inhibition also caused an increase of cerebellar cyclic guanosine cyclic monophosphate (GMP) (145). In other animal research, ethanol reduced the blood-brain barrier permeability of harmine (146). Following alcohol-withdrawal in rats, supersensitivity to harmine-induced tremors was observed (147). Several drugs may be used to negate this effect, including propranolol, mianserin, chlordiazepoxide, ritanserin, buspirone, fluoxetine, haloperidol, clonidine, flunarizine, and baclofen (147). AmphetamineAmphetamine: The effects of amphetamine on harmaline-induced tremor are unclear. In laboratory research, amphetamine suppressed harmine-induced tremors (148). However, in animal research, the tremor response to harmine was potentiated by amphetamine (149). In vivo, harmine was found to potentiate the stimulatory effects of D-amphetamine on dopamine release in rat striatum (150). AnalgesicsAnalgesics: In animal research, the alkaloid extract of Peganum harmala was found to exert antinociceptive effects in a dose-dependent manner (88; 106). AntiadrenergicsAntiadrenergics: In animal smooth muscle, Peganum harmala seed extract exerted a direct relaxant effect, which suggested that it has antiadrenergic effects (40). In contrast, in humans and animals, intravenous administration of harmine potentiated the effects of epinephrine, likely due to cholinesterase and monoamine oxidase inhibition (128). Antianxiety agentsAntianxiety agents: According to animal research, low doses of harmaline (5-10mg/kg) may cause anxiety, while higher amounts (20mg/kg) were found to exert an anxiolytic effect (54). AntibioticsAntibiotics: In laboratory tests, beta-carboline alkaloids (harmane, harmaline, harmalol, harmine) from Peganum harmala were found to exert antibacterial activity against Gram-positive and Gram-negative bacteria (33; 29; 31; 32; 151; 36; 119; 43). Antibacterial effects may also be due to constituents (quercetin and kaempferol) found in the plant (151). When applied as binary mixtures, the beta-carboline alkaloids were found to exert a synergistic effect (36). In laboratory research, Peganum harmala exerted inhibitory effects against Staphylococcus aureus and Escherichia coli (151). The constituent harmine has been found to inhibit Proteus vulgaris and Bacillus subtilis, with inhibition zones ranging between 21.2 and 24.7mm (36). In laboratory research, the chloroform extract from aerial part extracts of Peganum harmala displayed higher antibacterial activity than the ethyl acetate, butanol, and methanol extracts against Gram-positive than Gram-negative bacteria (43). AnticholinergicsAnticholinergics: In humans and animals, intravenous administration of harmine potentiated the effects of acetylcholine, likely due to cholinesterase and monoamine oxidase inhibition (128). In other animal research, harmaline and its metabolites increased acetylcholine levels; however, the inhibitory effect on striatal cholinergic neuron activity did not involve dopaminergic, serotonergic, or GABA neurons (152). In animal research, harmine-induced tremors were unaffected by cholinergic agents (4). AnticonvulsantsAnticonvulsants: In animal research, anticonvulsants (primidone, gabapentin, valproate and carbamazepine) suppressed harmaline-induced tremors (153). AntidiabeticsAntidiabetics: In animal research, harmine was found to act as a cell-type-specific regulator of peroxisome proliferator-activated receptor (PPAR)-gamma expression, mimicking the effects of PPAR-gamma ligands on adipocyte gene expression and insulin sensitivity (83). AntifungalsAntifungals: In laboratory tests, beta-carboline alkaloids (harmaline and harmine) from Peganum harmala have been found to exert antifungal activity (29; 36). Antifungal effects may also be due to constituents (quercetin and kaempferol) found in the plant (151). In laboratory research, Peganum harmala and the constituent harmine were found to inhibit Candida albicans (151). The inhibition zone of harmine against Candida albicans was found to range between 21.2 and 24.7mm (36). When applied as binary mixtures, the beta-carboline constituents were found to exert a synergistic effect (36). AntihistaminesAntihistamines: In animal smooth muscle, Peganum harmala seed extract exerted a direct relaxant effect, which suggested that it had antihistaminic effects (40).AntihypertensivesAntihypertensives: Harmine reduced systemic arterial blood pressure and total peripheral vascular resistance; harmaline displayed similar initial decreases, but they were followed by a secondary increase, and the effects of harmalol have been found to be inconsistent (137). AntineoplasticsAntineoplastics: In animal research, alkaloids of Peganum harmala have been found to exert antitumor activity (75). Synergistic effects have been noted after coadministration with the chemotherapeutic agents cisplatin and doxorubicin (75). In laboratory research, the combination of harmine and harmaline with tretinoin (ATRA) and granulocyte colony-stimulating factor (G-CSF) were not found to alter the extent of differentiation on HL-60 cells (76). In breast cancer cells, harmine inhibited breast cancer resistance protein (BCRP) and reduced resistance to mitoxantrone and camptothecin mediated by the protein (70). In vitro and in vivo, harmine has been found to regulate proinflammatory mediators involved in tumor development (61; 118), as evidenced by an increase in antitumor factors like interleukin-2 (IL-2), tissue inhibitor metalloprotease (TIMP), nuclear factor (NF)-kappaB, cAMP response element-binding (CREB), and activating transcription factor-2 (ATF-2) (118). Antiparkinson agentsAntiparkinson agents: In animal research, cholecystokinin octapeptide (CCK-8), ceruletide, and analogs of ceruletide (antiparkinsonian agents not available in the United States) were found to suppress harmine-induced tremors (154). In laboratory research, these constituents were weak inhibitors of MAO type B (MAO-B) (155; 81). AntiprotozoalsAntiprotozoals: In laboratory and animal tests, beta-carboline alkaloids (harmane, harmaline, harmalol, harmine) from Peganum harmala were found to exert antiprotozoal effects (31; 48; 50; 49; 47; 39). In in vitro research, harmane, harmine, and harmaline inhibited Leishmania activity (48; 50). AntipsychoticsAntipsychotics: According to animal research, harmaline may reportedly inhibit serotonin uptake into the nerve terminals and thus act additively to increase endogenous serotonin in the synaptic cleft following tryptophan administration, thereby causing excess stimulation of 5-HT1A and 5-HT2 receptors in the brain (112). AntiviralsAntivirals: In laboratory research, Peganum harmala displayed antiviral activity (43). A methanol extract from the aerial part of the plant displayed activity against Coxsackie B virus type 3 (43).ApomorphineApomorphine: In animal and laboratory research, apomorphine suppressed harmaline- and harmine-induced tremors (153; 148). In laboratory research, intraperitoneal injection of harmine, 30 minutes before apomorphine, resulted in reduced motor activity and 6-hydroxydopamine (6-OHDA)-induced lesion of the substantia nigra (156). In animal research, the jumping behavior induced by the combination of harmine and apomorphine was enhanced by pretreatment with p-chlorophenylalanine, methysergide, and clonidine; pretreatment with 5-hydroxytryptophan, haloperidol, perphenazine, atropine, and pilocarpine reduced the action (157). The mechanism was noted as being specific to the central action of harmine and the activation of the dopaminergic system. AprotininAprotinin: In animal research, aprotinin at low doses was found to shorten the length of harmine-induced tremors and decrease the concentration of harmine; high doses lengthened harmine-induced tremors (158). It was also noted that aprotinin may increase or decrease the blood-brain barrier permeability of harmine. BaclofenBaclofen: Baclofen, a gamma-aminobutyric acid (GABA)-B receptor agonist, was found to attenuate harmaline-induced tremors in rats (22). In other animal research, baclofen reportedly had a lack of an effect (153). BenzodiazepinesBenzodiazepines: In animal research, harmaline was found to exert weak and/or partial agonist effects on benzodiazepine receptors (159). In animal research, diazepam was found to inhibit harmaline- and harmine-induced tremors (160; 161; 162; 163; 4). This effect was reportedly not due to an inhibition of rhythmical complex activity of cerebellar Purkinje cells (161). In laboratory research, harmaline completely displaced bound 3H-flunitrazepam from the benzodiazepine receptor (163). Beta-blockers (beta-adrenergic antagonists)Beta-blockers (beta-adrenergic antagonists): Various beta-blockers, including propranolol, acebutolol, and butoxamine, have been found to inhibit harmaline- and harmine-induced tremor (153; 164; 165). In animal research, propranolol significantly attenuated harmaline-induced tremors (153). In other animal research, propranolol reduced the intensity (166) and suppressed harmine-induced tremors and behavioral changes by way of serotonin inhibitory activity (164). In animal research, acebutolol (a selective beta1-receptor antagonist) inhibited harmaline-induced tremors in a dose-dependent manner (165). Additionally, butoxamine (a selective beta2-receptor antagonist that is used primarily in experimental circumstances) inhibited harmaline-induced tremors in a dose-dependent manner to a greater extent than acebutolol. The greater potency of butoxamine was reportedly due to its action on peripheral beta 2-receptors and through a central mechanism associated with the 5-HT system (165). CaffeineCaffeine: In animal research, caffeine was found to exacerbate the intensity, duration, and amplitude of harmaline-induced tremors (167). In other animal research, caffeine reduced the blood-brain barrier permeability of harmine (146). CarbenoxoloneCarbenoxolone: In animal research, carbenoxolone (a synthetic derivative of glycyrrhetinic acid) was found to suppress harmaline-induced tremors (13). ChlormethiazoleChlormethiazole: In animal research, chlormethiazole inhibited harmaline induced tremors and the increase of cerebellar cyclic GMP from increased glutamate function (168). ChlorpromazineChlorpromazine: In animal research, chlorpromazine depressed the tremor response to harmine (149). Cholinergic agonistsCholinergic agonists: In animal research, harmine-induced tremors were unaffected by cholinergic agents (4). Chronotropes (positive and negative)Chronotropes (positive and negative): In animal research, ingestion harmine, harmaline, and harmalol caused a direct negative chronotropic effect (137). ClonidineClonidine: In animal research, clonidine (a central alpha-agonist) attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was potentiated by cyproheptadine, and antagonized by fluoxetine and quipazine (a selective 5-HT agonist). CyproheptadineCyproheptadine: In animal research, clonidine attenuated harmaline-induced tremor, in a dose-dependent manner; an effect that was potentiated by cyproheptadine (a 5-HT antagonist) (169). Cytochrome P450-modifying agentsCytochrome P450-modifying agents: In vitro, beta-carboline alkaloids (harmine, harmaline, harmalol, harmol, and harmane) from Peganum harmala were found to inhibit cytochrome P450 (CYP450) 3A4 and 2D6 (170). In other laboratory research, Peganum harmala extract significantly increased the expression of cytochrome P450 1A2, 2C19, and 3A4 isoenzymes but decreased CYP2B6, 2D6, and 2E1 in human hepatoma HepG2 cells (171). Caution is warranted, as these compounds may alter the effects and concentration levels of drugs metabolized by the enzyme system. In laboratory research, CYP3A4 and 2D6 isozymes were found to contribute to the O-demethylation of harmaline and harmine (172; 173). The predominant isozymes were CYP1A2 and polymorphic CYP2D6, and to a lesser extent, CYP1A1, CYP2C9, and CYP2C19 (172; 173). Dopamine agonists) Dopamine agonists: In animal research, harmine was found to affect the brain dopamine system, as evidenced by increases in extracellular concentrations of dopamine, a mechanism reportedly due to its MAO-A inhibitory effects (150). In animal research, dopaminergic agents (L-DOPA, apomorphine, piribedil, and d- and l-amphetamine) inhibited harmine-induced tremors (4; 148; 174; 175). Dopamine antagonistsDopamine antagonists: In animal research, harmine has been found to affect the brain dopamine system, as evidenced by increases in extracellular concentrations of dopamine, a mechanism reportedly due to its MAO-A inhibitory effects (150). EpinephrineEpinephrine: In humans and animals, intravenous administration of harmine potentiated the effects of epinephrine, likely due to cholinesterase and monoamine oxidase inhibition (128). FlumazenilFlumazenil: In vivo, pretreatment with flumazenil (a benzodiazepine antagonist) was not found to modulate the effects of harmine on dopamine output or metabolism (150). Gamma-hydroxybutyrate (GHB)Gamma-hydroxybutyrate (GHB): In animal research, gamma-hydroxybutyrate (GHB) significantly attenuated harmaline-induced tremors (153). HepatotoxinsHepatotoxins: In animal research, long-term consumption (six weeks) of Peganum harmala seed extracts resulted in increased liver weight and the depletion of alkaline phosphatase (ALP) (32). However, in other animal research, a chloroform extract of Peganum harmala was also found to exert hepatoprotective effects (92). ImmunosuppressantsImmunosuppressants: In vitro, harmaline at high concentrations (10-100mcM/L) suppressed immune function, specifically T cell regulatory and effector function, B cell function, and natural killer-cell function (90). InotropesInotropes: In in vitro and animal research, harmaline was found to exhibit a dual (positive and negative) inotropic effect on the atria (138; 139). LacosamideLacosamide: In animal research, lacosamide (a novel anticonvulsant) was found to reduce harmaline-induced tremors in a dose-dependent manner (176). LevodopaLevodopa: The effects of harmine on the pharmacokinetics of levodopa (a catecholamine precursor) have been evaluated in animal research (177); details are lacking. In animal research, cholecystokinin octapeptide (CCK-8), ceruletide, and analogs of ceruletide (antiparkinsonian agents not available in the United States) were found to suppress harmine-induced tremors (154). In laboratory research, these constituents were weak inhibitors of MAO type B (MAO-B) (155; 81). LidocaineLidocaine: In animal research, lidocaine (a local anesthetic) inhibited harmaline-induced tremors (178). LithiumLithium: In animal research, lithium (a mood stabilizer) suppressed harmaline-induced tremors (153). MefloquineMefloquine: In animal research, mefloquine was found to suppress harmaline-induced tremors (13). Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs): The beta-carboline alkaloids harmaline and harmine in Peganum harmala are known reversible inhibitors of monoamine oxidase inhibitor type A (MOA-A) (179; 180; 181; 155; 182; 64; 81; 4; 183; 184). In laboratory research, these constituents were weak inhibitors of MAO type B (MAO-B) (155; 81). Antagonism may occur between harmaline and long-acting MAO inhibitors (185). In animal research, harmine prevented pargyline (an MAO inhibitor) from antagonizing epinephrine depletion by Ro 4-1284 (a reversible vesicular monoamine transporter 2 [VMAT2] inhibitor) (186). In other animal research, harmaline administration 30 minutes before pargyline administration was found to block the effects of tryptophan; a lack of an effect was observed when administered after pargyline (112). Similarly, harmaline administration after pargyline was not found to inhibit MAO-A or MAO-B, but when administered before pargyline, it prevented the inhibition of MAO-A by pargyline (187). It also prevented elevations of epinephrine, norepinephrine, and dopamine concentrations in the brain and norepinephrine concentration in the heart, as well as reductions in the concentration of dopamine metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) caused by pargyline (187). Additionally, harmaline prevented inhibition of phenylethylamine and serotonin oxidation by pargyline in the rat heart (188). In animal research, coadministration of harmine and iproniazid (an MAO inhibitor, not U.S. Food and Drug Administration (FDA) approved) selectively depressed sympathetic transmission without affecting the parasympathetic transmission (189). MuscimolMuscimol: In animal research, muscimol (a GABA receptor subtype receptor agonist) suppressed harmaline-induced tremors (153). NMDA antagonistsNMDA antagonists: In animal research, memantine was found to exert neuroprotective effects on cerebellar and inferior olivary neurons and to suppress harmaline-induced tremors (190). In animal research, dizocilpine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, inhibited harmaline induced tremors and the increase of cerebellar cyclic GMP from increased glutamate function (191; 168). In animal research, phencyclidine, 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801), and D-4-[(2E)-3-phosphono-2-propenyl]-2-piperazinecarboxylic acid (d-CPPene) (NMDA receptor antagonists) attenuated harmaline-induced tremors (153). PentobarbitalPentobarbital: In animal research, pentobarbital inhibited harmaline-induced tremors and the increase of cerebellar cyclic GMP from increased glutamate function (168). PhotosensitizersPhotosensitizers: In laboratory research, harmine has been found to exert phototoxic effects (109; 192). QuipazineQuipazine: In animal research, clonidine attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was antagonized by quipazine, a selective 5-HT agonist. ReserpineReserpine: The effects of reserpine on harmine-induced tremors are unclear. Reserpine, a monoamine depleting agent, has been found to enhance harmine-induced tremors (175). However, in animal research, reserpine reduced the intensity of harmine-induced tremors, yet it did not eliminate it completely (166). Other animal research found that acute administration of reserpine depressed the tremor response to harmine but that chronic administration potentiated the response (149). Selective serotonin reuptake inhibitors (SSRIs)Selective serotonin reuptake inhibitors (SSRIs): In animal studies, imipramine (a tricyclic antidepressant [TCA]) and citalopram (a serotonin reuptake inhibitor [SSRI]) were found to exacerbate harmaline-induced tremors dose-dependently (193; 5). These agents were found to decrease 5-hydroxytryptophan (5-HTP) turnover (the 5HIAA:5HT ratio) in the brain stem, suggesting a possible role of serotoninergic impairment (193; 5). In laboratory research, imipramine has been found to promote the antioxidant activity of harmine in the brain, as evidenced by increases in superoxide dismutase (SOD) and catalase (CAT) activity and decreases in lipid and protein oxidation (46). In animal research, clonidine attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was antagonized by fluoxetine, a selective serotonin reuptake inhibitor (SSRI). Serotonin receptor antagonistsSerotonin receptor antagonists: In animal research, an interaction was noted with the use of a serotonin antagonist (unspecified) on harmaline-induced behavior and body temperature changes (194). Details are lacking. In animal research, clonidine attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was potentiated by cyproheptadine (a 5-HT antagonist). Tetrabenazine (not approved in the United States)Tetrabenazine (not approved in the United States): In animal research, harmaline antagonized the effects of tetrabenazine (a monoamine depleter) in a dose-dependent manner (195; 196). Tricyclic antidepressantsTricyclic antidepressants: In animal studies, imipramine (a tricyclic antidepressant [TCA]) and citalopram (a serotonin reuptake inhibitor [SSRI]) were found to exacerbate harmaline-induced tremors dose-dependently (193; 5). These agents were found to decrease 5-hydroxytryptophan (5-HTP) turnover (the 5HIAA:5HT ratio) in the brain stem, suggesting a possible role of serotoninergic impairment (193; 5). In laboratory research, imipramine has been found to promote the antioxidant activity of harmine in the brain, as evidenced by increases in superoxide dismutase (SOD) and catalase (CAT) activity and decreases in lipid and protein oxidation (46). VasodilatorsVasodilators: A methanolic extract from seeds of Peganum harmala exerted vasodilatory effects on rat aorta via adenosine monophosphate (AMP) phosphodiesterase inhibition (197). The extract noncompetitively blocked the alpha1-adrenoceptors. These vasorelaxant effects were potentiated by isoprenaline, a beta-agonist, and negatively affected by the nonspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Syrian rue/Herb/Supplement Interactions:
GeneralGeneral: Avoid oral consumption in any patient.Amino acidsAmino acids: In animal research, harmaline-induced climbing fiber activation caused amino acid release of glutamate and aspartate in the rodent cerebellar cortex (198). In laboratory research, harmaline was found to inhibit sodium-potassium adenosine triphosphatase (Na+ -K+ -ATPase) activity and the uptake of L-phenylalanine (199; 200). It inhibited L-phenylalanine influx at a concentration (not specified) at which no effects on intracellular ion concentrations were observed (199). In snail intestines, harmaline inhibited the initial entry of galactose into the tissue; concentrations above 5mM were found to inhibit those of phenylalanine (201). Inhibitory actions were found to be reversible if low concentrations of harmaline were used (202). AnalgesicsAnalgesics: In animal research, the alkaloid extract of Peganum harmala was found to exert antinociceptive effects in a dose-dependent manner (88; 106). AntiadrenergicsAntiadrenergics: In animal smooth muscle, Peganum harmala seed extract exerted a direct relaxant effect, which suggested that it has antiadrenergic effects (40). In contrast, in humans and animals, intravenous administration of harmine potentiated the effects of epinephrine, likely due to cholinesterase and monoamine oxidase inhibition (128). AntibacterialsAntibacterials: In laboratory tests, beta-carboline alkaloids (harmane, harmaline, harmalol, harmine) from Peganum harmala have been found to exert antibacterial activity against Gram-positive and Gram-negative bacteria (33; 29; 31; 32; 151; 36; 119; 43). Antibacterial effects may also be due to constituents (quercetin and kaempferol) found in the plant (151). When applied as binary mixtures, the beta-carboline alkaloids were found to exert a synergistic effect (36). In laboratory research, Peganum harmala exerted inhibitory effects against Staphylococcus aureus and Escherichia coli (151). The constituent harmine has been found to inhibit Proteus vulgaris and Bacillus subtilis, with inhibition zones ranging between 21.2 and 24.7mm (36). In laboratory research, the chloroform extract from aerial part extracts of Peganum harmala displayed higher antibacterial activity than the ethyl acetate, butanol, and methanol extracts against Gram-positive than Gram-negative bacteria (43). AnticholinergicsAnticholinergics: In humans and animals, intravenous administration of harmine potentiated the effects of acetylcholine, likely due to cholinesterase and monoamine oxidase inhibition (128). In other animal research, harmaline and its metabolites increased acetylcholine levels; however, the inhibitory effect on striatal cholinergic neuron activity did not involve dopaminergic, serotonergic, or GABA neurons (152). In animal research, harmine-induced tremor was unaffected by cholinergic agents (4). AnticonvulsantsAnticonvulsants: In animal research, anticonvulsant agents suppressed harmaline-induced tremors (153). AntifungalsAntifungals: In laboratory tests, beta-carboline alkaloids (harmaline and harmine) from Peganum harmala have been found to exert antifungal activity (29; 36). Antifungal effects may also be due to constituents (quercetin and kaempferol) found in the plant (151). In laboratory research, Peganum harmala and the constituent harmine were found to inhibit Candida albicans (151). The inhibition zone of harmine against Candida albicans was found to range between 21.2 and 24.7mm (36). When applied as binary mixtures, the beta-carboline constituents were found to exert a synergistic effect (36). AntihistaminesAntihistamines: In animal smooth muscle, Peganum harmala seed extract exerted a direct relaxant effect, which suggested that it had antihistaminic effects (40).AntineoplasticsAntineoplastics: In animal research, alkaloids of Peganum harmala have been found to exert antitumor activity (75). Synergistic effects have been noted after coadministration with the chemotherapeutic agents cisplatin and doxorubicin (75). In laboratory research, the combination of harmine and harmaline with tretinoin (ATRA) and granulocyte colony-stimulating factor (G-CSF) were not found to alter the extent of differentiation on HL-60 cells (76). In breast cancer cells, harmine inhibited breast cancer resistance protein (BCRP) and reduced resistance to mitoxantrone and camptothecin mediated by the protein (70). In vitro and in vivo, harmine has been found to regulate proinflammatory mediators involved in tumor development (61; 118), as evidenced by an increase in antitumor factors such as interleukin-2 (IL-2), tissue inhibitor metalloprotease (TIMP), nuclear factor (NF)-kappaB, cAMP response element-binding (CREB), and activating transcription factor-2 (ATF-2) (118). AntioxidantsAntioxidants: In animal and laboratory research, constituents of Peganum harmala displayed antioxidant activity, protecting against oxidative damage and inhibiting low-density lipoprotein (LDL) particles from oxidation (42; 43; 45; 44; 46; 203). In animal and laboratory research, the beta-carbolines (harmaline, harmalol, and harmine) protected against oxidative damage of brain mitochondria induced by dopamine or 6-hydroxydopamine by scavenging reactive oxygen species (ROS) and inhibiting thiol oxidation (44; 45; 204). Harmaline, however, did not protect against the damaging effects of peroxynitrite (204). In laboratory research, harmaline displayed a higher antioxidant capacity than harmine in scavenging capacity against free radicals, as well as preventing LDL particles from oxidation (42). In other laboratory research, a butanol extract from the aerial part of the plant displayed the highest antioxidant effects compared to ethyl acetate, chloroform, and methanol extracts (43). AntiparasiticsAntiparasitics: In laboratory and animal tests, beta-carboline alkaloids (harmane, harmaline, harmalol, harmine) from Peganum harmala were found to exert antiprotozoal effects (31; 48; 50; 49; 47; 39). In in vitro research, harmane, harmine, and harmaline inhibited Leishmania activity (48; 50). AntiparkinsoniansAntiparkinsonians: In animal research, cholecystokinin octapeptide (CCK-8), ceruletide, and analogs of ceruletide (antiparkinsonian agents not available in the United States) were found to suppress harmine-induced tremors (154). In laboratory research, these constituents were weak inhibitors of MAO type B (MAO-B) (155; 81) AntipsychoticsAntipsychotics: According to animal research, harmaline may reportedly inhibit serotonin uptake into the nerve terminals and thus act additively to increase endogenous serotonin in the synaptic cleft following tryptophan administration, thereby causing excess stimulation of 5-HT1A and 5-HT2 receptors in the brain (112). AntiviralsAntivirals: In laboratory research, Peganum harmala displayed antiviral activity (43). A methanol extract from the aerial part of the plant displayed activity against Coxsackie B virus type 3 (43).Caffeine-containing agentsCaffeine-containing agents: In animal research, caffeine was found to exacerbate the intensity, duration, and amplitude of harmaline-induced tremors (167). In other animal research, caffeine reduced the blood-brain barrier permeability of harmine (146). CholinergicsCholinergics: In animal research, harmine-induced tremors were unaffected by cholinergic agents (4). ChronotropicsChronotropics: In animal research, ingestion of harmine, harmaline, and harmalol caused a direct negative chronotropic effect (137). Cytochrome P450-modifying agentsCytochrome P450-modifying agents: In vitro, beta-carboline alkaloids (harmine, harmaline, harmalol, harmol, and harmane) from Peganum harmala were found to inhibit cytochrome P450 3A4 and 2D6 (170). In other laboratory research, Peganum harmala extract significantly increased the expression of cytochrome P450 (CYP450) 1A2, 2C19, and 3A4 isoenzymes but decreased CYP2B6, 2D6, and 2E1 in human hepatoma HepG2 cells (171). Caution is warranted, as these compounds may alter the effects and concentration levels of herbs and supplements metabolized by the enzyme system. In laboratory research, CYP3A4 and 2D6 isozymes were found to contribute to the O-demethylation of harmaline and harmine (172; 173). The predominant isozymes were CYP1A2 and polymorphic CYP2D6, and to a lesser extent, CYP1A1, CYP2C9, and CYP2C19 (172; 173). Dopamine agonists) Dopamine agonists: In animal research, harmine has been found to affect the brain dopamine system, as evidenced by increases in extracellular concentrations of dopamine, a mechanism reportedly due to its MAO-A inhibitory effects (150). In animal research, dopaminergic agents (L-DOPA, apomorphine, and d-amphetamine) inhibited harmine-induced tremors (4; 148). Dopamine antagonistsDopamine antagonists: In animal research, harmine has been found to affect the brain dopamine system, as evidenced by increases in extracellular concentrations of dopamine, a mechanism reportedly due to its MAO-A inhibitory effects (150). HepatotoxinsHepatotoxins: In animal research, long-term consumption (six weeks) of Peganum harmala seed extracts resulted augmented liver weight and the depletion of alkaline phosphatase (ALP) (32). However, in other animal research, a chloroform extract of Peganum harmala was also found to exert hepatoprotective effects (92). HypoglycemicsHypoglycemics: In animal research, harmine was found to act as a cell-type-specific regulator of peroxisome proliferator-activated receptor (PPAR)-gamma expression, mimicking the effects of PPAR-gamma ligands on adipocyte gene expression and insulin sensitivity (83). HypotensivesHypotensives: Harmine reduced systemic arterial blood pressure and total peripheral vascular resistance; harmaline displayed similar initial decreases, but they were followed by a secondary increase; and the effects of harmalol have been found to be inconsistent (137). IbogaineIbogaine: In radioligand binding studies, concurrent administration of ibogaine (a psychoactive substance found in various plants) and harmaline did not affect the GABA receptor-ionophore; the tremor producing-effects were reportedly due to their effects on sodium channels (26). ImmunomodulatorsImmunomodulators: In vitro, harmaline at high concentrations (10-100mmcM/L) suppressed immune function, specifically T cell regulatory and effector function, B cell function, and natural killer-cell function (90). InotropesInotropes: In in vitro and animal research, harmaline was found to exhibit a dual inotropic effect on the atria (138; 139). LicoriceLicorice: In animal research, a synthetic derivative of glycyrrhetinic acid was found to suppress harmaline-induced tremors (13). Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs): The beta-carboline alkaloids harmaline and harmine in Peganum harmala are known reversible inhibitors of monoamine oxidase inhibitor type A (MOA-A) (179; 180; 181; 155; 182; 64; 81; 4; 183; 184). In laboratory research, these constituents were weak inhibitors of MAO type B (MAO-B) (155; 81). Antagonism may occur between harmaline and long-acting MAO inhibitors (185). NiacinamideNiacinamide: In animal research, injection of 50, 65, or 95mg/kg of 3-acetylpyridine (3-AP) was followed by administration of niacinamide. With a time delay of less than two and half hours, advantageous effects on survival and increasing the extent of inferior olivary complex lesion were demonstrated (205). OnionOnion: Harmine administered with ultraviolet (UV) light was found to increase the frequency of the number of sister-chromatid exchanges and micronuclei in meristematic cells of Allium cepa (192). PhotosensitizersPhotosensitizers: In laboratory research, harmine has been found to exert phototoxic effects (109; 192). RutinRutin: In animal research, administration of rutin and harmaline was found to have a protective effect against reflux esophagitis, as evidenced by the inhibition of gastric acid secretion, oxidative stress, inflammatory cytokine production, and intracellular calcium mobilization in polymorphonucleocytes (PMNs) (206). SedativesSedatives: According to animal research, low doses of harmaline (5-10mg/kg) may cause anxiety, while higher amounts (20mg/kg) were found to exert an anxiolytic effect (54). Selective serotonin reuptake inhibitors (SSRIs)Selective serotonin reuptake inhibitors (SSRIs): In animal studies, imipramine (a tricyclic antidepressant [TCA]) and citalopram (a serotonin reuptake inhibitor [SSRI]) were found to exacerbate harmaline-induced tremors dose-dependently (193; 5). These agents were found to decrease 5-hydroxytryptophan (5-HTP) turnover (the 5HIAA:5HT ratio) in the brain stem, suggesting a possible role of serotoninergic impairment (193; 5). In laboratory research, imipramine was found to promote the antioxidant activity of harmine in the brain, as evidenced by increases in superoxide dismutase (SOD) and catalase (CAT) activity and decreases in lipid and protein oxidation (46). In animal research, clonidine attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was antagonized by fluoxetine, a selective serotonin reuptake inhibitor (SSRI). Serotonin receptor antagonistsSerotonin receptor antagonists: In animal research, an interaction was noted with the use of a serotonin antagonist (unspecified) on harmaline-induced behavior and body temperature changes (194). Details are lacking. In animal research, clonidine attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was potentiated by cyproheptadine (a 5-HT antagonist). VasodilatorsVasodilators: A methanolic extract from seeds of Peganum harmala exerted vasodilatory effects on rat aorta via adenosine monophosphate (AMP) phosphodiesterase inhibition (197). The extract noncompetitively blocked the alpha1-adrenoceptors. These vasorelaxant effects were potentiated by isoprenaline, a beta-agonist, and negatively affected by the nonspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). VasorelaxantsVasorelaxants: A methanolic extract from seeds of Peganum harmala exerted vasodilatory effects on rat aorta via adenosine monophosphate (AMP) phosphodiesterase inhibition (197). The extract noncompetitively blocked the alpha1-adrenoceptors. These vasorelaxant effects were potentiated by isoprenaline, a beta-agonist, and negatively affected by the nonspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). YohimbeYohimbe: In animal research, clonidine attenuated harmaline-induced tremors in a dose-dependent manner (169). This protective effect was not completely blocked with pretreatment of yohimbine. Syrian rue/Food Interactions:
SucroseSucrose: Harmaline is reportedly a full competitive inhibitor of sucrose; however, based on rabbit brush border, alkali metals were found to completely reverse the inhibitory activity of harmaline on sucrose (207). Tyraminecontaining foodsTyramine-containing foods: Beta-carboline alkaloids (harmine, harmaline, harmalol) of Peganum harmala are known to possess potent monoamine oxidase inhibitory properties, which, in turn, may inhibit the catabolism of dietary amines (4; 208). In reserpine-pretreated dogs, harmine potentiated the pressor responses to tyramine (209). Sufficient MAO-inhibition may lead to hypertensive crisis if Peganum harmala is consumed with tyramine-containing foods such as aged cheese, aged or cured meats, fava beans, sauerkraut, soy sauce, or tap beer. Syrian rue/Lab Interactions:
AcetylcholineAcetylcholine: Levels of striatal acetylcholine increased with harmaline administration in experimental animal research (210). This increase was potentiated when harmaline was administered with 5-hydroxytryptophan. Intravenous administration of harmine potentiated the effects of acetylcholine (128). Adrenocorticotropic hormone (ACTH) levelsAdrenocorticotropic hormone (ACTH) levels: Chronic administration of harmine (15mg/kg daily for seven days) was found to normalize ACTH circulating levels in animals exposed to chronic mild stress (79). Blood pressureBlood pressure: Harmine reduced systemic arterial blood pressure and total peripheral vascular resistance; harmaline displayed similar initial decreases, but they were followed by a secondary increase; and the effects of harmalol have been found to be inconsistent (137). Body temperatureBody temperature: According to historical use and animal research, the seeds of Peganum harmala and beta-carboline constituents (harmine and harmaline, specifically) may cause hypothermia (35; 7; 142; 143). BradykininBradykinin: In animal research, harmaline-induced climbing fiber activation caused release of corticotrophin release factor (CRF) in the rodent cerebellar cortex (198). Brain-derived neurotrophic factor (BDNF) protein levelsBrain-derived neurotrophic factor (BDNF) protein levels: High dosages of harmine (acute: 30mg/kg and chronic: 10 and 15mg/kg for 14 days) were found to increase brain-derived neurotrophic factor (BDNF) protein levels (78; 80; 79). Calcitonin gene-related peptide (CGRP)Calcitonin gene-related peptide (CGRP): In animal research, harmaline induced climbing fiber activation, causing a release of CGRP in the rodent cerebellar cortex (198). Corticotropin-releasing factor (CRF)Corticotropin-releasing factor (CRF): In animal research, CRF expression within the inferior olivary complex increased after harmaline administration (198; 8). Creatine kinaseCreatine kinase: In animal research, acute administration of harmine 5, 10, and 15mg/kg increased creatine kinase in the prefrontal cortex (211). In the striatum, doses of 5 and 10mg/kg caused an increase in creatine kinase, but it decreased with the 15mg/kg dose. Chronic administration with harmine 5mg/kg increased creatine kinase in the prefrontal cortex and the striatum. Follicular-stimulating hormone (FSH) levelsFollicular-stimulating hormone (FSH) levels: In animal research, the aqueous extract of Peganum harmala was found to decrease FSH levels (141). GlucoseGlucose: In animal research, harmaline-induced tremors were associated with hypermetabolism of glucose (increased glucose consumption) in the inferior olive and cerebellum (5; 212; 21). In animal research, 2-deoxy-D-glucose (a glucose molecule) was found to attenuate harmaline-induced tremors and increase brain serotonin levels (21). In animal research, harmaline inhibited glucose uptake (213). GlutamineGlutamine: In laboratory research, harmaline inhibited uptake of glutamine in Xenopus oocytes (214). Heart rateHeart rate: In animal research, ingestion harmine, harmaline, and harmalol caused a direct negative chronotropic effect, decreasing heart rate and increasing pulse pressure (137). Immune function testsImmune function tests: In vitro, harmaline at high concentrations (10-100mcM/L) suppressed immune function, specifically T cell regulatory and effector function, B cell function, and natural killer-cell function (90). Inflammatory mediatorsInflammatory mediators: In vitro and in vivo, harmine has been found to regulate proinflammatory mediators involved in tumor development (61; 118), as evidenced by an increase in antitumor factors like interleukin-2 (IL-2), tissue inhibitor metalloprotease (TIMP), nuclear factor (NF)-kappaB, cAMP response element-binding (CREB), and activating transcription factor-2 (ATF-2) (118). Liver function testsLiver function tests: In animal research, the chloroform extract of Peganum harmala was also found to exert hepatoprotective effects following thiourea treatment, as evidenced by a reduction in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels (92). In animal research, long-term consumption (six weeks) of Peganum harmala seed extracts resulted in increased liver weight and the depletion of alkaline phosphatase (ALP) (32). Neuron-specific enolaseNeuron-specific enolase: In animal research, ethanol and chloroform extracts of Peganum harmala protected against the carcinogenic effects induced by thiourea, as evidenced by normalization of neuron-specific enolase (92). SerotoninSerotonin: According to animal research, harmaline administration may enhance 5-hydroxytryptophan and 6-hydroxyindoleacetic acid (5-HIAA) levels, particularly in the caudate-putamen and frontal cortex (215; 210). Serum proteinsSerum proteins: In animal research, long-term consumption (six weeks) of Peganum harmala seed extracts resulted in the depletion of protein, albumin, and globulin (32). TestosteroneTestosterone: In animal research, the aqueous extract of Peganum harmala was found to decrease testosterone levels (141). ThyroglobulinThyroglobulin: In animal research, ethanol and chloroform extracts of Peganum harmala protected against the carcinogenic effects induced by thiourea, as evidenced by normalization of thyroglobulin levels (92).