Hypericum perforatum
St. John's wort/Drug Interactions:
GeneralGeneral: St. John's wort has the potential to reduce systemic bioavailability of many conventional drugs (5; 271; 272). However, the majority of clinical trials used small numbers of subjects and contained few safeguards against bias (such as random and concealed allocation of participants, inclusion of controls, and blinding). Moreover, the methods in the studies varied widely, with inadequate use of widely accepted standards of research practice. Few studies reported assaying the St. John's wort content of the preparations used, and the duration of dosing in these trials was highly variable, with few studies reporting a rationale for the dosing regimen tested. The methodological quality of many studies was limited, lacking in controls, randomization, or order of administration. Thus, the variable effects of St. John's wort on different conventional drugs, and the mechanism by which these effects may operate, remain inconclusive. Better-designed pharmacokinetic studies are required to guide clinical practice (273). 5HT1 agonists (triptans)5HT1 agonists (triptans): Human research has demonstrated serotonin syndrome when St. John's wort is coadministered with triptan medications, via enhanced serotonergic activity (64). Examples of triptans include naratriptan (Amerge?), rizatriptan (Maxalt?), sumatriptan (Imitrex?), and zolmitriptan (Zomig?). AlcoholAlcohol: In human research, St. John's wort (900mg daily) lacked a significant interaction with alcohol, in terms of cognitive capacities (274). However, St. John's wort extracts, ibogaine, and an ibogaine analog reduced intake of alcohol in animal research (275; 276). AnalgesicsAnalgesics: A case of decreased methadone levels associated with St. John's wort in a chronic methadone user has been reported (261). Interactions with oxycodone and fentanyl have also been proposed. In human research, St. John's wort has demonstrated efficacy for polyneuropathy (94). St. John's wort may affect analgesia brought on by morphine (262). In animal research, pretreatment with St. John's wort potentiated morphine's antinociceptive effect, although plasma and brain concentrations of morphine were unaffected (263). AnestheticsAnesthetics: According to human case reports, use of St. John's wort before anesthesia may cause complications, including cardiovascular collapse and delayed emergence (153; 154). There is one case report of cardiovascular collapse during anesthesia reported in a healthy 23 year-old woman who had been taking St. John's wort daily for six months prior to surgery. The patient had undergone uneventful general anesthesia two years earlier before she was taking St. John's wort (155). Antianxiety agentsAntianxiety agents: In laboratory research, St. John's wort was shown to act on various neurotransmitter receptors, including GABA and benzodiazepine receptors (277; 278). In clinical research, St. John's wort was shown to reduce the effectiveness of benzodiazepines, due to the induction of CYP450 3A4 by St. John's wort (65; 36; 66; 37; 41; 37). In an isolated case report, the addition of St. John's wort and ginkgo led to buspirone-induced hypomania; however, the patient was also comedicated with fluoxetine (a selective serotonin reuptake inhibitor), which may have caused the interaction (279). In some clinical research, St. John's wort was reported to reduce symptoms of mild-to-moderate anxiety when administered alone (175; 220; 280; 177; 281; 214) or in combination with valerian (172; 176) or chasteberry (282). However, in some studies, St. John's wort was reported to result in restlessness, insomnia, and anxiety (67; 53; 68; 69; 70). AntibioticsAntibiotics: Antibiotic agents that are transported by p-glycoprotein or metabolized by cytochrome P450 may be altered by concomitant use of St. John's wort, an inducer of p-glycoprotein and cytochrome P450 3A4 (108; 41; 109). In in vitro research, methanol, petroleum ether, chloroform, and ethyl acetate extracts of the aerial parts of St. John's wort inhibited the growth of the Gram-positive bacteria B. subtilis and B. cereus (9). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In human research, St. John's wort had an effect on warfarin (76; 165; 283; 284). The international normalized ratio (INR) decreased in most cases. Usually, the patients had been stabilized on warfarin for some time prior to ingesting St. John's wort. There was a lack of thromboembolic events; however, the decrease in INR was thought to be clinically significant. Increases in warfarin dose or discontinuation of St. John's wort resulted in the INR returning to target values. Proposed mechanisms for this interaction are induction of cytochrome P450 and p-glycoprotein (35; 165; 166). In contrast, St. John's wort administration in adult males for 21 days lacked an apparent clinically relevant impact on the single-dose pharmacokinetic parameters of S(+)- and R(-)-ibuprofen (285). In human research, St. John's wort increased the effects of clopidogrel (286). Antidepressant agentsAntidepressant agents: In human, animal and laboratory research, St. John's wort may have inhibited monoamine oxidase and serotonin reuptake (287; 288; 289; 277; 290; 291; 89). In human research, St. John's wort extract was associated with a reduction in depression, indicating that it may potentiate the effects of other antidepressants (173; 190; 95; 196; 197; 193; 100; 174; 206; 292; 293; 294; 295; 296; 297; 187; 274; 186; 189; 188; 184; 298; 180; 299; 300; 301; 89). Antidepressants: monoamine oxidase inhibitors (MAOIs)Antidepressants: monoamine oxidase inhibitors (MAOIs): In laboratory research, hypericin may have inhibited monoamine oxidase (MAO) A and B (287), as well as other components, such as xanthone and flavonols (302) and catechol-O-methyltransferase (COMT) (303). Other studies similarly reported weak MAOI properties in vitro (288; 289; 277; 290). Yet several of these authors, and others (288), subsequently suggested that the concentrations causing inhibition were likely inadequate to explain antidepressant activity. Cott reported that hypericin lacked significant MAO inhibition at concentrations up to 10mcM (277), and based upon other findings, such as one pharmacokinetic study (304), suggested that this inhibition may lack pharmacological relevance. In theory, St. John's wort may potentiate the effects of MAOIs, possibly leading to clinical toxicity, such as serotonin syndrome or hypertensive crisis (305; 306). Antidepressant agents, selective serotonin reuptake inhibitors (SSRIs)Antidepressant agents, selective serotonin reuptake inhibitors (SSRIs): In animal research, St. John's wort was associated with inhibiting the reuptake of serotonin (291). In human research, concomitant use of St. John's wort with SSRIs was associated with increased adverse effects typically associated with SSRI antidepressants, including serotonin syndrome or mania (83; 307; 308; 309; 306). Various clinical trials have reported that treatment with St. John's wort had similar efficacy as SSRIs in treating depression, suggesting that a potential synergistic effect may be possible (175; 91; 92; 204; 93; 205; 96; 194; 195), although other studies reported that St. John's wort lacked a statistically significant improvement on Liebowitz Social Anxiety Scale scores (90). Antidepressant agents, tricyclic (TCAs)Antidepressant agents, tricyclic (TCAs): In human research, St. John's wort caused a significant reduction in amitriptyline concentration (310; 163). A number of CYP enzymes, including 1A2, 2C19, 3A4, and 2D6, are involved in the metabolism of tricyclic antidepressants (311). Theoretically, concomitant use of St. John's wort and tricyclic antidepressants may increase the risk of serotonin syndrome, due to an increased risk of serotonergic adverse effects. However, a lack of difference in blood pressure or heart rate was found in comparisons of St. John's wort and imipramine in adults (246; 63). Various clinical trials have reported that treatment with St. John's wort had similar efficacy as TCAs in treating depression, suggesting that St. John's wort may potentiate the effects of these agents (199; 200; 201; 202; 203; 191; 312; 313). Antidiabetic agentsAntidiabetic agents: In human research, concomitant use of St. John's wort with tolbutamide resulted in hypoglycemia, although the mechanism is unlikely due to effects on cytochrome P450 2C9 (37). One study showed that St. John's wort significantly altered gliclazide pharmacokinetics in 17 out of 21 patients, and the interaction was independent of the individuals' cytochrome P450 2C9 (CYP2C9) genotype (314). St. John's wort has also been shown to alter glucose metabolism in in vitro research (86). In human research, St. John's wort demonstrated a lack of interaction with repaglinide (315). AntifungalsAntifungals: In human research, concomitant intake of St. John's wort was associated with a decrease in plasma levels of voriconazole (110). AntihistaminesAntihistamines: Clinical research has demonstrated increased clearance of fexofenadine in response to St. John's wort, presumed to be due to MDRI induction (66; 111). AntihypertensivesAntihypertensives: St. John's wort has reportedly caused hypertension (59; 106) and tachycardia in human case reports (60; 61; 104; 105). A case report described a 70 year-old homebound patient who experienced new-onset orthostatic hypotension and light-headedness while taking multiple prescription medications and herbal products, including St. John's wort (247). The effects of St. John's wort with antihypertensive agents remain unclear. Anti-inflammatory agentsAnti-inflammatory agents: In laboratory research, St. John's wort may result in proliferation of T lymphocytes and of the mixed EC lymphocyte reaction after topical application (316). In vitro inhibition of free radical production has been demonstrated in cell-free and human vascular tissue (11). According to in vitro research, St. John's wort may induce CYP450 2C9 (44). Some anti-inflammatory agents (e.g., piroxicam, ibuprofen) are metabolized by cytochrome P450 2C9, and concurrent use with St. John's wort may alter their effects. Human research, however, revealed a lack of significant effect of St. John's wort 300mg three times daily on ibuprofen (285). Antilipemic agentsAntilipemic agents: St. John's wort has reportedly lowered concentrations of simvastatin and its metabolite but did not have this effect on pravastatin (117; 118). The mechanism for this interaction is likely induction of CYP450 3A4 (118). St. John's wort significantly increased the serum level of LDL cholesterol and total cholesterol without a change in HDL cholesterol in hypercholesterolemic patients taking atorvastatin compared with those taking atorvastatin without St. John's wort (119). Antineoplastic agentsAntineoplastic agents: In in vitro research, St. John's wort reduced serum levels of etoposide (Etoposide?), a topoisomerase II inhibitor, presumably through induction of CYP3A4 (158). Theoretically, St. John's wort may antagonize other chemotherapeutic agents that are directed against topoisomerase II-alpha, such as anthracyclines or cytotoxic agents, as has been demonstrated in vitro (158). St. John's wort has also been shown to increase imatinib clearance in human research (317; 318). Concomitant use of St. John's wort with irinotecan has been shown to reduce the AUC of the active metabolite of irinotecan (SN-38) in human research, likely due to induction of CYP450 3A4 (156; 157). In human research, radiosensitization of temozolomide has been increased by St. John's wort (319). However, in cell and animal research, St. John's wort was found to inhibit the growth of, and induce apoptosis in, experimental animal and human cancer cell lines (320; 321; 322), as was found in animal studies (323; 322). AntipsychoticsAntipsychotics: Possible St. John's wort-induced mania has been described in several case reports; a majority of these patients had histories of affective illness, including unipolar (major depression) and bipolar (major depression and mania or hypomania) disorder (79; 80; 81; 82; 78). There may be an association between St. John's wort and hypomania (84). Also, a case report described psychotic features and delirium in a 76 year-old female with Alzheimer's dementia, associated with three weeks of self-medication with St. John's wort (85). First-episode psychosis was also observed in a case report (256). In a recent systematic review, 17 case reports associated the use of St. John's wort with psychotic events (257). Theoretically St. John's wort may interact with antipsychotic agents. Antiretroviral agents, non nucleoside reverse transcriptase inhibitors (NNRTIs)Antiretroviral agents, non nucleoside reverse transcriptase inhibitors (NNRTIs): In human research, St. John's wort has been shown to decrease plasma concentrations of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), possibly due to cytochrome P450 induction (132). Antiretroviral agents, protease inhibitorsAntiretroviral agents, protease inhibitors: In human research, St. John's wort has been shown to decrease plasma concentrations of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), possibly due to cytochrome P450 induction (132; 133; 35). Antiviral agentsAntiviral agents: In vitro studies have documented the antiviral properties of St. John's wort (324; 325; 326; 327; 328; 329; 330; 331; 332; 333). The effects of St. John's wort with antiviral agents are unclear. In human research, a topical combination product that contained copper sulfate pentahydrate and Hypericum perforatum demonstrated efficacy in improving symptoms of herpes lesions such as pain and erythema (334). BenzodiazepinesBenzodiazepines: In clinical research, St. John's wort was shown to reduce the effectiveness of benzodiazepines, due to the induction of CYP450 3A4 by St. John's wort (65; 36; 66; 41; 37). In human research, St. John's wort decreased plasma quazepam concentrations, probably by enhancing CYP3A4 activity, but it did lack an influence on the pharmacodynamic effects of the drug (65). A human research reported reductions of midazolam concentrations, presumed to be due to CYP3A4 induction (36; 66; 37). In a human case study, a psychiatric patient had symptoms due to decreased levels of clozapine, brought on by taking St. John's wort (335). Calcium channel blockersCalcium channel blockers: St. John's wort has been shown to reduce the effectiveness of calcium channel blockers, likely due to induction of cytochrome P450 3A4. Repeated administration of St. John's wort significantly decreased the bioavailability of R- and S-verapamil in humans (336). Reductions in nifedipine concentrations have also been noted (36). CarbamazepineCarbamazepine: In human research, St. John's wort was observed to lack effect on carbamazepine concentrations (337). Hypericin and pseudohypericin pharmacokinetics were only marginally influenced by comedication with the enzyme inhibitor cimetidine and the enzyme inducer carbamazepine (338). Cardiac glycosidesCardiac glycosides: According to human research, treatment with Hypericum extract may decrease digoxin levels and increase digoxin clearance, possibly through induction of p-glycoprotein (161; 162; 35; 127; 159; 160; 163; 164). The interaction may vary within St. John's wort preparations and doses, particularly of hyperforin (339). Low-hyperforin St. John's wort lacked an effect on plasma digoxin (340). Chlorzoxazone (Paraflex?, Parafon Forte?, Relaxazone?, Remular-S?)Chlorzoxazone (Paraflex?, Parafon Forte?, Relaxazone?, Remular-S?): Chlorzoxazone, an antispasmodic skeletal muscle relaxant, has been used as a probe drug for CYP 2E1 function. In clinical research, St. John's wort has been shown to induce 2E1 in vivo (40). ClopidogrelClopidogrel: In human research, St. John's wort increased the effects of clopidogrel (286).ClozapineClozapine: In a human case study, a psychiatric patient had symptoms due to decreased levels of clozapine, brought on by taking St. John's wort (335). CNS depressantsCNS depressants: Dizziness, fatigue, and insomnia have been noted in clinical studies assessing the effects of St. John's wort (99; 100; 101; 68; 91; 97). Also, nervous system disorders have been reported in clinical research (92), and isolated reports of paresthesia (67) and neuropathy have been reported (112). CNS stimulantsCNS stimulants: Dizziness, fatigue, and insomnia have been noted in clinical studies assessing the effects of St. John's wort (99; 100; 101; 68; 91; 97). Also, nervous system disorders have been reported in clinical research (92), and isolated reports of paresthesia (67) and neuropathy have been reported (112). In human research, Hypericum perforatum demonstrated efficacy for attention-deficit hyperactivity disorder (ADHD) (51). ContraceptivesContraceptives: Multiple human reports of reduced serum levels or half-lives of oral contraceptives in association with St. John's wort use, likely related to effects on P450 3A4, exist in the literature, as do concomitant alterations in hormone levels, increased breakthrough bleeding, unexpected pregnancies, and changes in menstrual flow (71; 72; 73; 264; 74; 75; 341; 76; 342; 77). In human research, St. John's wort with a low concentration of hyperforin (Ze 117) demonstrated a lack of interaction with a low dosage of oral contraceptives (343). In subjects taking St. John's wort and oral contraceptives, there was a 10.7% decrease in levels of testosterone and a 15.8% decrease in levels of fT (344). CorticosteroidsCorticosteroids: Concurrent administration of St. John's wort lacked a significant effect on the single-dose pharmacokinetics of prednisone or metabolic prednisolone in male subjects (345). CyclosporineCyclosporine: In a systematic review, reduced levels of plasma cyclosporine were reported to occur in clinical trials with St. John's wort treatment (77). There are numerous reports of significant reductions in cyclosporine drug levels and possible organ rejections with concomitant use of St. John's wort (134; 135; 66; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 77; 147; 148). A significant drop in cyclosporine levels was observed in kidney transplant recipients (149; 150; 135; 138; 139; 140; 141; 142), in heart transplant recipients (143; 145), and in a liver transplant recipient (144) taking St. John's wort, a drop which increased after St. John's wort was discontinued (136; 137). Many of these instances were also accompanied by organ rejection. Effects on cyclosporine levels may also be due to an induction of the drug pump p-glycoprotein (35; 142). Cytochrome P450 substratesCytochrome P450 substrates: St. John's wort is an inducer of cytochrome P450 enzymes, particularly the CYP3A4 and CYP1A2 family (38; 346; 347; 348; 335; 349). Moore et al. demonstrated that St. John's wort (hyperforin) activates a regulator (pregnane X receptor) of CYP3A4 transcription and thereby induces expression of 3A4 in human liver cells (39). Bray et al. demonstrated induction of 3A and 2E1 in mice (34). Upon review, it was noted that St. John's wort may inhibit CYP3A4 acutely and then induce this enzyme with repeated administration (350; 35). CYP2C9, 2D6, and 3A4 inhibition has also been reported in in vivo and in vitro research (32; 33). In a systematic review of 19 trials with available plasma data, three reported a lack of important interaction between St. John's wort and pharmaceutical drugs, and 17 described a decrease in systemic bioavailability of a conventional drug (273). According to in vitro, animal, and human studies, concurrent use of drugs metabolized via the CYP450 liver enzyme system may result in altered therapeutic levels of pharmacologic agents, due to induction or inhibition of enzymes by St. John's wort (41; 6; 36; 37; 38; 42; 32; 33; 34; 35; 43; 44; 45; 46; 47). However, other studies failed to show such induction or inhibition of enzymes (351; 37; 43; 44; 340). In a human case study, a psychiatric patient had symptoms due to decreased levels of clozapine, brought on by taking St. John's wort (335). In human research, cyclosporine was at subtherapeutic levels due to St. John's wort coadministration, which resulted in organ rejection in a case study (147; 148). In in vitro research, St. John's wort induced CYP450 2C9 (44). According to case reports and clinical research, St. John's wort has a cytochrome P450- or p-glycoprotein-mediated interaction with anesthetics, vasopressors, buspirone, bupropion, eletriptan, nefazodone, loperamide, nevirapine, paroxetine, phenprocoumon, sertraline, prednisone, theophylline, tacrolimus, tryptophan, tibolone, and venlafaxine, and an interaction that causes a decrease in the levels of alprazolam, amitriptyline, cyclosporine, debrisoquine, atorvastatin, chlorzoxazone, digoxin, erythromycin, imatinib, indinavir, fexofenadine, gliclazide, irinotecan, ivabradine, midazolam, nifedipine, mephenytoin, methadone, omeprazole, oral contraceptives, tacrolimus, talinolol, verapamil, quazepam, simvastatin, voriconazole, and warfarin (349). Treatment with high-dose hyperforin extracts (>10mg daily) has been associated with CYP3A induction. However, low-dose treatments (<4mg daily) lacked this interaction (90; 172). Dermatologic agentsDermatologic agents: In human research, topical hypericin demonstrated a benefit in mycosis fungoides or plaque psoriasis (352). However, numerous reports of photosensitization, adverse skin reactions, and phototoxicity have been reported with St. John's wort treatment (50; 51; 52; 53; 54; 55; 56; 57; 12; 58). Theoretically, St. John's wort may interact with certain dermatologic agents. DextromethorphanDextromethorphan: High doses of dextromethorphan in conjunction with SSRIs have been associated with dextromethorphan-induced serotonin syndrome (353). However, in clinical research, a lack of effect on dextromethorphan metabolism was observed in response to St. John's wort (354). DigoxinDigoxin: According to human research, treatment with Hypericum extract may decrease digoxin levels and increase digoxin clearance, possibly through induction of p-glycoprotein (161; 162; 35; 127; 159; 160; 163; 164). The interaction may vary within St. John's wort preparations and doses, particularly of hyperforin (339). Low-hyperforin St. John's wort lacked an effect on plasma digoxin (340). Drugs that may lower seizure thresholdDrugs that may lower seizure threshold: There is concern that St. John's wort may cause seizure (113). A case report cited a patient who experienced convulsions associated with an overdose of St. John's wort (114). Caution is warranted when using St. John's wort with agents that lower the seizure threshold. EstrogensEstrogens: Multiple reports of reduced serum levels or half-lives of oral contraceptives in association with St. John's wort use, likely related to effects on P450 3A4, exist in the literature, along with concomitant alterations in hormone levels, increased breakthrough bleeding, unexpected pregnancies, and changes in menstrual flow (71; 72; 73; 74; 75; 76; 77). Fertility agentsFertility agents: Inhibition of sperm motility due to St. John's wort has been observed in vitro (115). St. John's wort has been suggested as directly inhibiting rat and human vas deferens contractility (116). There have also been reports of altered menstrual flow, bleeding, and unwanted pregnancies with concomitant use of St. John's wort (76; 74; 77). FexofenadineFexofenadine: Clinical research has demonstrated increased clearance of fexofenadine in response to St. John's wort, presumed to be due to MDRI induction (66; 111). Gastrointestinal agentsGastrointestinal agents: In human research, St. John's wort demonstrated lack of efficacy for irritable bowel syndrome (208). In various studies in humans, gastrointestinal adverse effects have been reported (89; 53; 90; 77; 91; 92; 93; 94; 95; 96; 97; 51; 98; 69; 99; 100; 101; 68). Theoretically, St. John's wort may interact with gastrointestinal agents. Heart rate-regulating agentsHeart rate-regulating agents: Hypertension, tachycardia, and palpitations have been reported with St. John's wort use (60; 61; 104; 105; 68). HepatotoxinsHepatotoxins: One case report showed mixed-type liver injury with prolonged cholestasis and features of vanishing bile duct syndrome following 10 weeks of treatment with St. John's wort (102). A case report described a patient who experienced hepatotoxicity associated with ingestion of St. John's wort (103). Theoretically, St. John's wort may interact with other hepatotoxins. HMG-CoA reductase inhibitorsHMG-CoA reductase inhibitors: St. John's wort has reportedly lowered concentrations of simvastatin and its metabolite, but it lacked this effect on pravastatin (117; 118). The mechanism for this interaction is likely induction of CYP450 3A4 (118). St. John's wort significantly increased the serum level of LDL cholesterol and total cholesterol without a change in HDL cholesterol in hypercholesterolemic patients taking atorvastatin compared with those taking atorvastatin without St. John's wort (119). Hormonal agentsHormonal agents: In theory, the concurrent use of St. John's wort and HRT may result in altered therapeutic levels of hormones. WS? 5570 stimulated adrenocorticotropic hormone (ACTH) secretion and growth hormone (GH) release in healthy volunteers. There was a lack of effect on cortisol or prolactin (120). There may be an association between high levels of thyroid-stimulating hormone and St. John's wort (87). ImmunosuppressantsImmunosuppressants: Decreases in mycophenolic acid levels in association with St. John's wort use have been observed in human research (355). There are several clinical reports of decreases in tacrolimus levels in association with St. John's wort use, likely due to induction of CYP450 3A4 and p-glycoprotein by St. John's wort (356; 355; 357). There are numerous reports of significant reductions in cyclosporine drug levels and possible organ rejections with concomitant use of St. John's wort (134; 135; 66; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 77). A significant drop in cyclosporine levels was observed in kidney transplant recipients (149; 150; 135; 138; 139; 140; 141; 142), in heart transplant recipients (143; 145), and in a liver transplant recipient (144) taking St. John's wort, a drop which increased after St. John's wort was discontinued (136; 137). Many of these instances were also accompanied by organ rejection. Effects on cyclosporine levels may also be due to an induction of the drug pump p-glycoprotein (35; 142). Loperamide (Imodium?)Loperamide (Imodium?): Delirium and agitation were reported in one patient taking loperamide (Imodium?), St. John's wort, and valerian (358). The condition resolved rapidly with discontinuation of treatment. MethylphenidateMethylphenidate: St. John's wort may have decreased the effects of methylphenidate (359). Mood stabilizersMood stabilizers: In theory, the effects of St. John's wort on mood may potentiate or negate the effects of other mood-stabilizing agents.MorphineMorphine: St. John's wort may affect analgesia brought on by morphine (262). In animal research, pretreatment with St. John's wort potentiated morphine's antinociceptive effect, although plasma and brain concentrations of morphine were unaffected (263). Neurologic agentsNeurologic agents: Mixed animal and in vitro evidence has suggested that the activity of St. John's wort may be related to its inhibition of serotonin, norepinephrine, and/or dopamine synaptic reuptake (121; 122; 123; 124). OmeprazoleOmeprazole: Clinical research has shown that St. John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and greatly decreases the plasma concentrations of omeprazole (360). OpiatesOpiates: A case of decreased methadone levels associated with St. John's wort in a chronic methadone user has been reported (261). Interactions with oxycodone and fentanyl have also been proposed. St. John's wort may affect analgesia brought on by morphine (262). In animal research, pretreatment with St. John's wort potentiated morphine's antinociceptive effect, although plasma and brain concentrations of morphine were unaffected (263). Optic agentsOptic agents: In human research, a survey demonstrated a possible association between hypericin and cataracts (88). PDE5 selective inhibitorsPDE5 selective inhibitors: A 49 year-old man with a 10-year history of recurrent depression experienced orgasmic delay, erectile dysfunction, and inhibited sexual desire when taking the SSRI sertraline (Zoloft?) (126). The SSRI was discontinued with the resolution of symptoms; however, one week after beginning therapy with St. John's wort, the patient developed erectile dysfunction and orgasmic delay. Although coadministration of sildenafil (Viagra?) 25-50mg prior to sexual activity reversed the sexual dysfunction, theoretically St. John's wort may mediate the effects of this and similar agents. P-glycoprotein-regulated drugsP-glycoprotein-regulated drugs: St. John's wort is considered an inducer of p-glycoprotein (127; 128). Human and in vitro studies have shown that hyperforin and hypericin inhibit the active efflux of fluorescent markers daunorubicin and calcein-AM (361; 362). Further in vitro research has provided evidence that St. John's wort and hyperforin, excluding hypericin, increased the expression of p-glycoprotein and the efflux of digoxin in LS 180 cells; removal of St. John's wort resulted in restoration of levels within 48 hours. A lack of acute effects on p-glycoprotein-mediated transport of digoxin in response to St. John's wort was observed (363). St. John's wort increased the expression and enhanced the drug efflux function of p-glycoprotein in peripheral blood mononuclear cells of healthy volunteers (364). Photosensitizing agentsPhotosensitizing agents: It has been suggested that concurrent use of St. John's wort and photosensitizing agents, including several antibiotics and oral contraceptives, may increase the risk of photosensitization (48). A phototoxic reaction was observed in a patient experimentally treated with delta-aminolevulinic acid for breast cancer who also had been taking St. John's wort (49). Numerous other reports of photosensitization, adverse skin reactions, and phototoxicity with St. John's wort treatment have been documented (50; 51; 52; 53; 54; 55; 56; 57; 12; 58). A risk for significant photogenic damage due to the combination of Hypericum extracts and UVA phototherapy is possible, although it has been reported that the risk may be low in the majority of individuals (252). SedativesSedatives: Dizziness, fatigue, and insomnia have been noted in patients treated with St. John's wort (99; 100; 101; 68). In vitro, St. John's wort has been shown to act on various neurotransmitter receptors, some of which have been implicated as playing a role in sedation, including GABA and benzodiazepine receptors (277; 278). Smoking cessation agentsSmoking cessation agents: In human research, St. John's wort has demonstrated efficacy for smoking cessation (218). TestosteroneTestosterone: In subjects taking St. John's wort and oral contraceptives, there was a 10.7% decrease in levels of testosterone and a 15.8% decrease in levels of fT (344). TheophyllineTheophylline: It remains unclear if serum levels of theophylline or its metabolites are affected by St. John's wort (35). One report describes a 42 year-old woman who experienced lowered serum theophylline levels upon concomitant ingestion of 300mg of St. John's wort daily. The patient was on several other medications and smoked tobacco. Within one week of discontinuation of St. John's wort, her theophylline level rose from 9mcg/mL to 19mcg/mL (129). However, in a 48-hour study in 12 healthy volunteers given both agents (theophylline 400mg and St. John's wort 300mg), a lack of changes was observed in blood or serum levels of theophylline or its metabolites (13U, 1U, 3X). The duration of this study may have been insufficient to adequately assess this interaction. In a 15-day open-label crossover study, it was determined that it is unlikely that treatment with St. John's wort on CYPs is sufficient to cause a change in plasma theophylline concentrations (130). Thyroid hormonesThyroid hormones: According to a retrospective case-control study, elevated thyroid-stimulating hormone levels may be associated with taking St. John's wort (260). However, this small retrospective sample lacked a clear, significant relationship to imply causality. According to expert opinion, there may be an association between high levels of thyroid-stimulating hormone and St. John's wort in humans (87). ViagraViagra: A 49 year-old man with a 10-year history of recurrent depression experienced orgasmic delay, erectile dysfunction, and inhibited sexual desire when taking the SSRI sertraline (Zoloft?) (126). The SSRI was discontinued with resolution of symptoms; however, one week after beginning therapy with St. John's wort, the patient developed erectile dysfunction and orgasmic delay. Coadministration of sildenafil (Viagra?) 25-50mg prior to sexual activity reversed the sexual dysfunction. WarfarinWarfarin: In human research, St. John's wort has had an effect on warfarin (76; 165; 283; 284). The international normalized ratio (INR) decreased in most cases. Usually, the patients had been stabilized on warfarin for some time prior to ingesting St. John's wort. There was a lack of thromboembolic events; however, the decrease in INR was thought to be clinically significant. Increases in warfarin dose or discontinuation of St. John's wort resulted in the INR returning to target values. Proposed mechanisms for this interaction are induction of cytochrome P450 and p-glycoprotein (35; 165; 166). Weight loss agentsWeight loss agents: In human research, a combination product containing St. John's wort demonstrated efficacy for weight loss (365).Wound healing agentsWound healing agents: In human research, H. perforatum demonstrated efficacy for wound healing for Cesarean scars, although surgical site irritation was noted in some individuals (131). ZolpidemZolpidem: In human research, coadministration of St. John's wort and zolpidem resulted in decreased zolpidem levels (125). St. John's wort/Herb/Supplement Interactions:
GeneralGeneral: St. John's wort has the potential to reduce systemic bioavailability of many agents (5; 271; 272). However, the majority of clinical trials used small numbers of subjects and contained few safeguards against bias (such as random and concealed allocation of participants, inclusion of controls, and blinding). Moreover, the methods in the studies varied widely, with inadequate use of widely accepted standards of research practice. Few studies reported assaying the St. John's wort content of the preparations used, and the duration of dosing in these trials was highly variable, with few studies reporting a rationale for the dosing regimen tested. The methodological quality of many studies was limited, lacking in controls, randomization, or order of administration. Thus, the variable effects of St. John's wort on different herbs and supplements, and the mechanism by which these effects may operate, remain inconclusive. Better-designed pharmacokinetic studies are required to guide clinical practice (273). AlcoholAlcohol: In human research, St. John's wort (900mg daily) lacked a significant interaction with alcohol, in terms of cognitive capacities (274). However, St. John's wort extracts, ibogaine, and an ibogaine analog reduced intake of alcohol in animal research (275; 276). AnalgesicsAnalgesics: A case of decreased methadone levels associated with St. John's wort in a chronic methadone user has been reported (261). Interactions with oxycodone and fentanyl have also been proposed. In human research, St. John's wort demonstrated efficacy for polyneuropathy (94). In animal research, pretreatment with St. John's wort potentiated morphine's antinociceptive effect, although plasma and brain concentrations of morphine were unaffected (263). AnestheticsAnesthetics: In human case reports, use of St. John's wort before anesthesia has been associated with complications, including cardiovascular collapse and delayed emergence (154; 153). There is one case report of cardiovascular collapse during anesthesia reported in a healthy 23 year-old woman who had been taking St. John's wort daily for six months prior to surgery. The patient had undergone uneventful general anesthesia two years earlier before she was taking St. John's wort (155). Antianxiety agentsAntianxiety agents: In laboratory research, St. John's wort has been shown to act on various neurotransmitter receptors, including GABA and benzodiazepine receptors (277; 278). In clinical research, St. John's wort has been shown to reduce the effectiveness of benzodiazepines, due to the induction of CYP450 3A4 by St. John's wort (65; 36; 66; 37; 41). In an isolated case report, the addition of St. John's wort and ginkgo led to buspirone-induced hypomania; however, the patient was also comedicated with fluoxetine (a selective serotonin reuptake inhibitor), which may have caused the interaction (279). In some clinical research, St. John's wort was reported to reduce symptoms of mild-to-moderate anxiety when administered alone (175; 220; 280; 177; 281; 214) or in combination with valerian (172; 176) or chasteberry (282). However, in some studies, St. John's wort was reported to result in restlessness, insomnia, and anxiety (67; 53; 68; 69; 70). AntibacterialsAntibacterials: Antibiotic agents that are transported by p-glycoprotein or metabolized by cytochrome P450 may be altered by concomitant use of St. John's wort, an inducer of p-glycoprotein and cytochrome P450 3A4 (108; 41; 109). In in vitro research, methanol, petroleum ether, chloroform, and ethyl acetate extracts of the aerial parts of St. John's wort inhibited the growth of the Gram-positive bacteria B. subtilis and B. cereus (9). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In human research, St. John's wort had effects on warfarin (76; 165; 283). The INR decreased in most cases. Usually, the patients had been stabilized on warfarin for some time prior to ingesting St. John's wort. There was a lack of thromboembolic events; however, the decrease in INR was thought to be clinically significant. Increases in warfarin dose or discontinuation of St. John's wort resulted in the INR returning to target values. Proposed mechanisms for this interaction are induction of cytochrome P450 and p-glycoprotein (35; 165; 166). In contrast, St. John's wort administration in adult males for 21 days had lacked an apparent clinically relevant impact on the single-dose pharmacokinetic parameters of S(+)- and R(-)-ibuprofen (285). In human research, St. John's wort led to significantly elevated S-warfarin (284). In human research, St. John's wort increased the effects of clopidogrel (286). AntidepressantsAntidepressants: In human, animal and laboratory research, St. John's wort may have inhibited monoamine oxidase and serotonin reuptake (287; 288; 289; 277; 290; 291; 89). In human research, St. John's wort extract was associated with a reduction in depression, indicating that it may potentiate the effects of other antidepressants (173; 190; 95; 196; 197; 193; 100; 174; 206; 292; 293; 294; 295; 296; 297; 187; 274; 186; 189; 188; 184; 298; 180; 299; 300; 301; 89). Antidepressant agents, monoamine oxidase inhibitors (MAOIs)Antidepressant agents, monoamine oxidase inhibitors (MAOIs): According to laboratory research, hypericin may inhibit monoamine oxidase (MAO) A and B (287), as well as other components, such as xanthone and flavonols (302) and catechol-O-methyltransferase (COMT) (303). Other studies similarly reported weak MAOI properties in vitro (288; 289; 277; 290; 306). Yet several of these authors, and others (288), subsequently suggested that the concentrations causing inhibition were likely inadequate to explain antidepressant activity. Cott reported that hypericin lacked significant MAO inhibition at concentrations up to 10mcM (277), and based upon other findings, such as one pharmacokinetic study (304), suggested that this inhibition may lack pharmacological relevance. In theory, St. John's wort may potentiate effects of other herbs with MAOI properties, possibly leading to clinical toxicity, such as serotonin syndrome or hypertensive crisis (305). Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): In animal research, St. John's wort was associated with inhibition of the reuptake of serotonin (291). In human research, concomitant St. John's wort led to increased adverse effects typically associated with SSRI antidepressants, including serotonin syndrome or mania (308; 307; 309; 83; 306). Various clinical trials have reported that treatment with St. John's wort had similar efficacy as SSRIs in treating depression, suggesting that a potential synergistic effect may be possible (175; 91; 92; 204; 93; 205; 96; 194; 195), although other studies reported that St. John's wort did not produce a statistically significant improvement on the Liebowitz Social Anxiety Scale (90). Antidepressants, tricyclic (TCAs)Antidepressants, tricyclic (TCAs): In human research, St. John's wort was associated with a significant reduction in amitriptyline concentration (310; 163). A number of CYP enzymes, including 1A2, 2C19, 3A4, and 2D6, are involved in the metabolism of tricyclic antidepressants (311). Theoretically, concomitant use of St. John's wort and tricyclic antidepressants may increase the risk of serotonin syndrome, due to an increased risk of serotonergic adverse effects. However, a lack of difference in blood pressure or heart rate was found in comparisons of St. John's wort and imipramine in adults (246; 63). Various clinical trials have reported that treatment with St. John's wort had similar efficacy as TCAs in treating depression, suggesting that St. John's wort may potentiate the effects of these agents (199; 200; 201; 202; 203; 191; 312; 313). AntifungalsAntifungals: In human research, concomitant intake of St. John's wort was associated with a decrease in plasma levels of voriconazole (110). AntihistaminesAntihistamines: Clinical research has demonstrated increased clearance of fexofenadine in response to St. John's wort, presumed to be due to MDRI induction (66; 111). Anti-inflammatory herbs and supplementsAnti-inflammatory herbs and supplements: In laboratory research, St. John's wort resulted in proliferation of T lymphocytes and of the mixed EC lymphocyte reaction after topical application (316). In vitro inhibition of free radical production has been demonstrated in cell-free and human vascular tissue (11). In in vitro research, St. John's wort induced CYP450 2C9 (44). Some anti-inflammatory agents (e.g., piroxicam, ibuprofen) are metabolized by cytochrome P450 2C9, and concurrent use with St. John's wort may alter their effects. Human research, however, revealed a lack of significant effect of St. John's wort 300mg three times daily on ibuprofen (285) AntilipemicsAntilipemics: St. John's wort has reportedly lowered concentrations of simvastatin and its metabolite, but it lacked this effect on pravastatin (118; 117). The mechanism for this interaction is likely induction of CYP450 3A4 (118). St. John's wort significantly increased the serum level of LDL cholesterol and total cholesterol, with lack of change in HDL cholesterol, in hypercholesterolemic patients taking atorvastatin compared with those taking atorvastatin without St. John's wort (119). AntineoplasticsAntineoplastics: In in vitro research, St. John's wort reduced serum levels of etoposide (Etoposide?), a topoisomerase II inhibitor, presumably through induction of CYP3A4 (158). Theoretically, St. John's wort may antagonize other chemotherapeutic agents that are directed against topoisomerase II-alpha, such as anthracyclines or cytotoxic agents, as has been demonstrated in vitro (158). St. John's wort has also been shown to increase imatinib clearance in human research (317; 318). Concomitant use of St. John's wort with irinotecan has been shown to reduce the AUC of the active metabolite of irinotecan (SN-38) in human research, likely due to induction of CYP450 3A4 (156; 157). In clinical research, St. John's wort has been associated with increased imatinib clearance (317; 318). However, in cell and animal research, St. John's wort was found to inhibit the growth of, and induce apoptosis in, experimental animal and human cancer cell lines (320; 321; 322), as well as in animal studies (323; 322). AntioxidantsAntioxidants: St. John's wort was shown to have antioxidant effects in vitro (10; 11). AntipsychoticsAntipsychotics: Possible St. John's wort-induced mania has been described in several case reports; a majority of these patients had histories of affective illness, including unipolar (major depression) and bipolar (major depression and mania or hypomania) disorder (79; 80; 81; 82; 78). There may be an association between St. John's wort and hypomania (84). Also, a case report described psychotic features and delirium in a 76 year-old female with Alzheimer's dementia, associated with three weeks of self-medication with St. John's wort (85). First-episode psychosis has also been observed in a case report (256). In a recent systematic review, 17 case reports associated the use of St. John's wort with psychotic events (257). Theoretically St. John's wort may interact with antipsychotic agents. AntiviralsAntivirals: In vitro studies have documented the antiviral properties of St. John's wort (324; 325; 326; 327; 328; 329; 330; 331; 332; 333). The effects of St. John's wort with antiviral agents are unclear. In human research, a topical combination product that contained copper sulfate pentahydrate and Hypericum perforatum demonstrated efficacy in improving symptoms of herpes lesions such as pain and erythema (334). Cardiac glycosidesCardiac glycosides: According to human research, treatment with Hypericum extract may decrease digoxin levels and increase digoxin clearance, possibly through induction of p-glycoprotein (159; 160; 163; 161; 162; 127; 164; 35). The interaction may vary within St. John's wort preparations and doses, particularly of hyperforin (339). Low-hyperforin St. John's wort appears to lack an effect on plasma digoxin (340). Central nervous system stimulantsCentral nervous system stimulants: Dizziness, fatigue, and insomnia have been noted in clinical studies assessing the effects of St. John's wort (99; 100; 101; 68; 91; 97). Also, nervous system disorders have been reported in clinical research (92), and there have been isolated reports of paresthesia (67) and neuropathy (112). In human research, Hypericum perforatum demonstrated efficacy for ADHD (51). ChasteberryChasteberry: In some clinical research, St. John's wort was reported to reduce symptoms of mild-to-moderate anxiety when administered in combination with chasteberry (282). ContraceptivesContraceptives: Multiple human reports of reduced serum levels or half-lives of oral contraceptives in association with St. John's wort use, likely related to effects on P450 3A4, exist in the literature, as do reports of concomitant alterations in hormone levels, increased breakthrough bleeding, unexpected pregnancies, and changes in menstrual flow (71; 72; 73; 264; 74; 75; 341; 76; 342). In human research, Hypericum perforatum demonstrated efficacy for improving physical and behavioral symptoms in premenstrual syndrome (PMS) (97). In human research, St. John's wort with a low concentration of hyperforin (Ze 117) demonstrated lack of interaction with a low dosage of oral contraceptives (343). In subjects taking St. John's wort and oral contraceptives, there was a 10.7% decrease in levels of testosterone and a 15.8% decrease in levels of fT (344). Cytochrome P450 substratesCytochrome P450 substrates: St. John's wort is an inducer of cytochrome P450 enzymes, particularly the CYP3A4 and CYP1A2 family (38; 346; 347; 348; 335; 349). Moore et al. demonstrated that St. John's wort (hyperforin) activates a regulator (pregnane X receptor) of CYP3A4 transcription and thereby induces expression of 3A4 in human liver cells (39). Bray et al. demonstrated induction of 3A and 2E1 in mice (34). Upon review, it was noted that St. John's wort may inhibit CYP3A4 acutely and then induce this enzyme with repeated administration (350; 35). CYP2C9, 2D6, and 3A4 inhibition has also been reported in in vivo and in vitro research (32; 33). In a systematic review of 19 trials with available plasma data, three reported a lack of important interaction between St. John's wort and pharmaceutical drugs, and 17 described a decrease in systemic bioavailability of a conventional drug (273). According to in vitro, animal, and human studies, concurrent use of drugs metabolized via the CYP450 liver enzyme system may result in altered therapeutic levels of pharmacologic agents, due to induction or inhibition of enzymes by St. John's wort (41; 6; 36; 37; 38; 42; 32; 33; 34; 35; 43; 44; 45; 46; 47). However, other studies have failed to show such induction or inhibition of enzymes (351; 37; 43; 44; 340). In a human case study, a psychiatric patient had symptoms due to decreased levels of clozapine, brought on by taking St. John's wort (335). In human research, cyclosporine was at subtherapeutic levels due to St. John's wort coadministration, which resulted in organ rejection in a case study (147; 148). Treatment with high-dose hyperforin extracts (>10mg daily) has been associated with CYP3A induction. However, low dose treatments (<4mg daily) lacked this interaction (90; 172). Dermatologic herbs and supplementsDermatologic herbs and supplements: In human research, topical hypericin demonstrated a benefit in mycosis fungoides or plaque psoriasis (352). However, numerous reports of photosensitization, adverse skin reactions, and phototoxicity have been reported with St. John's wort treatment (50; 51; 52; 53; 54; 55; 56; 57; 12; 58). Theoretically, St. John's wort may interact with certain dermatologic agents. Fertility agentsFertility agents: Inhibition of sperm motility due to St. John's wort has been observed in vitro (115). St. John's wort has been suggested as directly inhibiting rat and human vas deferens contractility (116). There have also been reports of altered menstrual flow, bleeding, and unwanted pregnancies with concomitant use of St. John's wort (76; 74; 77). Gastrointestinal agentsGastrointestinal agents: In human research, St. John's wort demonstrated lack of efficacy for irritable bowel syndrome (208). In various studies in humans, gastrointestinal adverse effects have been reported (89; 53; 90; 77; 91; 92; 93; 94; 95; 96; 97; 51; 98; 69; 99; 100; 101; 68). Theoretically, St. John's wort may interact with gastrointestinal agents. Heart rate-regulating agentsHeart rate-regulating agents: Hypertension, tachycardia, and palpitations have been reported with St. John's wort use (60; 61; 104; 105; 68). Hepatotoxic agentsHepatotoxic agents: One case report showed mixed-type liver injury with prolonged cholestasis and features of vanishing bile duct syndrome following 10 weeks of treatment with St. John's wort (102). A case report described a patient who experienced hepatotoxicity associated with ingestion of St. John's wort (103). Hormone replacement therapy (HRT)Hormone replacement therapy (HRT): In theory, the concurrent use of St. John's wort and HRT may result in altered therapeutic levels of hormones. In human research, St. John's wort demonstrated efficacy in decreasing perimenopausal symptoms of sleep problems and quality of life (98). HypoglycemicsHypoglycemics: In human research, concomitant use of St. John's wort with tolbutamide resulted in hypoglycemia, although the mechanism is unlikely due to effects on cytochrome P450 2C9 (37). One study showed that St. John's wort significantly altered gliclazide pharmacokinetics in 17 out of 21 patients, and the interaction was independent of the individuals' cytochrome P450 2C9 (CYP2C9) genotype (314). St. John's wort has also been shown to alter glucose metabolism in in vitro research (86). HypotensivesHypotensives: St. John's wort has reportedly caused hypertension (59) and tachycardia, in human case reports (60; 61; 104; 105). A case report described a 70 year-old homebound patient who experienced new-onset orthostatic hypotension and light-headedness while taking multiple prescription medications and herbal products, including St. John's wort (247). The effects of St. John's wort with antihypertensive agents remain unclear. ImmunosuppressantsImmunosuppressants: Decreases in mycophenolic acid levels in association with St. John's wort use have been observed in human research (355). There are several clinical reports of decreases in tacrolimus levels in association with St. John's wort use, likely due to induction of CYP450 3A4 and p-glycoprotein by St. John's wort (356; 355; 357). There are numerous reports of significant reductions in cyclosporine drug levels and possible organ rejections with concomitant use of St. John's wort (134; 135; 66; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146). A significant drop in cyclosporine levels was observed in kidney transplant recipients (149; 150; 135; 138; 139; 140; 141; 142), in heart transplant recipients (143; 145), and in a liver transplant recipient (144) taking St. John's wort, a drop which increased after St. John's wort was discontinued (136; 137). Many of these instances were also accompanied by organ rejection. Effects on cyclosporine levels may also be due to an induction of the drug pump p-glycoprotein (35; 142). IronIron: Due to the presence of tannins in St. John's wort, iron absorption may be inhibited (48; 306). MelatoninMelatonin: St. John's wort has been found to affect nighttime melatonin levels (366). Mood stabilizersMood stabilizers: In theory, the effects of St. John's wort on mood may potentiate or negate the effects of other mood-stabilizing herbs.Neurologic agentsNeurologic agents: Mixed animal and in vitro evidence has suggested that the activity of St. John's wort may be related to its inhibition of serotonin, norepinephrine, or dopamine synaptic reuptake (121; 122; 123; 124). P-glycoprotein regulated agentsP-glycoprotein regulated agents: St. John's wort is considered an inducer of p-glycoprotein (127; 128). Human and in vitro studies have shown that hyperforin and hypericin inhibit the active efflux of markers affected by p-glycoprotein (360; 361; 362). Further in vitro research has provided evidence that St. John's wort and hyperforin, excluding hypericin, increased the expression of p-glycoprotein in LS 180 cells; removal of St. John's wort resulted in restoration of levels within 48 hours. A lack of acute effects on p-glycoprotein-mediated transport of digoxin in response to St. John's wort was observed (363). St. John's wort increased the expression and enhanced the drug efflux function of p-glycoprotein in peripheral blood mononuclear cells of healthy volunteers (364). PhotosensitizersPhotosensitizers: It has been suggested that concurrent use of St. John's wort and photosensitizing agents may increase the risk of photosensitization (48). A phototoxic reaction was observed in a patient experimentally treated with delta-aminolevulinic acid for breast cancer who also had been taking St. John's wort (49). Numerous other reports of photosensitization, adverse skin reactions, and phototoxicity with St. John's wort treatment have been documented (50; 51; 52; 53; 54; 55; 56; 57; 12; 58). A risk for significant photogenic damage due to the combination of Hypericum extracts and UVA phototherapy is possible, although it has been reported that the risk may be low in the majority of individuals (252). PhytoestrogensPhytoestrogens: Multiple reports of reduced serum levels or half-lives of oral contraceptives in association with St. John's wort use, likely related to effects on P450 3A4, exist in the literature, along with concomitant alterations in hormone levels, increased breakthrough bleeding, possible unwanted pregnancies in some cases, and changes in menstrual flow (71; 72; 73; 74; 75; 76). In human research, Hypericum perforatum demonstrated efficacy for improving physical and behavioral symptoms in PMS (97; 215). In human research, St. John's wort demonstrated efficacy in decreasing perimenopausal symptoms of sleep problems and quality of life (98). SedativesSedatives: Dizziness, fatigue, and insomnia have been noted in patients treated with St. John's wort (99; 100; 101; 68). In vitro, St. John's wort has been shown to act on various neurotransmitter receptors, some of which have been implicated as playing a role in sedation, including GABA and benzodiazepine receptors (277; 278). eizure threshold-lowering agentsSeizure threshold-lowering agents: There is concern that St. John's wort may cause seizure (113). A case report cited a patient who experienced convulsions associated with an overdose of St. John's wort (114). Caution is warranted when using St. John's wort with agents that lower the seizure threshold. Smoking cessation herbs and supplementsSmoking cessation herbs and supplements: In human research, St. John's wort demonstrated efficacy for smoking cessation (218). Thyroid agentsThyroid agents: According to human research, elevated thyroid-stimulating hormone levels may be associated with taking St. John's wort (260). ValerianValerian: In human research, delirium and agitation were associated with concomitant use of valerian (Valeriana officinalis), St. John's wort, and loperamide (Imodium?) (358). However, in other clinical research, St. John's wort was reported to reduce symptoms of mild-to-moderate anxiety when administered in combination with valerian (172; 176). Weight loss herbs and supplementsWeight loss herbs and supplements: In human research, a combination product containing St. John's wort demonstrated efficacy for weight loss (365).Wound healing herbs and supplementsWound healing herbs and supplements: In human research, H. perforatum demonstrated efficacy for healing of Cesarean scars (131). St. John's wort/Food Interactions:
Tyramine-containing foods/beveragesTyramine-containing foods/beverages: Weak monoamine oxidase inhibitor (MAOI) activity of St. John's wort has been observed in vitro (287; 302; 288; 303; 289; 277; 290). Similar to warnings accompanying the use of MAOI antidepressants, consumption of tyramine-containing foods in combination with St. John's wort may pose an increased risk of a hypertensive crisis. In a telephone survey of 43 subjects who had taken St. John's wort, 39 persons reported ingesting tyramine-rich foods or products. Two persons taking 600-900mg daily reported associated flushing and pounding headaches (60). St. John's wort/Lab Interactions:
Blood glucoseBlood glucose: In in vitro research, St. John's wort was associated with effects on glucose metabolism (86). Blood pressureBlood pressure: In human research, hypertension was associated with St. John's wort use (60; 61; 104; 105). Coagulation panelCoagulation panel: In human research, St. John's wort was associated with reduced effects of warfarin (lowered international normalized ratio [INR]) (76; 165). In most cases, the patients had been stabilized on warfarin for some time prior to ingesting St. John's wort. There was a lack of thromboembolic events; however, the decrease in INR was thought to be clinically significant. Increases in warfarin dose or discontinuation of St. John's wort resulted in the INR returning to target values. Proposed mechanisms for this interaction are induction of cytochrome P450 and p-glycoprotein (35; 165; 166). In contrast, St. John's wort administration in adult males for 21 days had a lack of apparent clinically relevant impact on the single-dose pharmacokinetic parameters of S(+)- and R(-)-ibuprofen (285). CortisolCortisol: In preliminary human research, St. John's wort increased cortisol (367). CytokinesCytokines: Hyperforin may stimulate IL-8 expression in human intestinal epithelia cells (IEC) and primary hepatocytes. Hyperforin was shown to induce IL-8 mRNA through an SXR-independent transcriptional activation pathway. IL-8 induction by hyperforin required the activation of AP-1, but activation of NF-kappaB transcription factor was lacking. Further research revealed that extracellular signal-regulated kinase-1 and -2 (ERK1/2) were required for the hyperforin-induced expression of IL-8 (368). Hyperforin inhibited IL-6 release from human astrocytoma cells (U373MG) in vitro. In whole blood, however, hyperforin levels needed to inhibit IL-6 release are about one order of magnitude higher than the hyperforin levels measured in the plasma of rats or humans treated with pharmacologically active doses of St. John's wort or hyperforin (369). Heart rateHeart rate: In human research, tachycardia was associated with St. John's wort use (60; 61; 104; 105). Hormone levelsHormone levels: Multiple reports of reduced serum levels or half-lives of oral contraceptives in association with St. John's wort use, likely related to effects on P450 3A4, exist in the literature, as do reports of concomitant alterations in hormone levels, increased breakthrough bleeding, unexpected pregnancies, and changes in menstrual flow (71; 72; 73; 74; 75). Inflammatory markersInflammatory markers: According to laboratory research, St. John's wort may result in proliferation of T lymphocytes and of the mixed EC lymphocyte reaction after topical application (316). In vitro inhibition of free radical production has been demonstrated in cell-free and human vascular tissue (11). Lipid profileLipid profile: The concentration of simvastatin and its metabolite were significantly lowered with concomitant St. John's wort, though this effect was lacking on pravastatin (118; 117). St. John's wort significantly increased the serum level of LDL cholesterol and total cholesterol, with lack of change in HDL cholesterol, in hypercholesterolemic patients taking atorvastatin compared with those taking atorvastatin without St. John's wort (119). Thyroid function panelThyroid function panel: According to human research, elevated TSH levels may be associated with taking St. John's wort (260).