Much literature is available on the interaction potential of SJW, most notably Cott’s evaluation of existing effect and mechanistic evidence10, the review by Henderson et al. 11, the comprehensive presentation in Botanical Medicines (McKenna, Jones and Hughes) 5 and the medical assessment and recommendations advanced in the publication by Awang and Fugh-Berman. 12
There is ample evidence now available indicating that SJW affects the bioavailability of a substantial percentage of co-administered drugs, by influencing both their metabolism and absorption. On the metabolic side, the cytochrome P450 (CYP 450) family of isozymes is implicated, particularly CYP 3A4, the most abundant hepatic enzyme, claimed to oxidize more than half of all medications subject to oxidative metabolism.10 CYP 450 enzymes are concentrated in the liver and intestinal mucosa, but are also found in the kidneys, lungs, skin and other tissues. SJW is a potent inducer of CYP 3A within physiologically relevant concentrations, apparently moreso in the intestine, than in the liver, according to studies with rats. It has been estimated that SJW can effect almost a doubling of CYP 3A4 activity and a corresponding reduction of drug levels, apparently by activation of the pregnane X receptor. 13 In addition, the adenosine triphosphate (ATP) transporter P-glycoprotein (Pgp) has been identified as a significant contributor to reduced bioavailability of drugs affected by SJW. An inducible membrane transport protein, Pgp is a barrier to xenobiotic accumulation and a determinant of oral bioavalability of many drugs. 14
Hyperforin, once regarded as a prime active principle responsible for SJW’s antidepressant activity but now thought to be neither directly nor dominantly relevant to its therapeutic effect15 . A byperforin free SJW extracts has been shown in clinical pharmacokinetic studies to lack interaction potential with either CYP 3A4 or Pgp. 16
Cyclosporin(e)
Nine cases of decreased cyclosporine levels have been associated with concomitant SJW consumption, and several transplant rejections have been reported.17 Although oral bioavailability variation of cyclosporine was previously ascribed to CYP 3A4, it is now known that Pgp variably reduces the rate of its intestinal absorption. 18
Two cardiac graft rejections were recently reported.19 Both were with men in their 60s receiving azothiaprine, cysclosporine, and corticosteroids, who were hospitalized due to early signs of rejection 3 weeks after beginning standardized SJW (300 mg t.i.d.). Discontinuing SJW increased cyclosporine levels and led to recovery of both patients.
A 29-year-old woman who received cadaveric kidney and pancreas transplants began taking a SJW supplement. After 4 weeks her previously stable cyclosporine levels became subtherapeutic and associated with signs of organ rejection. Four weeks after stopping SJW, cyclosporine concentrations were restored to therapeutic levels and transplant rejection obviated. 20
Reserpine
Animal studies have demonstrated that SJW extract can significantly prolong narcotic – induced sleeping times and antagonize the effects of reserpine. 21 Digoxin
SJW interacts with digoxin, a known substrate of Pgp transport that is not metabolized by CYP 450 isoenzymes.
In a single-blind, placebo-controlled parallel group study, 25 healthy volunteers brought to steady–state digoxin levels continued to receive digoxin (0.25 mg/d), either with placebo or 900 mg/d SJW extract (LI 160) for 10 days. The first dose of SJW had no appreciable effect, but 10 days of treatment decreased digoxin area under the curve (AUC) 25% (p=0.0035), reduced trough concentrations 33% (p=0.0023), and reduced maximum concentration by 26% (p=0.0095). 22
A similar randomized, double-blind, placebo-controlled parallel group study examined the interaction between digoxin and a proprietary SJW extract (Jarsin®, Lichtwer). After 14 days of comedication (900 mg SJW/d, plus a maintenance dose of digoxin), the 24h. AUC of digoxin was reduced by 24.6% as compared with coadministered placebo. 23
Theophylline
The widely alleged interaction between SJW and the asthma drug theophylline has been questioned by Cott, who also undermines the theory that SJW is metabolized by CYP 1A2. 10 Cott concludes that the “single report of a possible theophylline – SJW interaction is probably a spurious association.”
A 42-year-old woman who smoked half a pack of cigarettes daily (CYP 1A2 enzymes are induced by tobacco) and took 11 other prescription drugs (most of which affect CYP 450 enzymes) took SJW for 2 months and was found to have subtherapeutic theophylline levels, which rose within 7 days of discontinuing SJW. 24
Protease Inhibitors
Indinavir, a protease inhibitor used to treat HIV, is a substrate of CYP 3A4 and Pgp. 25
Eight healthy, HIV-negative subjects in whom study-state kinetic parameters for indinavir were established were treated with 300 mg t.i.d. SJW extract for 14 days. Indinavir AUC decreased by 57% after the SJW therapy.26
Anticoagulants
SJW significantly decreases drug levels of the anticoagulants warfarin and phenprocoumon (the latter not available in the U.S.)
Seven cases of patients stabilized on warfarin showing reduced INRs associated with SJW comedication have been reported. .27 No thromboemblic complications were noted. While warfarin has been shown to be metabolized by CYP 2C9, a study with rats indicates a possible induction of Pgp: reduced plasma levels of warfarin were not associated with any appreciable changes in liver enzyme activity. 28
A randomized, single-blind, placebo-controlled crossover study after a 2-week washout period examined the potential interaction between SJW and phenprocoumon. Ten healthy male volunteers, aged 18 to 50 years, were treated with 300 mg t.i.d. of SJW extract (LI 160) or placebo for 10 days. A single dose of 12 mg phenprocoumon on day 11 caused a significant reduction in plasma concentration of free phenprocumon AUC (~ 17%; p=0.007) compared to placebo. 29
Oral Contraceptives
Steroids are known substrates of CYP 3A4. The potential interaction of SJW with oral contraceptives is mainly based on 11 reported cases of breakthrough (intermenstrual) bleeding in women taking SJW while on oral contraceptives. 31 However, breakthrough bleeding is a well-documented occurrence in women taking low-dose (3rd generation) oral contraceptives. 32 Also, breakthrough bleeding does not necessarily decrease contraceptive efficacy and can be dealt with by changing the pill formulation. 13 However, two unintended pregnancies have been associated with the use of SJW by long-term oral contraceptive users; as reported by the Swedish Medical Products Agency32 ; both of these users had successfully used oral contraceptives for 8 years and both became pregnant within 5 months of starting SJW.
Carbamazepine
Recognizing the use of SJW by approximately 7% of patients with epilepsy, for treating mood disturbance and fatigue, the effect of the herb on carbamazaepine, a widely prescribed drug for control of seizures was investigated. 33 Treatment of 8 healthy subjects with SJW for 14 days did not induce any overall difference in clearance of carbamazepine, itself an inducer of CYP 3A4. However, one of the eight subjects experienced a 24% increase in clearance of the drug, recommending general monitoring for untoward effects when SJW is used for depression, along with carbamazepine. It has been concluded that either SJW is not a particularly powerful CYP 3A4 inducer or that it cannot induce carbamazeipine metabolism beyond the extent to which carbamazepine induces its own metabolism. 10
Antidepressants
The lack of any animal or clinical studies in support of MAO inhibition suggests that such inhibition may be an in vitro artifact. 34 On the other hand, there have been a few case reports of mild Ěserotonin syndrome ě associated with concomitant use of SJW and selective serotonin reuptake inhibitors (SSRIs) – in the U.S., but non in Europe. Increased serotonergic effects such as nausea, vomiting and restlessness have been reported for the SSRI sertraline and the atypical antidepressant nefazodone (one case). 35 All patients had been stable on medication and experienced these effects within 3 or 4 days of adding SJW. Since no such cases of similar adverse effect have been attributed to the use of SJW alone, true herb-drug interaction with SSRIs is suggested.
Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.
Other Common Names: Hypericum, Goatweed, Klamath weed, Hard hay.
St. John’s wort is a herbceous aromatic perennial 30 to 90 cm in height, indigenous to Europe, naturalized in Asia, Africa, western North America and Australia, and considered an aggressive weed in the latter two locations. Small dark spots on the flowers contain a red pigment, chiefly hypericin. The leaves are oblong with spots that contain the volatile oil and resin.
The medicinal parts are the fresh buds and flowers, the aerial parts, and the entire fresh flowering plant. St. John’s wort (SJW) consists of the above ground parts of H. perforatum collected and dried during the flowering season.
123
Numerous constituents have demonstrated biological activity, including naphthodianthrones, such as hypericin and pseudohypericin, flavonoids, such as amentoflavone, hyperin (hyperoside), rutin, quercitin, quercitrin and I3 ě, II8-biapigenin, the phloroglucinols hyperforin and adhyperforin, xanthones and essential oil monoterpenes and sesquiterpenes.
15
The following functions have been tested experimentally:
Anti-depressant: hyperforin inhibits the re-uptake of serotonin, norepinephrine, dopamine and other neurotransmitters during in vitro studies and in rats; xanthones.
Anti-inflammatory: flavonoid constituents, notably amentoflavone and biapigenin (oily extracts).
Anti-bacterial: hyperforin inhibited the growth
of gram- positive bacteria and demonstrated
efficacy against penicillin-resistant
Staphylococcus aureus and methicillin-resistant
S. aureus.
Side effects include photosensitization, more likely in fair-skinned individuals using SJW at high doses. However, it has been estimated that in order to produce the phototoxicity (hypericisin) observed in grazing white or light-coated animals7, humans would have to consume 30-50 times the normal therapeutic dose of SJW.8 AIDS patients administered 30-40 mg of intravenous hypericin – for its antiretroviral effect – developed phototoxic reactions (facial pain and erythema) after direct exposure to sunlight; this dose was judged equivalent to total hypericin/pseudohypericin in 50-70 tablets of the highest dose SJW product. 9
Allergic reactions.
Dizziness/confusion, tiredness/sedation and restlessness.
Contraindications:
A small percentage of people complained of GI upset, dry mouth and anorexia (0.6% or less of patients).
Possible uterotonic activity observed in vitro in animal models, recommends caution in pregnancy or nursing; consult a physician before using while pregnant or nursing.
Characterization of Active Antidepressant
Preparations
Among the nine groups of SJW constituents regarded as potential active principles responsible for the plant’s antidepressant activity36, the most prominent have been the naphthodianthrones (mainly hypericin and psudohypericin), the phloroglucinols (hyperforin and adhyperforin) and flavonoids (amentoflavone, biapigenin, hyperoside, isoquercitrin, etc.). Activity profiles of different SJW preparations in rodent behavioral models, mainly the forced swimming and tail suspension tests (FST and TST), lend support to the view that the antidepressant activity of SJW is due to a variety of compounds acting by different mechanisms.37, . Notably, an extract devoid of both hyperforin and hypericin, but enriched in flavonoids, was found to exert significant antidepressant activity, comparable to hyperforin and hypericin containing extracts, consistent with the results of clinical studies with the proprietary low hyperforin formulation, Ze 117(Zeller AG, Switzerland). 38
An interesting observation was made when investigating the activity of a series of ethanolic and methanolic SJW extracts in the forced swimming test FST with rats. 39, All extracts but one showed strong activity; the inactive methanolic extract was found by HPLC analysis to have a much reduced level of the diglycoside rutin. Addition of rutin to the inactive extract to produce a concentration in the normal range resulted in a pharmacological effect comparable to that of the other original active extracts. The action of rutin appears to be synergistic since the flavonoid itself does not possess antidepressant activity. Flavonoids are known to modulate bioavailability of drugs by influencing drug transport through biological membranes likely either by interaction with P-glycoprotein or the CYP450 enzyme system. Mild to Moderate Depression: diagnosed according to the tenth editin of International Classification of Disease (ICD–10). 38,
Since 1979, more than 30 controlled clinical trials have been conducted to assess the efficacy and tolerability of SJW in the treatment of mild to moderate depression.
A systematic review and meta-analysis of 21 randomized controlled trials of SJW extracts was published in 2001.40 SJW was judged superior to placebo, with efficacy comparable to that of standard tricylic pharmaceuticals. However, the majority of equivalence studies were not of size sufficiently large to allow detection of differences in efficacy less than 20%.
Evaluation of data from 16 controlled trials of SJW extracts found them to be superior to placebo against depression, with the number of responders (55%), being more than twice that of the placebo groups (22%).41 However, the general lack of application of acceptable diagnostic criteria rendered it difficult to determine whether clinically significant antidepressant effects are produced in patients suffering not only from depressive symptoms but also from a depressive disorder. The author of this review noted that the majority of studies lasted for only 4 weeks and that in only 4 of the 16 studies did the number of subjects in the treatment arms exceed 50. Furthermore, no response to placebo was observed in 2 studies, whereas a 30% to 60% response to placebo normally occurs in clinical trials of antidepressants.
A systematic meta-analysis of 23 randomized clinical trials of SJW extracts was conducted which include a 1,757 outpatients with mild to moderate depressive disorders. 42 Fifteen of the trials were placebo-controlled, while 8 compared SJW with standard antidepressant medications. SJW preparations were estimated to be almost 3 times more effective than placebo and of efficacy comparable to that of the other drug treatments. A need was recognized for long-term, better-controlled studies comparing SJW with standard antidepressants, and for data on long-term side effects.
In a review comparing the results of 25 controlled studies in a total of 1,592 patients it was concluded that SJW extract exhibited significant efficacy in the treatment of mild to moderate depression. 43 Comparative studies revealed roughly equivalent responder rates for SJW extracts and synthetic antidepressants, including amitriptyline, bromazepam, desipramine, diazepam, imipramine and maprotiline. Side effects from SJW were generally less severe and more tolerable.
Three studies compared SJW extract to imipramine (one study compared it to placebo as well) for 6 to 8 weeks. The Hamilton Depression (HAMD) scale showed decreases in both groups, indicating that SJW extract was equivalent to imipramine and is tolerated better by patients for the treatment of mild to moderate depression. One study found that an average dose of 350 mg of SJW three times daily was more effective than placebo and at least as effective as 100 mg (low dose) of imipramine. 444546
A study comparing St. John’s wort to fluoxetine was done on 149 outpatients with mild or moderate depression. Patients were given either 800 mg of St. John’s wort extract Lo Hyp-57 or a low dose 20 mg of fluoxetine (usual recommended dose for patients aged 60 – 80) for 6 weeks. The study concluded that St. John’s wort was just as effective as low dose fluoxetine. 47
A multi-center randomized double-blind study assessed the effectiveness and tolerability of the Hypericum extract LI 160 as compared to the standard antidepressant maprotiline. 48 Efficacy of the two treatments was judged comparable, again with SJW better tolerated and causing fewer side effects.
Shelton et al. published, in 200149 , the results of a large-scale, randomized, double-blind, placebo-controlled multicenter trial of a SJW extract in 200 outpatients with major depression. The patients of mean age 42.4 years and having had an average history of depression of over 2 years, were diagnosed according to the HAMD scale and DSM–IV (Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, 1994). At baseline, participants had a score of at least 20 on the HAMD scale. After a one-week placebo run-in phase during which the most susceptible placebo responders were eliminated, patients were treated with 300 mg t.i.d. of either placebo or SJW for 4 weeks or more, and 400 mg t.i.d. if improvement was not noted after 4 weeks. No significant difference was observed in primary outcome measures between SJW and placebo, the only significant difference being a greater incidence of reported headaches (41%) in SJW-treated patients compared with those on placebo (25%). It has been noted 5 that considering the reported beneficial effect of high dose (1800mg/day) SJW in major depression46 , perhaps the dose employed by Shelton et al. (900-1200mg/day) was insufficient. It has also been suggested50 that the patients in this study were too severely and chronically depressed to respond to any medication. In addition, an unusually low placebo response (18.6%) was observed. However, according to one definition of remission, a significantly greater percentage of patients responded to SJW (14.3%) than to placebo (4.9%).
A double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the U.S. tested the efficacy and safety of a proprietary H. perforatum extract against placebo and the SSRI antidepressant sertraline over 8 weeks in 340 adult outpatients scoring at least 20 on the HAMD scale. Based on clinical response, the daily dose of SJW ranged from 900 to 1500 mg and that of sertraline from 50 to 100 mg. The main outcome measures were change in the HAMD total score and the rates of full response determined by the HAMD and Clinical Global Impressions (CGI) scores. The study concluded that efficacy of SJW in moderately severe depression was not supported – with no mention of the ineffectiveness of sertraline. The authors of this study speculated that the negative results may have been due to “low assay sensitivity.” As with Shelton et al. 49 critics of this study have suggested that the data of Davidson et al. 51 imply that the particular group of patients tested had relatively long-term chronic depression and that many of them were already treatment resistant, perhaps explaining the apparent lack of response to sertraline, a well established pharmaceutical antidepressant. It was also pointed out that the HAMD entry score for investigational antidepressants is routinely 17 on the 17-item HAMD scale, whereas this study required an entry score of at least 20[~52~] , indicating severely depressed subjects.
The dietary supplement information contained on this site has been compiled from published sources thought to be reliable, but it cannot be guaranteed. Efforts have been made to assure this information is accurate and current. However, some of this information may be purported or outdated due to ongoing research or discoveries. The authors, editors and publishers cannot accept responsibility for errors or omissions or for any consequences from applications of the information in this site and make no warranty, expressed or implied, with respect to the contents herein.
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