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Psychosomatics 44:271-282, August 2003
© 2003 The Academy of Psychosomatic Medicine

Review

St. John's Wort: A Systematic Review of Adverse Effects and Drug Interactions for the Consultation Psychiatrist

Paul Hammerness, M.D., Ethan Basch, M.D., Catherine Ulbricht, Pharm.D., E.-P. Barrette, M.D., Ivo Foppa, M.D., Sc.D., Samuel Basch, M.D., Steve Bent, M.D., Heather Boon, B.Sc.Phm., Ph.D., and Edzard Ernst, M.D., Ph.D., F.R.C.P., for the Natural Standard Research Collaboration

Received May 30, 2002; revision received July 3, 2002; accepted Dec. 13, 2002. From Harvard Medical School, Boston; Massachusetts General Hospital, Boston; Northeastern University, Chicago; the Natural Standard Research Collaboration, the University of Rhode Island, Kingston, R.I.; the University of California, San Francisco; Mt. Sinai School of Medicine, New York; the University of Toronto, Toronto, Ont. Canada; the University of Exeter, Exeter, U.K.; the University of Plymouth, Plymouth, U.K.; Case Western Reserve University School of Medicine, Cleveland; and Harvard School of Public Health, Boston. Address reprint requests to Dr. Ulbricht, Natural Standard Research Collaboration, P.O. Box 390709, Cambridge, MA 02139-0008; kate{at}naturalstandard.com (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
St. John's wort is an herb commonly used in Europe for decades and more recently the topic of scientific investigation in this country. St. John's wort has been found more effective than placebo and equally as effective as tricyclic antidepressants in the short-term management of mild-to-moderate depression. Comparisons to selective serotonin reuptake inhibitors have provided equivocal data. While it is generally well tolerated in clinical use, there is accumulating evidence of significant interactions with drugs. This evidence-based presentation of the literature includes a brief description of pharmacodynamics and clinical applications, followed by a systematic review of adverse effects, toxicity, and drug interactions.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
References to the use of Hypericum perforatum L. (St. John's wort) can be found in the last 2,000 years, dating back to the early Greeks. The most common modern-day application of St. John's wort is for the treatment of depressive disorders. Meta-analyses of small heterogeneous studies conducted over the past two decades and several subsequent randomized trials have found St. John's wort to be more effective than placebo and equally as effective as tricyclic antidepressants in the short-term management of mild to moderate depression. Comparisons to selective serotonin reuptake inhibitors (SSRIs) have provided equivocal data. Recently, controversy has been raised by the negative results of two well-conducted trials. Overall, evidence supporting the efficacy of St. John's wort remains compelling.

St. John's wort is widely used in this country and abroad and has been generally considered a benign, well-tolerated herb in clinical use for depression. However, there is accumulating evidence of significant interactions with drugs, particularly when used with medications metabolized by the cytochrome P-450 system. This evidence-based presentation of the literature includes a brief review of pharmacodynamics and clinical application, followed by a systematic review of adverse effects, toxicity, and drug interactions.

To prepare this review, electronic searches were conducted in nine databases, including AMED, CANCERLIT, CINAHL, CISCOM, the Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts, MEDLINE, and NAPRALERT. Search terms included the common names, scientific names, and all listed synonyms for St. John's wort. Manual searches were conducted in 20 additional journals (not indexed in common databases) and in bibliographies from 50 selected secondary references. No restrictions were placed on languages or on quality of publications.


  MECHANISM OF ACTION

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
The apparent broad mechanism of action of St. John's wort is not fully understood, yet biologically active constituents may include hyperforin and adhyperforin, hypericin and pseudohypericin, flavonoids, xanthones, oligomerics, procyanidines, and amino acids.1,2 St. John's wort's antidepressant activity may be mediated by serotonergic (5-HT), noradrenergic, and dopaminergic systems,3–7 as well as by means of {gamma}-aminobutyric acid (GABA) and glutamate amino acid neurotransmitters.8–11 The mechanism of St. John's wort's activity may be different from that of standard antidepressants.12 Weak activity in vitro suggests a combination of multiple mechanisms.13

Early in vitro work reported inhibition of monoamine oxidase (MAO) A and B.14,15 Thiede and Walper16 found MAO and catechol O-methyltransferase (COMT) inhibition. However, these authors, along with others,8,17,18 concluded that the concentrations causing inhibition were not adequate to explain antidepressant activity. A more recent proposal is that the activity of St. John's wort's is by means of inhibition of serotonin, norepinephrine, and dopamine synaptic reuptake.4,9,19 In addition, significant down-regulation of B-receptor density and an increase in 5-HT2 receptors has been demonstrated in the animal cortex after treatment with Hypericum extract.4 The number of both 5-HT1A and 5-HT2A receptors was significantly increased by 50% in relation to that of control subjects in another report.20

Benzodiazepine, adenosine, inositol triphosphate, GABA, N-methyl-D-aspartic acid,8 and cholinergic21 receptor activity may also contribute to psychotropic effects. Likewise, St. John's wort has been found to affect nighttime melatonin levels, modulate cytokine expression,22 increase cortisol levels,23 inhibit sigma opioid receptor activity,21 and antagonize naloxone.3


  PHARMACODYNAMICS AND KINETICS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
Systemic availability of hypericin and pseudohypericin after oral administration has been estimated at 14% and 21%, respectively.24 Time to peak is 2–6 hours,25 with dose-dependent half-life of various compounds ranging from 24–36 hours.1 A steady state is reached after 4 days.18

St. John's wort may have multiple effects on various enzymes of the liver cytochrome P-450 system, as described in detail in the following section on drug interactions. P-Glycoprotein, an ATP-dependent drug transporter found in the intestinal tract, genitourinary system, and CNS, may be activated by St. John's wort.26–28


  INDICATIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
Mood Disorders
St. John's wort has been reported to be more effective than placebo and equally as effective as tricyclic antidepressants in the short-term management of mild to moderate depression (1–3 months). Overlapping meta-analyses and systematic reviews over the last two decades and several more recent, short-term, randomized trials support this conclusion. Comparisons to SSRIs have provided limited equivalence data. Questions have been raised regarding the methodological quality of available studies, which have examined heterogeneous patient populations and inconsistently used standardized symptom rating instruments. Negative results were published in two recent well-conducted trials; however, one did not include a reference-agent arm (only placebo), and the other yielded negative results for an SSRI as well as for St. John's wort. One small randomized trial and one open-label self-report study were suggestive of efficacy in seasonal affective disorder.29–31 Overall, the evidence supporting the efficacy of St. John's wort in mild to moderate depression remains compelling.

Anxiety Disorders
While studies of depression have reported benefit in anxiety symptom reduction, there is limited evidence to support the use of St. John's wort for the primary treatment of anxiety disorders. One randomized double-blind trial compared a combination herbal product (St. John's wort and valerian root) with the benzodiazepine diazepam in patients with moderately severe anxiety states and noted significant benefit.32 A small open-label trial showed efficacy for St. John's wort in the management of obsessive-compulsive disorder.33


  ADVERSE SIDE EFFECTS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
Toxicologic Effects
Toxicological research with St. John's wort extract LI 160 has shown a dose with no effects to be above 5000 mg/kg in mice and rats. Study of long-term toxicity in rats and dogs has found only nonspecific symptoms, such as weight loss.34 In vivo and in vitro studies35,36 have not demonstrated significant mutagenic properties of St. John's wort. One study of bacteria found genotoxicity in Salmonella typhimurium and explained that this effect was due to quercetin.37,38

Pregnancy and Lactation Effects
Although case reports exist of human exposure to St. John's wort during pregnancy,39 there is insufficient data to recommend use during pregnancy or lactation. In animal studies, administration of St. John's wort to mice before and throughout gestation did not significantly affect cognitive tasks performed by their offspring.40 A recent evaluation of breast milk samples from a woman with postpartum depression who was taking St. John's wort41 found no adverse effects on the mother or infant. Only the hyperforin constituent of St. John's wort was excreted into the breast milk at quantifiable levels.

General Adverse Effects
In published studies, St. John's wort has been generally well tolerated at recommended doses for up to 1–3 months. The most common adverse effects included gastrointestinal symptoms, skin reactions, fatigue and sedation, restlessness or anxiety, dizziness, headache, and dry mouth.42–45 Several recent meta-analyses and a clinical trial46–49 have concluded that the rates of adverse events are comparable to those of placebo and less than that of standard antidepressant treatment.46,48,50–52 Data from observational studies have indicated that adverse events may occur in 1%–3% of patients. A review of adverse events in patients under treatment with 1.08 mg/day of hypericin from 1991 to 1999, involving approximately 8 million people, documented 95 reports of adverse events.45 A European drug-monitoring study of 3,250 patients receiving 1.08 mg/day of hypericin42 included an overall rate of adverse reactions of 2.4%. A postmarketing study of Aristoforat documented the incidence of adverse events to be 1% among 2,404 ambulatory patients over a 4–6 week period.43 Plasma levels of the drug to 300 ng/ml have been tolerated.53

Allergic Effects
Infrequent allergic skin reactions, including rash, itching, and pruritus, have been reported in clinical trials. In a drug-monitoring study of 3,250 patients, there were 17 cases of allergic reactions and 10 cases of allergy-related treatment discontinuation.42

Dermatologic Effects
Allergy
Infrequent allergic skin reactions, including rash, itching, and pruritus, have been reported in clinical trials. A review of adverse events under treatment with 1.08 mg/day of hypericin from 1991 to 1999, involving approximately 8 million people, documented 27 adverse skin reactions.45

Photosensitization
Photosensitization has been reported since the early 1900s in grazing animals consuming St. John's wort plants.54 Several human cases of reversible photosensitivity to St. John's wort have been reported. One patient developed itchy erythematous lesions in light-exposed areas of her skin after taking 240 mg/day of Hypericum extract for 3 years.55 In another case, a burning, erythematous eruption occurred after 4 days of treatment with 333 mg/day of Hypericum extract.55,56 Lane-Brown57 presented three cases of phototoxicity associated with topical and oral St. John's wort: erythematobullous dermatosis and facial bullae related to sun exposure and ultraviolet B phototherapy-related follicular erythema and urticarial edema. Phase I studies of intravenous and oral hypericin in HIV-infected adults58 documented severe cutaneous phototoxicity in 11 of 23 subjects. A variety of photosensitivity reactions were observed in 14 of 19 subjects with hepatitis C.59 However, Brockmöller et al.60 found no correlations between photosensitivity and total plasma Hypericum concentrations in human volunteers after a single oral dose of 900–3600 mg of hypericin extract. The same report noted a small but significant increase in solar and ultraviolet A light sensitivity over 15 days of 1800 mg/day of Hypericum extract. Another study61 found no phototoxic potential with administration of oral L160. Another study62 found peak hypericin levels in skin blister fluid after administration of an oral dose of 1800 mg or steady-state administration (900 mg/day for 7 days) to be at least 20 times below the estimated phototoxic concentration of 100 µg/ml. An additional investigation63 found phototoxicity after irradiation with ultraviolet A and visible light only at high concentrations.

Alopecia
Persistent scalp and eyebrow hair loss was described in a 24-year-old woman with schizophrenia who was treated with the antipsychotic olanzapine that occurred 5 months after augmentation with 900 mg/day of St. John's wort.64

Neurologic Effects and the CNS
Headache
In a large controlled trial,47 headache occurred more frequently in the St. John's wort group than in the placebo group (in 40% versus 26% of respective patients) (p<0.02). However, in multiple other reports,43–45 headache has been rarely found.

Neuropathy
Isolated reports of paresthesia44 and neuropathy have been reported. Bove65 described the case of a 35-year-old woman who developed subacute toxic neuropathy after taking 500 mg/day of St. John's wort for 4 weeks. The subject experienced a stinging pain upon exposure to mechanical stimuli that worsened during and after exposure to the sun on her face and the dorsum of both hands. Her symptoms began to improve after St. John's wort was withdrawn and gradually disappeared over 2 months.

Psychiatric Effects
Anxiety
Restlessness, insomnia, and anxiety have been noted. Fifteen psychiatric adverse events were reported in a World Health Organization database as of 1998.44 Eight reports of anxiety occurred in a sample of 3,250 subjects.66 In a postmarketing trial of 2,404 patients, five patients reported nervousness and anxiety.43

Mania
Mania possibly induced by St. John's wort has been described in several case reports;67–72 a majority of the affected individuals had histories of affective illness, including major depression and bipolar disorder. Barbenel et al.73 described a manic episode in a 28-year-old man after 5 weeks of simultaneous ingestion of St. John's wort and the SSRI sertraline (50 mg/day). Fahmi71 described a case of mania induced by high doses of Hypericum perforatum in a 28-year-old depressed woman with no history of mania or hypomania and no concomitant use of antidepressants. Spinella72 described the case of a female patient with a history of mild traumatic brain injury and resulting depression who experienced hypomania after adding St. John's wort and Ginkgo biloba to her regimen of fluoxetine and buspirone. Symptoms remitted after discontinuation of the herbal medicines.

Serotonin syndrome
There is a case report of possible serotonin syndrome associated with monotherapy with St. John's wort that was manifested by transient flushing, diaphoresis, hypertension, disorientation, dyspnea, and tremors in a 40-year-old man.64 The patient, who had a history of depression and SSRI-induced mania, was not taking any other medications. Another report74 described a 33-year-old woman with mild anxiety who experienced multiple anxiety episodes with autonomic arousal (maximum blood pressure: 195/110 mm Hg) after three doses of St. John's wort. In a self-report telephone survey,75 one woman reported nausea, diaphoresis, muscle cramping, weakness, and elevated pulse and blood pressure after a single dose of combination St. John's wort, kava kava, and valerian root. Several case reports have described the symptoms of serotonin syndrome with concurrent SSRI medication, as described in the following drug interaction section.

Psychosis
Lal and Iskandar76 reported psychotic decompensation in two schizophrenic patients that was temporally associated with the consumption of St. John's wort. However, both patients had discontinued antipsychotic medication before their relapse. Another case report77 described psychotic features and delirium in a 76-year-old woman with Alzheimer's dementia that was associated with 3-weeks of self-medication with St. John's wort.

Cardiovascular Effects
Elevation of blood pressure or pulse has been reported in possible cases of serotonin syndrome. A recent case report74 described recurrent episodes of autonomic arousal with blood pressures up to 195/110 mm Hg in a previously healthy woman after she took three doses of St. John's wort. Another report78 described sudden onset of hypertension (to 201/140) with delirium in a 41-year-old man after taking St. John's wort, eating aged cheeses, and drinking a glass of red wine. Other rare incidences of hypertension and tachycardia have been described.64 Conversely, no differences in blood pressure or heart rate were found in a 6-week comparison of 1800 mg/day St. John's wort and 150 mg/day of imipramine in 200 adults,50 and no cardiac conduction abnormalities were found in a study of high-dose St. John's wort.79

Gastrointestinal Effects
Infrequent dyspepsia, anorexia, diarrhea, nausea, and constipation have been described in controlled trials.51,80 In a large sample of 3,250 adult subjects, 18 cases of gastrointestinal symptoms were reported.66

Genitourinary Effects
Anorgasmia was reported in 25% of the patients taking 900–1500 mg/day of St. John's wort for 8 weeks compared to 16% of the patients taking placebo and 32% of the patients taking sertraline.81 In addition, we know of two published reports of sexual dysfunction associated with St. John's wort. A 42-year-old man with mood and anxiety disorders experienced decreased libido after ingesting St. John's wort for 9 months.82 Notably, the subject had subsequent recurrent depressive symptoms. His sexual libido returned when St. John's wort was discontinued and the SSRI citalopram was initiated. In the other case, 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.83 The SSRI was discontinued, with resolution of symptoms; however, 1 week after beginning therapy with St. John's wort, the patient developed erectile dysfunction and orgasmic delay. Coadministration of sildenafil reversed the sexual dysfunction. Inhibition of sperm motility has been observed in vitro with use of St. John's wort.84 Frequent urination was reported in 27% of the patients taking 900–1500 mg/day of St. John's wort for 8 weeks versus 11% of the patients taking placebo and 21% of the patients taking sertraline.81


  DRUG INTERACTIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
Drugs Metabolized by Means of Cytochrome P-450
Concurrent use of drugs metabolized by means of the cytochrome CYP-450 liver enzyme system may result in altered therapeutic levels because of induction or inhibition of enzymes by St. John's wort. Human studies have reported induction of CYP 3A/3A4 by reductions of drug concentrations in a pharmacokinetic study.85 Moore et al.86 demonstrated that hyperforin activates a regulator (pregnane X receptor) of CYP 3A4 transcription and thereby induces expression of CYP 3A4 in human liver cells. Although authors have reported in vivo and in vitro CYP 2C9, 2D6, and 3A4 inhibition,87,88 a brief, 3-day human trial did not demonstrate a similar significant effect on drugs metabolized by CYP 2D6 or 3A4 enzymes.89 Bray90 demonstrated induction of CYP 3A and 2E1 in mice. Upon review, it appears that St. John's wort inhibits CYP 3A4 acutely and then induces this enzyme with repeated administration.26 Pharmacokinetic studies are ongoing in this area.

Carbamazepine (CYP 3A4)
A 2-week open study of eight healthy volunteers did not find a significant difference in carbamazepine concentrations with concomitant therapy with St. John's wort. This lack of effect may be due to a system already induced (auto-induction) or to greater clearance of hyperforin by carbamazepine.91

Cyclosporin (CYP 3A4)
A significant decrease in cyclosporin levels was observed in 30 kidney transplant recipients taking St. John's wort. Cyclosporin levels markedly increased after St. John's wort was discontinued.92,93 There are multiple case reports of reduced cyclosporin serum levels in kidney transplant patients receiving concomitant St. John's wort.27,94–96 A case report of two heart transplant patients97 demonstrated reductions in cyclosporin levels and acute transplant rejection in those taking St. John's wort. In addition, a 63-year-old patient developed severe acute rejection 14 months after liver transplantation. Rejection was associated with a sudden decrease in cyclosporin A levels, which occurred during a 2-week period of ingesting 1800 mg/day St. John's wort.98 Reductions in cyclosporin-A levels in heart transplant patients have been described elsewhere.99 Effects on cyclosporin levels may also be due to an induction of the drug pump P-glycoprotein.26,27

Ethinylestradiol, desogestrel, and oral contraceptives (CYP 3A4)
The Medical Products Agency of Sweden received eight case reports of breakthrough bleeding and one case report of changes in menstrual flow from women who were longtime users of oral contraceptives and St. John's wort. The time period between initiation of St. John's wort and the reported event was approximately 1 week.100 Ratz et al.101 reported a case of irregular bleeding with combined St. John's wort and oral contraceptives. In early 2002, warnings emerged following several reports from Sweden and the United Kingdom of unwanted pregnancies in women taking oral contraceptives and St. John's wort.102 Pharmacokinetic and dynamic studies are ongoing in this area. Others have reported on the knowledge base regarding such drug interactions in young undergraduate women.103

Hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors ("statins") (CYP 3A4)
The concentration of simvastatin and its metabolite (but not pravastatin) were significantly lower with concomitant use of St. John's wort.104

Midazolam (CYP 3A4)
A human study resulted in reductions of midazolam concentrations, presumed to be because of CYP 3A4 induction.105

Nifedipine (CYP 3A4)
A human study resulted in reductions of nifedipine concentrations, presumed to be because of CYP 3A4 induction.105

Protease inhibitors and nonnucleoside reverse transcriptase inhibitors (CYP 3A4)
St. John's wort has been shown to decrease plasma concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors, possibly because of cytochrome P-450 induction. The oral clearance of nevirapine was significantly increased in five HIV-positive patients treated with nevirapine and concomitant St. John's wort.106 An open-label study demonstrated a significant reduction in concentrations of indinavir when taken concurrently with St. John's wort by healthy volunteers.107 Effects of St. John's wort with these medications may also be due to an induction of the drug pump P-glycoprotein.26 In February 2000, the Food and Drug Administration (FDA) issued an advisory regarding the findings of the Piscitelli study.107

Irinotecan (CPT-11, CYP 3A4)
CPT-11 is a chemotherapeutic agent that is principally eliminated by means of cytochrome P-450 3A4 oxidation. An abstract presented by Mathijssen et al.108 at the annual meeting of the American Association for Cancer Research covered the effects of St. John's wort in patients taking CPT-11. A group of patients was administered intravenous CPT-11, 350 mg/m2 once every 3 weeks. Subjects were randomly assigned to receive either concomitant St. John's wort, 300 mg orally three times a day for a 21-day period starting 2 weeks before CPT-11 therapy, or no additional therapy. Subjects were then crossed over. Complete pharmacological data was available for three subjects. The addition of St. John's wort to CPT-11 therapy resulted in a >50% mean reduction in AUC for the CPT-11 metabolite SN-38, while the AUC for CPT-11 itself was not significantly altered.

Theophylline (CYP 1A2)
One report109 described a 42-year-old woman who experienced decreased serum theophylline levels with concomitant ingestion of 300 mg/day of St. John's wort. The patient was taking multiple other medications and smoked tobacco. Within 1 week of discontinuation of St. John's wort, her theophylline level rose from 9 to 19 µg/ml.

Warfarin (CYP 2C9)
Seven cases of reduced effects of warfarin (lowered international normalized ratio) with concomitant use of St. John's wort have been reported.100 In most cases, the patients had been stabilized with warfarin treatment before ingesting St. John's wort. None of the patients developed thromboembolic events; however, the decrease in their international normalized ratio was thought to be clinically significant. Increases in warfarin dose or discontinuation of St. John's wort resulted in their international normalized ratio returning to target values. This interaction may have been due to an induction of the drug pump P-glycoprotein.26

Tricyclic antidepressant drugs (multiple CYPs)
A 14-day open study of 12 depressed patients110,111 resulted in a significant reduction in amitriptyline concentrations with concurrent ingestion of St. John's wort (900 mg/day). A number of CYP enzymes, including 1A2, 2C19, 3A4, and 2D6 are involved in the metabolism of tricyclic antidepressants.112


  SSRIs

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
One report113 appears consistent with serotonin syndrome: a healthy 61-year-old woman took a single 20-mg dose of paroxetine on the day of presentation, 3 days after she stopped taking St. Johns wort (600 mg/day). She came to the hospital restless, diaphoretic, and hypertensive, with hyperreflexia and involuntary movements of all extremities. Her creatine kinase level peaked at 1024 U/liter. She was discharged 2 days later after supportive treatment.

A case series of elderly depressed patients detailed dizziness, nausea, vomiting, headache, anxiety, confusion, irritability, and restlessness.114 Symptoms were associated with the addition of St. John's wort to ongoing treatment with sertraline (four cases) and nefazodone (one case). Symptoms resolved within 1 week after discontinuation of St. John's wort. In another case report,115 a 50-year-old woman with depression became incoherent, groggy, and lethargic after a single evening dose of 20 mg of paroxetine was added to her ongoing 600 mg/day of St. John's wort. The patient had previously tolerated paroxetine for 8 months.

Mania possibly induced by St. John's wort has been described in several case reports. In one report involving coadministration with an SSRI, Barbenel et al.73 described a manic episode in a 28-year-old man after 5 weeks of simultaneous ingestion of St. John's wort and 50 mg/day of sertraline. Spinella72 described the case of a female patient with a history of mild traumatic brain injury and resulting depression who experienced hypomania after adding St. John's wort and Ginkgo biloba to her regimen of fluoxetine and buspirone.

Monoamine Oxidase Inhibitors (MAOIs)
Although there are no known reports of interactions, on the basis of an in vitro study, St. John's wort may theoretically potentiate the effects of MAOIs, leading to clinical toxicity, such as serotonin syndrome or hypertensive crisis. A recent case report78 described sudden onset of hypertension (to 201/140) with delirium in a 41-year-old man after taking St. John's wort, eating aged cheeses, and drinking a glass of red wine.

5-HT1 Receptor Agonists (Triptans)
Interaction with various migraine medications by means of enhanced serotonergic activity is possible in theory.

Alcohol
A 7-day, randomized, controlled crossover trial (N=32) resulted in the conclusion that St. John's wort (900 mg/day) did not significantly interact with alcohol, in terms of cognitive capacities.116

Anesthetic Drugs
It has been hypothesized that St. John's wort may interact with anesthetic drugs.117 There is a case report of cardiovascular collapse during anesthesia that was reported in a healthy 23-year-old woman who had been taking St. John's wort daily for 6 months before surgery.118 The patient had undergone uneventful general anesthesia 2 years earlier when she was not taking St. John's wort. A recent case report119 described delayed emergence from anesthesia in a 21-year-old woman admitted for incision and drainage of a Bartholin abscess. At the time of her procedure, she had been taking St. John's wort, 1,000 mg three times daily, for 3 months for depression.

Antineoplastic Drugs
Theoretically, St. John's wort may antagonize chemotherapeutic agents that are directed against topoisomerase II alpha, such as anthracyclines or cytotoxic agents, as shown in vitro.120

Digoxin
A controlled study demonstrated that 10 days of treatment with Hypericum extract resulted in a 25% decrease in digoxin in the AUC. The mechanism of action may be induction of the P-glycoprotein drug transporter.26,121

Loperamide
Delirium and agitation were reported in one patient taking loperamide, St. John's wort, and valerian root (Valeriana officinalis).122 The condition resolved rapidly with discontinuation of treatment.

Opioids
A pharmacokinetic-dynamic study designed to evaluate possible interactions between St. John's wort and two opioid medications (oxycodone and fentanyl) aimed to assess the clinical significance of this theoretical interaction with respect to efficacy and adverse effects. Results are pending.

Photosensitizing Products
Concurrent use with these numerous agents, including several antibiotics and oral contraceptives, may increase the risk of photosensitization.123 A phototoxic reaction was observed in a patient who was experimentally treated with {delta}-aminolaevulinic acid for breast cancer and who also had been taking St. John's wort.124

Thyroid Agents
A retrospective case-control study noted elevated thyroid-stimulating hormone (TSH) levels to be associated with St. John's wort; odds ratio=2.12 (95% confidence interval [CI]=0.36–12.36).125


  INTERACTIONS WITH HERBS AND SUPPLEMENTS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
Red Yeast Rice (Monascus purpureus) (CYP 3A4)
Red yeast contains constituents that are identical to the HMG CoA reductase inhibitor lovastatin. Because statins such as lovastatin are known substrates of CYP 3A4, which is induced by St. John's wort, it is likely that the cholesterol-lowering effects of red yeast would be diminished by the presence of St. John's wort. The concentrations of a different statin, simvastatin, and its metabolite (but not pravastatin) were significantly decreased with concomitant St. John's wort.104 The principal product that had been available containing red yeast, Cholestin, is no longer available in the United States. The name brand Cholestin, manufactured by Pharmanex, has since been reformulated to contain policosanol (polycosanol) and is still marketed for treatment of high cholesterol.

Herbs With SSRI or MAOI Properties
As discussed in the drug interaction section, concomitant use of St. John's wort may lead to increased adverse effects typically associated with SSRI and MAOI medications. A recent case report78 described sudden onset of hypertension (to 201/140) with delirium in a 41-year-old man after taking St. John's wort, eating aged cheeses, and drinking a glass of red wine.

Cardiac Glycoside Herbs
Cardiac glycoside herbs, such as foxglove and oleander, contain cardiac glycosides that behave similarly to digoxin. A controlled study121 demonstrated that 10 days of treatment with Hypericum extract resulted in a decreased digoxin level by 25%.

Iron
Because of the presence of tannins in St. John's wort, iron absorption may be inhibited.123

Photosensitizing Herbs and Supplements
Concurrent use of St. John's wort with other photosensitizing agents may increase the risk of photosensitization,123 as, for example, with capsaicin. A phototoxic reaction was observed in a patient who was experimentally treated with {delta}-aminolaevulinic acid for breast cancer and who also had been taking St. John's wort.124

Valerian Root (Valeriana officinalis)
Delirium and agitation was reported in a patient taking valerian root, St. John's wort, and loperamide.122 The condition resolved rapidly with discontinuation of treatment.


  FOOD INTERACTIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 
Weak MAOI activity of St. John's wort has been observed in vitro.8,14–17,126,127 Similar to warnings accompanying the use of MAOIs, consumption of tyramine-containing foods while taking St. John's wort may pose an increased risk of hypertensive crisis. In a telephone survey of 43 subjects who had taken St. John's wort,75 39 individuals reported ingesting tyramine-rich foods or products. Two persons taking 600–900 mg/day of St. John's wort reported associated flushing and pounding headaches. A recent case report78described sudden onset of hypertension (to 201/140) with delirium in a 41-year-old man after taking St. John's wort, eating aged cheeses, and drinking a glass of red wine.


  LABORATORY INTERACTIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
SUMMARY
 REFERENCES
 
A retrospective case-control study reported elevated TSH levels associated with St. John's wort (odds ratio=2.12 [95% CI=0.36–12.36].)125 This small retrospective study does not present a clear significant relationship or imply causality.


  SUMMARY

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
REFERENCES
 
The use of alternative medicines, such as St. John's wort, has dramatically increased in this country during the past decade, in particular for such chronic conditions as anxiety and depression. However, despite millions of Americans' investing billions of dollars in alternative treatments, a minority of such therapies is disclosed to primary care physicians.128 Individuals cite doctors' lack of knowledge or interest as factors in their nondisclosure.129

While it is generally well tolerated, there is accumulating evidence of clinically significant interactions of St. John's wort and drugs, particularly when used with medications metabolized by the cytochrome P-450 system. The frequency by which individuals with emotional illness seek alternative treatments necessitates an understanding of the risks inherent in the use of this herb. Education and interest on the part of physicians will improve disclosure and facilitate communication with patients. As such, the following recommendations are offered to the consultation-liaison psychiatrist or general practitioner based on a systematic review of the literature to date.

  • Avoid use if there is a known allergy or hypersensitivity to St. John's wort or to any of its constituents.
  • Avoid in patients with HIV or AIDS who are taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as suggested by the FDA, because of documented reductions in drug concentrations with concomitant use.
  • Avoid in transplant recipients taking cyclosporin because of multiple case reports of significant reductions in drug levels and possible organ rejection with concomitant use.
  • Avoid in women taking oral contraceptives as birth control because of several reports from Sweden and the United Kingdom of unwanted pregnancies in women taking concomitant St. John's wort.
  • Use cautiously in patients taking medications or herbs metabolized by cytochrome P-450, in particular with substrates of CYP 3A4, which St. John's wort appears to acutely inhibit and induce over the long term. Examples of medications or herbs with altered clinical effects or drug concentrations with concomitant use of St. John's wort include oral contraceptives, CPT-11, simvastatin, and nifedipine.
  • Use cautiously in patients taking warfarin because of case reports of reduced efficacy (international normalized ratio) with use of concomitant St. John's wort.
  • Use cautiously in patients taking MAOIs or SSRIs or herbal medicines with similar properties because of theoretical serotonin syndrome or hypertensive crisis with concomitant use.
  • Use cautiously in persons with a history of mania, hypomania, or affective illness because of case reports of manic episodes possibly induced by St. John's wort.
  • Use cautiously in patients taking digoxin because of a controlled study that demonstrated a reduced drug concentration with concomitant use.
  • Use cautiously in patients with sensitive skin or those taking photosensitizing drugs or herbal medicines because of the risk of photosensitivity, which has been documented in case reports.
  • Use cautiously in patients with iron deficiency states because of the theoretical risk of inhibition of iron absorption by tannins in St. John's wort.


  ACKNOWLEDGMENTS

 
The authors thank John Martinson for his support, the Natural Standard for its ongoing research, and Michelle Nhuch, Regina Gorenshteyn, Mamta Vora, and the members of the Natural Standard for their help. The Natural Standard is a privately funded multidisciplinary project that employs evidence-based criteria to analyze complementary therapies and create decision-support materials for clinicians and patients. Subscriptions to a database with more than 100 monographs are available at http://www.naturalstandard.com.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 MECHANISM OF ACTION
 PHARMACODYNAMICS AND KINETICS
 INDICATIONS
 ADVERSE SIDE EFFECTS
 DRUG INTERACTIONS
 SSRIs
 INTERACTIONS WITH HERBS AND...
 FOOD INTERACTIONS
 LABORATORY INTERACTIONS
 SUMMARY
 REFERENCES
 

  1. Bombardelli E, Morazzoni P: Hypericum perforatum. Fitoterapia 1995; 66:43-68
  2. Nahrstedt A, Butterweck V: Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 1997; 30(suppl 2):129-134
  3. Butterweck V, Wall A, Lieflander-Wulf U, Winterhoff H, Nahrstedt A: Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry 1997; 30(suppl 2):117-124
  4. Müller WE, Rolli M, Schafer C, Hafner U: Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 1997; 30(suppl 2):102-107
  5. Bhattacharya SK, Chakrabarti A, Chatterjee SS: Activity profiles of two hyperforin-containing Hypericum extracts in behavioral models. Pharmacopsychiatry 1998; 31(suppl 1):22-29
  6. Calapai G, Crupi A, Firenzuoli F, Inferrera G, Squadrito F, Parisi A, De Sarro G, Caputi A: Serotonin, norepinephrine and dopamine involvement in the antidepressant action of Hypericum perforatum. Pharmacopsychiatry 2001; 34:45-49[Medline]
  7. Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E: Effect of acute administration of Hypericum perforatum-CO2 extract on dopamine and serotonin release in the rat central nervous system. Pharmacopsychiatry 2000; 33:14-18
  8. Cott JM: In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry 1997; 30(suppl 2):108-112
  9. Chatterjee SS, Bhattacharya SK, Singer A, Wonnemann M, Mueller WE: Hyperforin inhibits synaptosomal uptake of neurotransmitters in vitro and shows antidepressant activity in vivo. Pharmazie 1998; 53:9
  10. Wonnemann M, Singer A, Muller WE: Inhibition of synaptosomal uptake of 3H-L-glutamate and 3H-GABA by hyperforin, a major constituent of St John's wort: the role of amiloride sensitive sodium conductive pathways. Neuropsychopharmacology 2000; 23:188-197[CrossRef][Medline]
  11. Nathan PJ: Hypericum perforatum (St John's wort): a non-selective reuptake inhibitor? a review of the recent advances in its pharmacology. J Psychopharmacol 2001; 15:47-54[Abstract/Free Full Text]
  12. Yu PH: Effect of the Hypericum perforatum extract on serotonin turnover in the mouse brain. Pharmacopsychiatry 2000; 33:60-65[CrossRef][Medline]
  13. Bennett DA Jr, Phun L, Polk JF, Voglino SA, Zlotnik V, Raffa RB: Neuropharmacology of St John's wort (Hypericum). Ann Pharmacother 1998; 32:1201-1208[Abstract]
  14. Suzuki O, Katsumata Y, Oya M, Bladt S, Wagner H: Inhibition of monoamine oxidase by hypericin. Planta Med 1984; 50:272-274[Medline]
  15. Demisch L, Holzl J, Gollnik B, Kaczmarczyk P: Identification of selective MAO-type-A inhibitors in Hypericum perforatum L. Pharmacopsychiatry 1989; 22:194
  16. Thiede HM, Walper A: Inhibition of MAO and COMT by Hypericum extracts and hypericin. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S54-S56
  17. Bladt S, Wagner H: Inhibition of MAO by fractions and constituents of Hypericum extract. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S57-S59
  18. Staffeldt B, Kerb R, Brockmoller J, Ploch M, Roots I: Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S47-S53
  19. Neary JT, Bu Y: Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Res 1999; 816:358-363[CrossRef][Medline]
  20. Teufel-Mayer R, Gleitz J: Effects of long-term administration of Hypericum extracts on the affinity and density of the central serotonergic 5-HT1 A and 5-HT2 A receptors. Pharmacopsychiatry 1997; 30(suppl 2):113-116
  21. Raffa RB: Screen of receptor and uptake-site activity of hypericin component of St John's wort reveals sigma receptor binding. Life Sci 1998; 62:L265-L270
  22. Thiele B, Brink I, Ploch M: Modulation of cytokine expression by Hypericum extract. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S60-S62
  23. Schule C, Baghai T, Ferrera A, Laakmann G: Neuroendocrine effects of Hypericum extract WS 5570 in 12 healthy male volunteers. Pharmacopsychiatry 2001; 34(suppl 1):S127-S133
  24. Kerb R, Brockmoller J, Staffeldt B, Ploch M, Roots I: Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother 1996; 40:2087-2093[Abstract]
  25. Stock S, Holzi J: Pharmacokinetics test of [14C]labeled pseudohypericin from Hypericin perforatum and kinetics of hypericin in man. Planta Med 1991; 57:A61-A62
  26. Cott JM: Herb-drug interactions. CNS Spectrums 2001; 6:827-832
  27. Turton-Weeks SM, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR: St John's wort: a hidden risk for transplant patients. Prog Transplant 2001; 11:116-120[Medline]
  28. Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K: St John's wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP 3A4. Clin Pharmacol Ther 2000; 68:598-604[CrossRef][Medline]
  29. Martinez B, Kasper S, Ruhrmann S, Moller HJ: Hypericum in the treatment of seasonal affective disorders. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S29-S33
  30. Kasper S: Treatment of seasonal affective disorder (SAD) with Hypericum extract. Pharmacopsychiatry 1997; 30(suppl 2):89-93
  31. Wheatley D: Hypericum in seasonal affective disorder (SAD). Curr Med Res Opin 1999; 15:33-37[Medline]
  32. Panijel M: [Treatment of moderately severe anxiety states]. Therapiewoche 1985; 35:4659-4668 (German)
  33. Taylor LH, Kobak KA: An open-label trial of St John's wort (Hypericum perforatum) in obsessive-compulsive disorder. J Clin Psychiatry 2000; 61:575-578[Medline]
  34. Leuschner G: Preclinical toxicology profile of Hypericum extract LI 160. Phytomedicine Suppl 1996; 1:104
  35. Okpanyi SN, Lidzba H, Scholl BC, Miltenburger HG: [Genotoxicity of a standardized Hypericum extract]. Arzneimittelforschung 1990; 40:851-855 (German)[Medline]
  36. Greeson JM, Sanford B, Monti DA: St John's wort: a review of the current pharmacological, toxicological, and clinical literature. Psychopharmacology (Berl) 2001; 153:402-414[CrossRef][Medline]
  37. Poginsky B, Westendorf J, Prosenc N, Kuppe M, Marquardt H: Johanniskraut (Hypericum perforatum L): Genotoxizität bedingt durch den Quercetingehalt. Dtsch Apoth Ztg 1988; 128:1364-1366
  38. Schimmer O, Hafele F, Kruger A: The mutagenic potencies of plant extracts containing quercetin in Salmonella typhimurium TA98 and TA100. Mutat Res 1988; 206:201-208[CrossRef][Medline]
  39. Grush LR, Nierenberg A, Keefe B, Cohen LS: St John's wort during pregnancy (letter). JAMA 1998; 280:1566[Free Full Text]
  40. Rayburn WF, Gonzalez CL, Christensen HD, Stewart JD: Effect of prenatally administered Hypericum (St John's wort) on growth and physical maturation of mouse offspring. Am J Obstet Gynecol 2001; 184:191-195[CrossRef][Medline]
  41. Klier CM, Schafer MR, Schmid-Siegel B, Lenz G, Mannel M: St John's wort (Hypericum perforatum)—is it safe during breast-feeding? Pharmacopsychiatry 2002; 35:29-30[CrossRef][Medline]
  42. Woelk H, Burkard G, Grunwald J: Benefits and risks of the Hypericum extract LI 160: drug-monitoring study with 3,250 patients. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S34-S38
  43. Schakau D, Hiller K-O, Schultz-Zehden W, Teschner F: Risk/benefit profile of St John's wort extract: STEI 300 in 2,404 patients with various degrees of psychiatric disturbance. Psychopharmakotherapie 1996; 3:116-122
  44. Ernst E, Rand JI, Barnes J, Stevinson C: Adverse effects profile of the herbal antidepressant St John's wort (Hypericum perforatum L). Eur J Clin Pharmacol 1998; 54:589-594[CrossRef][Medline]
  45. Schulz V: Incidence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomedicine 2001; 8:152-160[Medline]
  46. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D: St John's wort for depression—an overview and meta-analysis of randomized clinical trials. Br Med J 1996; 313:253-258[Abstract/Free Full Text]
  47. Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U: Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA 2001; 285:1978-1986[Abstract/Free Full Text]
  48. Kim HL, Streltzer J, Goebert D: St John's wort for depression: a meta-analysis of well-defined clinical trials. J Nerv Ment Dis 1999; 187:532-539[CrossRef][Medline]
  49. Gaster B, Holroyd J: St John's wort for depression: a systematic review. Arch Intern Med 2000; 160:152-156[Abstract/Free Full Text]
  50. Vorbach EU, Arnoldt KH, Hubner WD: Efficacy and tolerability of St John's wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997; 30(suppl 2):81-85
  51. Schrader E: Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000; 15:61-68[Medline]
  52. Linde K, Mulrow CD: St John's wort for depression. Cochrane Database Syst Rev 2000; 2:CD000448
  53. Biber A, Fischer H, Romer A, Chatterjee SS: Oral bioavailability of hyperforin from Hypericum extracts in rats and human volunteers. Pharmacopsychiatry 1998; 31(suppl 1):36-43
  54. Araya OS, Ford EJ: An investigation of the type of photosensitization caused by the ingestion of St John's wort by calves. J Comp Pathol 1981; 91:135-141[CrossRef][Medline]
  55. Golsch S, Vocks E, Rakoski J, Brockow K, Ring J: [Reversible increase in photosensitivity to UV-B caused by St John's wort extract]. Hautarzt 1997; 48:249-252 (German)[CrossRef][Medline]
  56. Holme SA, Roberts DL: Erythroderma associated with St John's wort. Br J Dermatol 2000; 143:1127-1128[CrossRef][Medline]
  57. Lane-Brown MM: Photosensitivity associated with herbal preparations of St John's wort (Hypericum perforatum) (letter). Med J Aust 2000; 172:302
  58. Gulick RM, McAuliffe V, Holden-Wiltse J, Crumpacker C, Liebes L, Stein DS, Meehan P, Hussey S, Forcht J, Valentine FT: Phase I studies of hypericin, the active compound in St John's wort, as an antiretroviral agent in HIV-infected adults: AIDS Clinical Trials Group Protocols 150 and 258. Ann Intern Med 1999; 130:510-514[Abstract/Free Full Text]
  59. Jacobson JM, Feinman L, Liebes L, Ostrow N, Koslowski V, Tobia A, Cabana BE, Lee D, Spritzler J, Prince AM: Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St John's wort plant, in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2001; 45:517-524[Abstract/Free Full Text]
  60. Brockmöller J, Reum T, Bauer S, Kerb R, Hubner WD, Roots I: Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 1997; 30(suppl 2):94-101
  61. Schempp CM, Muller K, Winghofer B, Schulte-Monting J, Simon JC: Single-dose and steady-state administration of Hypericum perforatum extract (St John's wort) extract does not influence skin sensitivity to UV radiation, visible light, and solar-simulated radiation (letter). Arch Dermatol 2001; 137:512-513; correction, 137:1380[Free Full Text]
  62. Schempp CM, Pelz K, Wittmer A, Schopf E, Simon JC: Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria (letter). Lancet 1999; 353:2129
  63. Bernd A, Ramirez-Bosca A, Kippenberger S, Diaz Alperi J, Miquel J, Villalba Garcia JF, Pamies Mira D, Kaufmann R: Phototoxic effects of Hypericum extract in cultures of human keratinocytes compared with those of psoralen. Photochem Photobiol 1999; 2:218-221[CrossRef]
  64. Parker V, Wong AH, Boon HS, Seeman MV: Adverse reactions to St John's wort. Can J Psychiatry 2001; 46:77-79[Medline]
  65. Bove GM: Acute neuropathy after exposure to sun in a patient treated with St John's wort. Lancet 1998; 352:1121-1122[CrossRef]
  66. Woelk H, Burkard G, Grunwald J: Nutzen und Risikobewertung des Hypericum-extraktes LI 160 auf der Basis einer Drug-Monitoring-Studie mit 3250 patienten. Nervenheilkunde 1993; 12:308-313
  67. Schneck C: St John's wort and hypomania (letter). J Clin Psychiatry 1998; 59:689
  68. Nierenberg AA, Burt T, Matthews J, Weiss AP: Mania associated with St John's wort. Biol Psychiatry 1999; 46:1707-1708[CrossRef][Medline]
  69. Moses EL, Mallinger AG: St John's wort: three cases of possible mania induction. J Clin Psychopharmacol 2000; 20:115-117[CrossRef][Medline]
  70. Guzelcan Y, Scholte WF, Assies J, Becker HE: [Mania during the use of a combination preparation with St John's wort]. Ned Tijdschr Geneeskd 2001; 145:1943-1945 (Dutch)[Medline]
  71. Fahmi M: A case of mania induced by hypericum. World J Biol Psychiatry 2002; 3:58-59[Medline]
  72. Spinella M: Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild traumatic brain injury. Brain Inj 2002; 16:359-367[CrossRef][Medline]
  73. Barbenel DM, Yusufi B, O'Shea D, Bench CJ: Mania in a patient receiving testosterone replacement postorchidectomy taking St John's wort and sertraline. J Psychopharmacol 2000; 14:84-86[Abstract/Free Full Text]
  74. Brown TM: Acute St John's wort toxicity. Am J Emerg Med 2000; 18:231-232[CrossRef][Medline]
  75. Beckman SE, Sommi RW, Switzer J: Consumer use of St John's wort: a survey on effectiveness, safety, and tolerability. Pharmacotherapy 2000; 20:568-574[CrossRef][Medline]
  76. Lal S, Iskandar H: St John's wort and schizophrenia. Can Med Assoc J 2000; 163:262-263[Free Full Text]
  77. Laird RD, Webb M: Psychotic episode during use of St John's wort. J Herbal Pharmacotherapy 2001; 1:81-87[CrossRef]
  78. Patel S: Hypertensive crisis associated with St. John's wort. Am J Med 2002; 112:507-508
  79. Czekalla J, Gastpar M, Hubner WD, Jager D: The effect of Hypericum extract on cardiac conduction as seen in the electrocardiogram compared to that of imipramine. Pharmacopsychiatry 1997; 30(suppl 2):86-88
  80. Schrader E, Meier B, Brattstrom A: Hypericum treatment of mild-moderate depression in a placebo-controlled study: a prospective, double blind, randomized, placebo-controlled, multicenter study. Hum Psychopharmacol 1998; 13:163-169[CrossRef]
  81. Hypericum Depression Trial Study Group: Effect of Hypericum perforatum in major depressive disorder: a randomized controlled trial. JAMA 2002; 287:1807-1814[Abstract/Free Full Text]
  82. Bhopal JS: St John's wort-induced sexual dysfunction. Can J Psychiatry 2001; 46:456-457[Medline]
  83. Assalian P: Sildenafil for St John wort-induced sexual dysfunction. J Sex Marital Ther 2000; 26:357-358[CrossRef][Medline]
  84. Ondrizek RR, Chan PJ, Patton WC, King A: Inhibition of human sperm motility by specific herbs used in alternative medicine. J Assist Reprod Genet 1999; 16:87-91[CrossRef][Medline]
  85. Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH: St John's wort: effect on CYP3A4 activity. Clin Pharmacol Ther 2000; 67:451-457[CrossRef][Medline]
  86. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA: St John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000; 97:7500-7502[Abstract/Free Full Text]
  87. Budzinski JW, Foster BC, Vandenhoek S, Arnason JT: An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 2000; 7:273-282[Medline]
  88. Obach RS: Inhibition of human cytochrome P450 enzymes by constituents of St John's wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 2000; 294:88-95[Abstract/Free Full Text]
  89. Markowitz JS, DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC: Effect of St John's wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci 2000; 66:L133-L139
  90. Bray BJ, Perry NB, Menkes DB, Rosengren RJ: St John's wort extract induces CYP3A and CYP2E1 in the Swiss webster mouse. Toxicol Sci 2002; 66:27-33[Abstract/Free Full Text]
  91. Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W: Lack of effect of St John's wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000; 68:605-612[CrossRef][Medline]
  92. Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J: Profound drop of cyclosporin A whole blood trough levels caused by St John's wort (Hypericum perforatum) (letter). Transplantation 2000; 69:2229-2230[CrossRef][Medline]
  93. Breidenbach T, Hoffmann MW, Becker T, Schlitt H, Klempnauer J: Drug interaction of St John's wort with cyclosporin (letter). Lancet 2000; 355:1912
  94. Mai I, Kruger H, Budde K, Johne A, Brockmoller J, Neumayer HH, Roots I: Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perforatum) with the immunosuppressant cyclosporin. Int J Clin Pharmacol Ther 2000; 38:500-502[Medline]
  95. Barone GW, Gurley BJ, Ketel BL, Abul-Ezz SR: Herbal supplements: a potential for drug interactions in transplant recipients. Transplantation 2001; 71:239-241[CrossRef][Medline]
  96. Moschella C, Jaber BL: Interaction between cyclosporine and Hypericum perforatum after organ transplantation. Am J Kidney Dis 2001; 38:1105-1107[Medline]
  97. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G: Acute heart transplant rejection due to Saint John's wort (letter). Lancet 2000; 355:548-549[CrossRef][Medline]
  98. Karliova M, Treichel U, Malago M, Frilling A, Gerken G, Broelsch CE: Interaction of Hypericum perforatum (St John's wort) with cyclosporin A metabolism in a patient after liver transplantation. J Hepatol 2000; 33:853-855[CrossRef][Medline]
  99. Ahmed SM, Banner NR, Dubrey SW: Low cyclosporin-A level due to Saint-John's-wort in heart transplant patients (letter). J Heart Lung Transplant 2001; 20:795[CrossRef][Medline]
  100. Yue QY, Bergquist C, Gerden B: Safety of St John's wort. Lancet 2000; 355:576-577[Medline]
  101. Ratz AE, von Moos M, Drewe J: [St John's wort: a pharmaceutical with potentially dangerous interactions]. Schweiz Rundsch Med Prax 2001; 90:843-849 (German)[Medline]
  102. Schwarz UI: Unwanted pregnancy on self-medication with St John's wort despite hormonal contraception. Br J Clin Pharmacol 2003; 55:112-113[CrossRef][Medline]
  103. Hindmarch M: Interactions of the oral contraceptive pill with antibiotics and St John's wort: knowledge of female college students. Fam Pract 2002; 19:708[Free Full Text]
  104. Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A: Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 2001; 70:518-524[CrossRef][Medline]
  105. Smith M, Lin KM, Zheng YP: PIII-89 an open trial of nifedipine-herb interactions: nifedipine with St John's wort, ginseng or ginkgo biloba. Clin Pharmacol Ther 2001; 69:P86
  106. de Maat MM, Hoetelmans RM, Mathot RA, van Gorp EC, Meenhorst PL, Mulder JW, Beijnen JH: Drug interaction between St John's wort and nevirapine. AIDS 2001; 15:420-421[CrossRef][Medline]
  107. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J: Indinavir concentrations and St John's wort (letter). Lancet 2000; 355:547-548; correction, 2001; 357:1210
  108. Mathijssen RHJ, Verweij J, De Bruijn P, De Jonge MJA, Sparreboom A: Modulation of irinotecan (CPT-11) metabolism by St John's wort in cancer patients, in 2002 Proceedings of the American Association for Cancer Research. Philadelphia, AACR, 2002, abstract 2443
  109. Nebel A, Schneider BJ, Baker RK, Kroll DJ: Potential metabolic interaction between St John's wort and theophylline (letter). Ann Pharmacother 1999; 33:502[CrossRef][Medline]
  110. Roots I, Johne A, Schmider J, Brockmöller J, Maurer A, Störmer E, Donath F: Interaction of a herbal extract from St John's wort with amitriptyline and its metabolites (abstract). Clin Pharmacol Ther 2000; 67:159
  111. Johne A, Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, Scholler G, Langheinrich M, Roots I: Decreased plasma levels of amitriptyline and its metabolites on co-medication with an extract from St John's wort (Hypericum perforatum). J Clin Psychopharmacol 2002; 22:46-54[CrossRef][Medline]
  112. Sadock BJ, Sadock VA (eds): Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 7th ed. Baltimore, Lippincott Williams & Wilkins, 2000
  113. Waksman JC, Hard K, Jolliff H, et al: Serotonin syndrome associated with the use of St John's wort and paroxetine (abstract). J Toxicol Clin Toxicol 2000; 38:521
  114. Lantz MS, Buchalter E, Giambanco V: St John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999; 12:7-10
  115. Gordon JB: SSRIs and St John's wort: possible toxicity? (letter). Am Fam Physician 1998; 57:950, 953[Medline]
  116. Schmidt U, Harrer U, Kuhn W, Berger-Deinert W, Luther D: Interaction of Hypericum extract with alcohol: placebo-controlled study with 32 volunteers. Nervenheilkunde 1993; 12:314-319
  117. Koupparis LS: Harmless herbs: a cause for concern? Anaesthesia 2000; 55:101-102
  118. Irefin S, Sprung J: A possible cause of cardiovascular collapse during anesthesia: long-term use of St John's wort. J Clin Anesth 2000; 12:498-499
  119. Crowe S: Delayed emergence and St John's wort. Anesthesiology 2002; 96:1025-1027[CrossRef][Medline]
  120. Peebles KA, Baker RK, Kurz EU, Schneider BJ, Kroll DJ: Catalytic inhibition of human DNA topoisomerase II alpha by hypericin, a naphthodianthrone from St John's wort (Hypericum perforatum). Biochem Pharmacol 2001; 62:1059-1070[CrossRef][Medline]
  121. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I: Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66:338-345[CrossRef][Medline]
  122. Khawaja IS, Marotta RF, Lippmann S: Herbal medicines as a factor in delirium. Psychiatr Serv 1999; 50:969-970[Free Full Text]
  123. Miller LG: Drug interactions known or potentially associated with St John's wort. J Herbal Pharmacother 2001; 1:51-64
  124. Ladner DP, Klein SD, Steiner RA, Walt H: Synergistic toxicity of delta-aminolaevulinic acid-induced protoporphyrin IX used for photodiagnosis and Hypericum extract, an herbal antidepressant (letter). Br J Dermatol 2001; 144:916-918[CrossRef][Medline]
  125. Ferko N, Levine MA: Evaluation of the association between St John's wort and elevated thyroid-stimulating hormone. Pharmacotherapy 2001; 21:1574-1578[CrossRef][Medline]
  126. Cott J: NCDEU update: natural product formulations available in Europe for psychotropic indications. Psychopharmacol Bull 1995; 31:745-751[Medline]
  127. Miller AL: St John's wort (Hypericum perforatum): clinical effects on depression and other conditions. Altern Med Rev 1998; 3:18-26[Medline]
  128. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC: Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998; 280:1569-1575[Abstract/Free Full Text]
  129. Eisenberg DM, Kessler RC, Van Rompay MI, Kaptchuk TJ, Wilkey SA, Appel S, Davis RB: Perceptions about complementary therapies relative to conventional therapies among adults who use both: results from a national survey. Ann Intern Med 2001; 135:344-351[Abstract/Free Full Text]



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