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St. John's Wort

Botanical Name: Hypericum perforatum L.
Pharmacopoeial Name: Hyperici herba.
Common Names: St. John’s wort, Klamath weed (historic: Fuga daemonum, herba solus).

Summary Table
Drug/Class Interaction TypeMechanism and SignificanceManagement

Drug is 3A4 substrate. St. John’s wort (SJW) lowers bioavailability by inducing 3A4 enzyme production.
Interaction proved experimentally; no clinical reports.
May be significant for intravenous midazolam preoperatively.
Coadministration usually contraindicated.
Tertiary tricyclic antidepressants

Drug 3A4/P-glycoprotein (P-gp) cosubstrate.
Herb lowers bioavailability.
Interaction proved experimentally; no clinical reports.
Coadministration usually contraindicated.
Anesthesia, general
Potential pharmacokinetic and pharmacodynamic interactions with premedications and anesthetics. Reports scarce.
Cessation SJW 1 to 2 weeks before procedure suggested.
Disclosure essential.
Indinavir, nevirapine
Protease inhibitors
/ /
Most antiretroviral agents are 3A4/P-gp cosubstrates.
Decreased bioavailability demonstrated.
No clinical reports.
Generally avoid.
Coadministration requires specialist supervision and monitoring of drug levels.
Immunosuppressive agents
Cyclosporine A is cosubstrate of 3A4/P-gp. Decreased bioavailability demonstrated.
Numerous serious reports of graft rejection.
Cardiac glycosides
Drug is P-gp substrate. Possible biphasic response, short-term increase, long-term decrease in bioavailability.
Isolated report of bigeminy, short term.
If coadministered, ramp/taper the addition/cessation of herb, and monitor drug levels with vigilance during transition.
Topoisomerase II inhibitors
/ /
Possible combination pharmacokinetic and pharmacodynamic interaction, decreased availability (drug is 3A4 substrate), and interference with therapeutic action by hypericin, blocking topo II inhibition.
Histamine H1-receptor antagonist antihistamine
Drug is P-gp substrate. Decreased bioavailability demonstrated.
No clinical reports; minimal significance.
Unlikely to cause problems.
Tyrosine kinase inhibitors

Gleevec is 3A4 substrate; decreased drug bioavailability demonstrated. Possible compromise to targeted anticancer therapy. No case reports.
Camptothecin analogs
Variable pharmacokinetic interaction probable. Significance unknown. Camptothecin-11 responses subject to high inherent variability.
Proton pump inhibitors
Prilosec is 3A4/2C19 substrate; SJW reduces bioavailability, as experimentally demonstrated.
No clinical reports, although large size of effect may be clinically significant.
Avoid, or monitor and increase dose drug.
Oral contraceptives (OCs)
Steroids hormones are 3A4 substrates. SJW increases breakthrough bleeding, may reduce OC compliance. OC failure not established despite theoretical risk.
Avoid, or adopt barrier methods during coadministration.
Paclitaxel, docetaxel
Theoretically, induction of CYP3A4 and P-gp could influence drug disposition. Significance not established. Drug mostly eliminated via CYP2C8.
Paroxetine, trazodone
SSRI and SSRI/SNRI antidepressants

Herb may lead to varying combined pharmacokinetic and pharmacodynamic interactions, at least with some SSRI/NSRI drugs. Mild symptoms of serotonergic excess possible. Several reports of varying reliability. Significance not established.
Avoid, except with professional monitoring during drug taper.
HMG-CoA reductase inhibitors (statins)

Some older statins are cosubstrates of 3A4/P-gp.
Minimal significance; no reports available.
Consider newer statins if coadministration indicated.
Cyclosporine A is a cosubstrate of 3A4/P-gp. Experimental evidence that tacrolimus is also 3A4 substrate, but no interactions reports for tacrolimus.
Calcium channel blockers
Verapamil (and all calcium channel blockers) are 3A4 substrates. SJW induces intestinal 3A4 and increases drug clearance.
No reports. Interaction significance not established.
Monitored coadministration unlikely to be problematic. END_
Triazole antifungals
Drug is 3A4/2C19/2C9 substrate. SJW reduces bioavailability, as experimentally demonstrated.
No clinical reports, although large size of effect may be clinically significant.
Warfarin, Phenprocoumon
Oral vitamin K antagonist anticoagulants

Mechanism not established. Possible pharmacokinetic effect; may lead to reduced INR. Significance minimal to moderate.
Reliable clinical reports or trials unavailable.
Unlikely to cause problems. If coadministered, monitor INR once or twice weekly, and titrate anticoagulant dosage when starting or stopping SJW therapy, until INR stable.
NNRTIs , Nonnucleoside reverse-transcriptase inhibitors; SSRI , selective serotonin reuptake inhibitor; SNRI , serotonin-norepinephrine reuptake inhibitor; HMG-CoA , 3-hydroxy-3-methylglutaryl–coenzyme A; INR , international normalized ratio.
herb description


Clusiaceae (Guttiferae, Hypericaceae).

Habitat and Cultivation

Perennial; native in Europe Asia and North Africa; naturalized in the United States and considered a noxious weed in many areas; widespread in temperate zones, favoring disturbed ground.

Parts Used

Flowering tops.

Common Forms

  • Dried Plant:   Flowering tops.

  • Tincture:   60% ethanol, 1:2 to 1:5 weight/volume.

  • Standardized Extract:   0.3% hypericin, 2.0% to 4.5% hyperforin.

  • Infused Oil:   Fresh flowers, for external use.

herb in clinical practice


A well-documented botanical medicine since Greco-Roman times, St. John's wort (SJW) has a long history of folk and traditional use as a vulnerary (“wound healer”) and for banishing mental afflictions, particularly melancholy. For example, Gerard 1 (1633) described its use as a balm for wounds, burns, ulcers, and bites as being without equal. The oil made from the macerated flowers was listed in the first Pharmacopoeia Londinensis (1618). Hypericum perforatum was proved and introduced into the homeopathic materia medica by Muller in the mid-1800s and has been included in the Homeopathic Pharmacopoeia of the United States since that era, with primary indications focusing on nerve pain and traumatic injuries (e.g., concussion, coccygeal impact, sequelae).

More recently, clinical trial evidence accumulated through the 1980s and 1990s established the efficacy and safety of standardized SJW extracts for treating mild to moderate depression, and the “natural antidepressant” label propelled the herb to second-best-selling supplement in the United States by the late 1990s. In 2000, reports of serious interactions with prescription drugs began to appear, and the resulting adverse publicity caused sales of the herb to fall significantly, although SJW remains one of the top-selling U.S. botanicals. It was approved by the German Commission E for “depressive moods” (internally) and “contused injuries” (externally) in 1984. 2 The pharmacology and clinical effects of the herb are currently the focus of considerable research interest and, because of rapid accumulation of data, relatively recent literature reviews (e.g., 1997 American Herbal Pharmacopoeia monograph) are in some respects dated. 3 More recent reviews of the extensive literature include the 2003 European Scientific Cooperative on Phytotherapy (ESCOP) monograph 4 and a comprehensive monograph by McKenna et al. 5

Historical/Ethnomedicine Precedent

Traditionally, SJW was used as a calming herb for symptoms of nervous tension, including anxiety and insomnia, as well as a restorative for melancholic conditions that might currently be diagnosed as depression. Folk use attributed the herb with properties of protection against enchantments, including demonic possession, and it was used for warding off evil spirits. Hypericum was characterized as “hot and dry” in the Galenic humoral system of medicine and has classically been associated with the liver and spleen, as well as the Sun. Historically considered a “woundwort,” SJW is still used both internally and externally for pain relief, particularly neuralgic pain, shingles, mild contusions, and burns to the skin. For external use, the fresh flowers, traditionally harvested on St. John's Day (immediately following Summer Solstice), are the basis of a macerated oil, which is usually red (by the dianthrone hypericin). This red color was considered an indication of its vulnerary nature (likened to blood) by the Doctrine of Signatures. Before the modern clinical trial–driven indications of the herb for “mild to moderate depression,” the nervous system indications were less clearly defined and included “psychovegetative” disorders, as well as such conditions as nocturnal eneuresis and night terrors. Its psychological effects were considered much less pronounced than those of prescription medications; Weiss 6 classified the herb as a “mild (i.e., gentle) psychotropic” agent.

Known or Potential Therapeutic Uses

Analgesic, antiviral, anti-inflammatory, anxiety, coccygeal impact, concussion depression (mild to moderate), hepatoprotection, herpes simplex infection (orofacial and genital), herpes zoster (shingles and postherpetic neuralgia), menopause-related psychological symptoms, psychosomatic and somatiform disorders (mild), nervousness, neuralgia, nocturnal eneuresis, photodynamic antitumor activity, premenstrual syndrome, restlessness, sacral irritation and spinal injuries, sciatica, seasonal affective disorder, tissue healing and wound repair.

Key Constituents

Characteristic napthodianthrones, including hypericin; phloroglucinols, including hyperforin and adhyperforin.

Flavonoids, including proanthocyanidin polymers of catechin and epicatechin; flavonols; phenylpropanoids; essential oil; amino acids; xanthones.

Therapeutic Dosing Range

  • Dried Plant:   2 to 5 g/day.

  • Tincture and Fluid Extract:   As 1:1 equivalents, 1 to 3 mL/day.

  • Standardized Extracts:   900 mg/day in divided doses.

  • Topical:   Oleum hyperici , oily macerate from fresh flowering tops (applied as needed).

Also used in ultradilute succussed preparations based on homeopathic indications.

interactions review

Strategic Considerations/Background

Although an old medicine, SJW has a pivotal place in the relatively recent field of herb-drug interactions. The publication of convincing reports of interactions between SJW and digoxin 7 in 1999 and cyclosporine 8 and indinavir 9 in 2000 was seminal, initiating a widespread reevaluation of the safety of this popular herb, previously considered to be benign, in the context of conventional medications. 10 It also propelled the issue of potential interactions between botanicals and pharmaceuticals into media prominence and research focus. The subsequent years have seen increased understanding of the pharmacology of SJW, and the herb is now known to be associated with a number of clinically significant pharmacokinetic interactions, as suggested by the original reports. These interactions are mediated by its effects on several key components of drug metabolism, including the cytochrome P450 (CYP450) mixed-oxidase system, various conjugases and transferases, as well as the transporter proteins that modulate drug efflux across intestinal, renal, and biliary epithelia. These systems compose what are now often referred to as phases (or stages) I, II, and III of drug metabolism/detoxification.

The initial reports of SJW interactions with narrow-therapeutic-range drugs prompted sweeping warnings in professional and consumer media about the dangers of SJW herb-drug interactions (and often of herb-drug interactions in general). At the time, however, the actual number of reports of documented SJW-related drug interactions was, and in fact remains, relatively small, with data of widely varying reliability. Surveying the available cases in 2001, Fugh-Berman and Ernst 11 found 54 published reports claiming SJW interactions. Of these, 29 were rejected as unclassifiable, and the remaining 25 were evaluated for reliability according to the authors’ “reliability rating score” system. Of these, 12 were classified as “unreliable,” 11 as “possible,” and only two as “likely.” More recently, Meyer et al. 12 analyzed six documented potential herb-drug interactions, including SJW-cyclosporine and SJW-digoxin, across a wide range of “tertiary sources” and found high variability in the reporting of the data, with only three sources even mentioning all six known interactions. Interestingly, as recently reviewed by Izzo, 13 clinical reports of SJW-drug interactions seem to be decreasing rather than increasing in frequency.

Mills et al. 14 recently conducted a systematic review of trials investigating SJW pharmacokinetic interactions with conventional drugs. The authors found the methodological quality of the studies was limited; in particular lacking accepted controls such as correct randomization, observance of established blinding procedures, and allowance for time-dependent effects. They also found that only 15 of the 22 available studies assayed the SJW content of the preparations used, and that varied dosing regimens and duration of exposure to the herb were common, without presenting a rationale for the tested dosing patterns. These limitations mean that most trials on SJW interactions do not appear to conform to the U.S. Food and Drug Administration (FDA)–recommended standards for safeguards against bias in pharmacokinetic trials. 15 This in turn results in questions about the interpretation and applicability of the available data that can only be resolved by more and better-designed studies, as well as consistent application of necessary standards in pharmacovigilance.

Official and regulatory reaction was also triggered by the initial SJW interaction reports. In 2000 the U.K. Committee on Safety of Medicines (CSM) 16 issued a general advisory letter on SJW interactions to all physicians and pharmacists. This included a fact sheet listing medications for which SJW might interact and advised patients to “stop taking St John's Wort,” while warning against immediate discontinuation in the event that drug levels might rise, causing serious adverse effects. Lists of drugs that might interact with SJW, causing “serious adverse interactions,” were provided, including selective serotonin reuptake inhibitors (SSRIs), anticonvulsants, and triptans. In 2001 the Irish Medical Board (IMB) 17 restricted SJW to physician prescription only, effectively removing the herb (along with ginkgo and several others) from general public access, citing the monoamine oxidase inhibitor (MAOI) activity of SJW as potentially interacting with tyramine foods and potentiating MAOI drugs, as well as claiming SJW caused phototoxicity and other (unspecified) adverse effects. The FDA issued an advisory to health care professionals warning about the SJW-indinavir interaction in 2000, also suggesting physicians alert patients about potential drug interactions involving “any drug metabolized via the cytochrome P450 pathway.” 18

Effects on Drug Metabolism and Bioavailability

Cytochrome P450

The complete spectrum of induction and inhibition effects of SJW on the CYP450 system in vivo in humans is not yet fully characterized. Possibly because of a number of differing investigative methodologies, as well as differences between the various types of extracts used, the available studies are inconclusive. In vitro evidence exists for inhibition effects by crude SJW extracts, its flavonoid components, and hypericin and hyperforin on CYP450 1A2, 2C9, 2C19, 2D6, and 3A4. 19,20In vivo studies using single probe drugs that are specific CYP substrates have found induction effects by SJW on 3A4, 21 and with multiprobe drug “cocktails,” for 3A4, 2E1, 1A2, and 2D6 22 and 2C19. 23 By contrast, no significant effects on 2D6 and 3A4 were found by two other groups, 24,25and a further probe cocktail study found no effect on 1A2, 2C9, or 2D6. 26 More recent studies have confirmed in vivo coordinate induction effects by SJW on hepatic and intestinal 3A4 and P-glycoprotein (P-gp). 27,28

Summarizing the data available at this time, SJW definitely induces human 3A4; probably induces 1A2, 2C19, and 2E1; and probably does not significantly affect 2C9 or 2D6. It also induces P-gp and possibly other, related transporters. There is a degree of tissue specificity, with induction of both hepatic and intestinal 3A4, as well as a possible biphasic effect, at least on 3A4 and P-gp, with short-term inhibition followed by an increasing induction of enzymes over 7 to 10 days. However, evidence from isolated constituent studies suggests that hyperforin plays the main role in induction activity. 23,29-34The initial inhibition may be caused by hypericin, but also by flavonoid constituents; a number of flavonoids are known to inhibit 3A4, with those from grapefruit and other citrus-derived flavonoids being the best-known examples. 35,36This “biphasic” effect of a short-term enzyme inhibition succeeded by longer-term induction has recently been demonstrated in a clinical study of voriconazole pharmacokinetics. This open-label study with 16 healthy male volunteers determined that that SJW coadministration with voriconazole (a substrate of CYP2C19) led to a short-term but clinically insignificant increase in the area under curve (AUC) of 22%, and after 15 days, AUC was reduced by 59% compared with controls. 37,38

Pregnane X Receptor

The recent finding that hyperforin, an active phloroglucinol constituent compound of SJW, acts as a high-affinity ligand for the orphan nuclear receptor pregnane X receptor (PXR) is highly significant. 39,40The PXR and related nuclear receptors, such as the constitutive androstane receptor (CAR) and the retinoid X receptor (RXR), have been described as “promiscuous” because of the unprecedented structural diversity of compounds that interact with their ligand-binding domain (LBD). 41-43Activation of the PXR leads to upregulation of genes controlling multiple aspects of xenobiotic metabolism, including phase I (CYP450 1A1, 1A2, 2B6, 2C9, and 3A4) mixed oxidases, phase II conjugases (uridine diphosphate [UDP] glucuronosyltransferases, glutathione- S-transferases, sulfonyltransferases), and phase III drug transporters (MDR1/P-gp, MDR2, organic anion-transporting polypeptides [OATPs]). 19 , 26 , 29 , 30 , 32 , 33 , 44-51

The implication is that the PXR and related nuclear receptors may effectively act to coordinate xenobiotic detoxification. 41-43,52-56The PXR itself is subject to a degree of genetically determined polymorphism, the importance of which remains to be clarified, but pronounced interspecies differences are known to exist in activator compounds, with marked differences among rodent, rabbit, and human ligands. 41,57,58Pascussi et al. 59 have aptly described expression of the genes controlling xenobiotic metabolism as a “tangle of networks of nuclear and steroid receptors, where receptors share partners, ligands, DNA response elements and target genes and where the different pathways exhibit cross-talk at several levels.”

A broader view of SJW emerges from these recent developments. The herb can be conceptualized as a master inducer of detoxification, or more accurately as a xenosensory activator, capable of triggering the complex adaptive system evolved to metabolically eliminate toxic compounds, both endogenous and xenobiotic. 60,61The downstream consequences of PXR activation on drug metabolism suggest that, to some extent, SJW interactions may be predicted (and thus managed) on the basis of whether a given coadministered drug is a substrate of the enzymes or transporters induced by PXR activation, particularly 3A4 and P-gp. 55,62


Induction of P-gp by SJW further complicates the picture and may confound attempts to predict interactions. P-glycoprotein is a membrane-associated, adenosine triphosphate (ATP)–dependent “pumping” protein that ejects foreign or toxic compounds from cells and mediates “multidrug resistance” when induced in cancer cells. Durr et al. 28 estimated the induction of intestinal P-gp by SJW at a 1.5-fold increase in healthy human volunteers. Ernst 63 noted drugs that are dual substrates of both P-gp and CYP3A4 likely present an increased risk of pharmacokinetic interaction as a result of co-induction by SJW. However, the relative contributions of P-gp and 3A4 to drug efflux appear to be complex and differ for different agents that are dual substrates. 64

The existence of several polymorphisms in P-gp phenotypes affects normal levels of expression of both hepatic and intestinal P-gp. These polymorphisms are known to exhibit variation with racial and gender characteristics. 65,66As with P450 enzymes, dietary food ingredients may also affect P-gp expression; known examples include piperine from black pepper and some citrus flavonoids. 67,68Alpha-tocopherol can also influence P-gp, probably through PXR activation. 52 Finally, the role of non–P-gp drug transporters, such as the OATP family, has recently emerged as another potential mechanism in controlling drug bioavailability, although modulating influences on OATP expression are not currently well characterized.

Overall, the interplay between CYP3A4 and P-gp (and other transporters) is not well understood, but this “drug-efflux metabolism alliance,” as aptly named by Benet and Cummins, 69 remains of a crucial research area for future elucidation of drug interactions. 70,71

Managing Pharmacokinetic Interactions

Numerous pharmaceuticals are metabolized by CYP3A4, which is a low-affinity, high-throughput P450 enzyme expressed primarily in the small intestinal mucosa and liver. This has led to suggestions that SJW may interact with more than 50% of all known drugs. Indeed, evidence is now rapidly accumulating from preclinical screening studies that confirms SJW induction effects on a range of drugs, particularly 3A4 substrates, often in the absence of any clinical interactions data. However, the magnitude of SJW induction effects is considerably less than that of other known PXR ligands, the best-known example being rifampin, a mainstay of conventional tuberculosis therapy. Rifampin is a coordinate inducer of P-gp and 3A4 with an induction effect on midazolam (a 3A4-specific substrate) that is 25 times that of SJW. 72 Red wine has similar order-of-magnitude effects as SJW on oral clearance of cyclosporine (a dual substrate). 73

Theoretical predictions should be confirmed by clinical data before an interaction can be assumed inevitable. For example, carbamazepine is a well-known substrate and inducer of 3A4. When SJW was given for 14 days to patients previously stabilized on carbamazepine, no effect of SJW on carbamazepine kinetics or drug levels was observed. 74 This suggests that close attention must be paid to the precise metabolic pathways involved for each specific drug and to the associated effects on induction or inhibition of P450, enzymes, transferases, and transporters. Unfortunately, older drugs were not always well characterized by their manufacturers in terms of their interaction with the P450 metabolizing enzymes, leading to obvious problems for prediction and management of metabolic interactions.

Proposed coadministration should also consider different temporal patterns of combining herb and pharmaceutical agents. Three alternative scenarios are possible. First, adding an inducer (SJW) to a substrate (drug) will induce a lowering of previously stable drug levels over 1 to 2 weeks through increased drug metabolism, risking consequent loss of therapeutic efficacy. Moreover, in the case of SJW, initial inhibition may complicate this pattern, creating an apparent biphasic effect. Second, if the substrate (drug) is added to inducer (SJW), standard drug-dosing levels may be inadequate and may result in failure of therapy. Notably, this would not apply to drugs whose level is established by monitoring and titration to a therapeutic endpoint (e.g., coumarin/INR value). Third, withdrawal of an inducer (SJW) from a regimen of previously stable coadministration with a substrate drug will reverse induction and possibly cause rebound toxicity from elevated drug levels. Theoretically, this series of patterns would be “reversed” if the drug concerned was a prodrug, depending on activation for the metabolic transformation by the CYP450 induced. Armstrong et al. 75 well describe this schema of possible pharmacokinetic interaction patterns among inducers, inhibitors, and substrates of CYP450 drug-metabolizing enzymes.

In summary, if appropriate data about metabolic pathways of a drug are available, the pharmacokinetics of any drug proposed for coadministration with SJW should be reviewed before prescription and, wherever possible, drugs metabolized by multiple routes selected. If this is not possible, and if compelling reasons exist for coadministration of the herb with the drug, precautionary measures should be adopted; this is mandatory for any drug with narrow therapeutic indices. Introduction or cessation of SJW should be ramped or tapered, respectively, and serum levels of the pharmaceutical need to be monitored to titrate drug levels and thus counter increased clearance rates. When factors such as financial cost or intermediate metabolite toxicity militate against compensatory increases in drug doses, avoidance of coadministration is the optimum management solution.

The literature on SJW interactions continues to expand, with persistent calls in secondary sources for large-scale in vitro screening of herbs to establish the “risk” of potential (pharmacokinetic) interactions with drugs. These calls ignore that drug disposition is unpredictably mediated by a wide variety of dietary 62 compounds, foods, herbs, beverages, and lifestyle products and also affected by a wide range of individual variables, from genomics through biological, lifestyle, and socioeconomic factors, all of which render meaningful screening virtually impossible.

One study analyzing responses of six different ethnic groups to SJW did not uncover significant differences in induction effects on CYP3A4 and P-gp. 76 However, Gurley et al. 77 examined CYP450 phenotypes in elderly versus younger subjects and found age-related differences in responsiveness to botanical agents regarding CYP3A4 induction, concluding that population vulnerabilities may exist in elders. The results of in vitro tests are often contradictory and may be at odds with clinical reality because of the inherent differences between experimental systems and the in vivo complexities of herbal administration; therefore these tests have limited predictive value. Butterweck et al. pointed out that logically, systematic screening for pharmacokinetic interactions should first be applied to narrow-therapeutic-index drugs. 78,79

Some argue that understanding and managing variability in drug responses would be better than scaremongering about overstated adverse effects of herbs. 80,81More recent mainstream papers suggest that the emphasis is beginning to shift in a more constructive direction. 62,82Equally, the development of “low-hyperforin” extracts of SJW may provide efficacy in antidepressant indications without invoking PXR-mediated downstream effects on drug disposition. 34,83However, hyperforin confers numerous other properties on SJW whole-plant extracts, including anti-inflammatory, antitumor, and antiangiogenic effects. 84

Pharmacodynamic Interactions

In addition to pharmacokinetic interactions, pharmacodynamic interactions based on the antidepressant activity of SJW have been widely suggested, principally when combined with the SSRI antidepressants. The evidence for pharmacodynamic interactions is more problematic than that supporting the metabolic interactions, partly related to the general unreliability of SJW case reports, as previously noted. 11,14Qualitative data sources such as postal surveys of psychiatrists have been used to suggest adverse reports and interactions that in effect are unassessable. 85 Safety and efficacy data from clinical trials of SJW suggest that adverse effects of the herb are an order of magnitude less (1%-3%) than those of pharmaceutical antidepressants. 86 Despite the known interactions issues, SJW remains a first-line treatment for mild to moderate depression in Europe. 87 Significantly, the adverse effect data from clinical trials of the herb suggest a completely different profile of adverse effects than with common antidepressant drugs. This correlates with current understanding of the underlying mechanisms of SJW's observed antidepressant effects. The herb is now believed to work through novel and apparently complex mechanisms, dissimilar to those of known pharmaceutical antidepressants.

Initial research presumed a typical druglike biogenic amine mechanism for SJW, but early in vitro data suggesting MAOI activity have not been substantiated by in vivo studies. Reports of hypertensive MAOI-SJW interactions are lacking, as are reliable reports of interactions between SJW and tyramine-containing food substances 88,89(see also Theoretical, Speculative, and Preliminary Interactions Research later). Extensive research in vitro and on animals has examined the effects of both full-spectrum SJW extracts and isolated constituents on neurotransmitter uptake for serotonin, dopamine, noradrenaline, gamma-aminobutyric acid (GABA), andL-glutamate. 90-100The emerging conclusion is that the phloroglucinol-derivative hyperforin acts as a synaptosomal uptake inhibitor for all five of these neurotransmitters. Müller 97 has described this effect as “broad-band” reuptake inhibition. The molecular mechanism of the “pseudo-nonselective reuptake” effect is thought to be related to activation by hyperforin of a sodium ion channel that causes an increase in intracellular sodium content, modifying the sodium gradient that is the common basis of all neuronal neurotransmitter transport proteins. 90,92,99,100

Although hyperforin appears to be unique in having an approximately equal inhibitory effect on all five neurotransmitters, its effects also are at least an order of magnitude less than that of pharmaceutical antidepressants when quantified in vitro. 97 The improbability of achieving in vivo concentrations of hyperforin from oral SJW consumption that could correspond to effects of synthetic neurotransmitter uptake inhibitors is rarely considered when suggestions of “serotonin syndrome” are made relating to SJW interactions. 89 Serotonin syndrome, first characterized by Sternbach 101 in 1991, was initially described as the result of the adverse interaction of SSRIs with MAOI drugs. The clinical concept of serotonin syndrome has been overused and frequently misapplied in the drug interactions literature. 102 The concept has been reviewed and revised by Radomski et al., 103 who found a high level of misdiagnosis and distinguished several subsets of the serotonin syndrome based on symptom severity, from transient mild symptoms to fatal toxic states. The latter must also be differentiated from neuroleptic malignant syndrome. 104

Although hyperforin appears to be the only constituent that can affect uptake of all five neurotransmitters, it cannot be considered responsible for all the observed antidepressant effects of SJW. In some animal behavioral models of depression (e.g., the Porsolt test), hyperforin-free extracts exhibited significant activity, suggesting that other constituents have an effect. Clinical trials with a low-hyperforin extract also demonstrated antidepressant activity against placebo, fluoxetine, and imipramine. 105,106Furthermore, methodological controversy continues to surround clinical trials comparing SJW with placebo and pharmaceutical antidepressants, particularly because of the well-documented, powerful placebo responses associated with these trials. 107-109

Despite the absence of definitive understanding of the mechanism of SJW antidepressant activity, caution regarding potential interactions with pharmaceutical antidepressants is more than warranted. Also, several classes of psychiatric drugs are substrates or inhibitors of CYP3A4 and P-gp, suggesting combined pharmacokinetic and pharmacodynamic interactions with SJW. Common agents likely to be encountered in general and psychiatric practice include triazolobenzodiazepines (alprazolam, estazolam, midazolam, triazolam), which are substrates of 3A4, as are the nonbenzodiazepine hypnotics zolpidem and zaleplon and the “atypical” anxiolytic buspirone.

herb-drug interactions
Alprazolam, Midazolam, and Related Triazolobenzodiazepines
Amitriptyline and Related Tertiary Tricyclic Antidepressants
Anesthesia, General
Antiretrovirals: Protease Inhibitors and Nonnucleoside Reverse-Transcriptase Inhibitors
Digoxin, Digitoxin, and Related Cardiac Glycosides
Etoposide and Related Topoisomerase II Inhibitors
Omeprazole and Related Proton Pump Inhibitors
Oral Contraceptives and Related Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
Paclitaxel, Docetaxel: Taxane Microtubule-Stabilizing Agents
Paroxetine and Related Selective Serotonin Reuptake Inhibitor and Serotonin-Norepinephrine Reuptake Inhibitor (SSRI and SSRI/SNRI) Antidepressants and Nonselective Serotonin Reuptake Inhibitors (NSRIs)
Simvastatin and Related HMG-COA Reductase Inhibitors (Statins)
Verapamil and Related Calcium Channel Blockers
Voriconazole and Related Triazole Antifungal Agents
Warfarin and Oral Vitamin K Antagonist Anticoagulants
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Monoamine Oxidase (MAO) Inhibitors
Photosensitizing Agents
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