Clinical use of St. John's wort

INTRODUCTION — St. John's wort (Hypericum perforatum) is a five-petal yellow flower (picture 1) that has been used medicinally since antiquity [1]. It was commonly referred to as "Fuga daemonum" (the devil's scourge) since it was used to protect against demonic possession and "evil spirits" [2]. One of the earliest references to the name St. John's wort is noted in a Gaelic legend from the sixth century where the missionary St. Columba carried a piece of St. John's wort because of his high regard for St. John [1]. It is believed that the name may have been derived from the fact that the flowers bloom around June 24^th, the birthday of St. John the Baptist. Wort represents the old English term for plant.

EPIDEMIOLOGY — St. John's wort has been utilized primarily for its possible antidepressant activity but also for its purported antiinflammatory and wound healing properties [3]. In 2002, St. John's wort was the sixth most popular natural product in the United States, used by 2.2 percent of American adults [4]. In 2007 and 2012, the National Health Interview Survey found large decreases in St. John's wort use by adults in the United States, when it was not among the 20 most commonly used dietary supplements [5]. This decrease may reflect the public's response to interim news reports of negative clinical trials [6-8] and potentially harmful interactions with prescription drugs [9-22].

PROPOSED MECHANISMS OF ACTION — A number of compounds isolated from St. John's wort possess pharmacologic activity, including naphthodianthrones (hypericin, pseudohypericin, protohypericin, protopseudohypericin, and cyclopseudohypericin), flavonoids (quercetin, rutin, and luteolin), hyperforin, several amino acids, and tannins [23].

Neuropharmacology — The majority of in vitro studies of St. John's wort have attempted to define its neuropharmacology. Hyperforin and hypericin have been studied most extensively. Although hypericin was originally thought to be the major active component for St. John's wort in depression, it is now believed that hyperforin and related compounds are mostly responsible for St. John's wort's effect on mood.

In animal studies, hyperforin extracts have been shown to modulate neurotransmitter levels including serotonin, norepinephrine, and dopamine [24,25]. This may be in part from inhibition of neurotransmitter uptake. Other studies have found that hypericum extract possesses a weak catechol-O-methyl transferase activity [26], and the hypericum extract LI 160 causes 50 percent inhibition of serotonin uptake by rat synaptosomes [27]. The latter occurred only at relatively high concentrations.

In in vitro studies, St. John's wort standardized extract LI 160 is capable of decreasing cell surface 5-hydroxytryptamine (5-HT) receptors, and it also suppresses the release of interleukin 6 (IL-6), which induces the release of corticotropin-releasing hormone (implicated in depression) [28,29]. St. John's wort extracts also have been shown to inhibit in vitro binding at the muscarinic cholinergic receptor (mAchR), 5-HT, and norepinephrine uptake sites, but only at high concentrations [30]. These neuropharmacologic changes, however, have not been demonstrated in human studies.

In vitro antiviral and antibacterial activity — St. John’s wort has in vitro antiviral activity against murine cytomegalovirus, parainfluenza 3 virus, Sindbis virus, vesicular stomatitis virus, and equine infectious anemia virus [31-33].Similarly, despite hypericin demonstrating in vitro antibacterial activity against gram-positive and gram-negative organisms [34], including methicillin-resistant and non-resistant Staphylococcus aureus [35], robust data supporting its efficacy against bacterial infections in humans are lacking.

LIMITED EVIDENCE OF EFFICACY FOR MOST CONDITIONS — Patients considering the use of St. John's wort should be counseled and cautioned regarding the limited evidence of efficacy, the variability in commercially available products, the lack of regulation in St. John's wort products in the United States, and the potential for herb-drug interactions.

Depression — St. John's wort is widely used in the management of depression. However, given the inconsistent evidence for efficacy and the lack of regulated standardized herbal products, we suggest not treating depression with St. John's wort. In addition, there are also multiple interactions between St. John's wort and many commonly used medications. (See "Unipolar depression in adults: Investigational and nonstandard treatment", section on 'Omega-3 fatty acids' and 'Drug interactions' below.)

In a 2008 meta-analysis of 29 trials (23 Europe, 4 United Sates, 1 Canada, 1 Brazil) including 5500 adults with depression, standardized extracts of St. John's wort were more effective than placebo and comparable in efficacy to standard antidepressants for the treatment of mild to moderate depression at 12 weeks [36]. However, these results were not observed in the United States trials [6-8,37]. Reasons for this discrepancy may include differences in enrolled patients, lack of concealment of treatment allocation, or variations in the individual preparations studied.

Somatic symptom disorders — There is evidence of efficacy in the treatment of somatic symptom disorders with St. John's wort, although the results are limited by short follow-up. In two European randomized double-blind placebo-controlled trials, St. John's wort LI 160 was efficacious in treating patients with somatic symptom disorders (and no coexisting depression) and was well tolerated, although follow-up was limited to six weeks [38,39]. In one study involving 149 patients, more patients improved with St. John's wort compared with placebo (81 versus 50 percent, respectively) [38]. Response rates were also better compared with placebo in another study of 173 patients (45 versus 21 percent, respectively) [39].

Menopausal symptoms — We suggest not treating menopause symptoms with St. John's wort. Some evidence suggests that St. John's wort may reduce menopause-related hot flashes. However, methodological weaknesses of available trials make it difficult to draw definitive conclusions. Clinicians should counsel their patients who wish to use St. John's wort as detailed above. (See 'Limited evidence of efficacy for most conditions' above.)

●One systematic review of six randomized trials suggests St. John's wort may reduce the frequency and severity of hot flashes when compared to placebo [40-43]. As an example, in one study of 100 women, those randomized to receive St. John's wort extract (standardized to 0.2 percent hypericin) experienced reductions in hot flash frequency, duration, and severity at eight weeks, compared to those who received placebo [41].

●Trial weaknesses include small sample sizes, incomplete characterization of the herbal product used, and inconsistent assessment of the effectiveness of patient blinding.

Other conditions — For many other conditions tested, there is no evidence of efficacy of treatment with St. John's wort. As examples:

●Attention deficit/hyperactivity disorder – In a trial including 54 children and adolescents with attention deficit/hyperactivity disorder, there was no improvement in attention or hyperactivity symptoms with St. John's wort (300 mg three times daily for eight weeks) compared with placebo [44]. Adverse events were similar with St. John's wort or placebo. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Other alternative therapies'.)

●HIV infection – In a phase I trial including 30 HIV-infected patients with CD4 counts less than 350 cells/mm³, patients received either intravenous (0.25 or 0.5 mg/kg body weight twice weekly or 0.25 mg/kg three times weekly) or oral (0.5 mg/kg daily) hypericin [45]. Treatment was discontinued in over 50 percent of subjects before eight weeks due to moderate or severe phototoxicity; only two patients completed 24 weeks of treatment. There was no demonstrable antiretroviral activity at the doses tested, and furthermore, therapy was considered too toxic.

●Smoking cessation – In one adequately powered placebo-controlled randomized trial evaluating St. John's wort for smoking cessation, abstinence rates were less than 10 percent and not different than placebo [46]. In another randomized controlled placebo-controlled trial, there was no benefit of treatment compared with placebo; however, the study was underpowered and had a high dropout rate [47].

●Irritable bowel syndrome – In a 12 week trial of St. John's wort (900 mg daily) in 70 patients with irritable bowel syndrome, St. John's wort was less effective than placebo as measured by self-reported bowel symptom score [48].

SAFETY

Adverse effects — A systematic review of clinical trials evaluating St. John's wort found that dropout rates and adverse effects rates in patients receiving St. John's wort were comparable to placebo, lower than tricyclic antidepressants, and slightly lower than selective serotonin reuptake inhibitors (SSRIs) [9,49]. The most common adverse effects included gastrointestinal symptoms, dizziness/confusion, tiredness/sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling [7,9].

Case reports of photosensitivity have been reported in patients taking oral St. John's wort [45,50,51]. These involved a delayed hypersensitivity/photodermatitis following ingestion of herbal tea [50] and reversible photosensitivity after taking 240 mg of hypericum extract daily for three years [51]. Erythematous lesions in light-exposed areas developed but cleared with discontinuation. Limited phototoxicity was seen in a randomized placebo-controlled multiple crossover study of 13 subjects receiving hypericum extract at various doses who were exposed to solar and ultraviolet A (UVA) light before and four hours after drug intake [52]. External use of hypericum extracts have been noted in several anecdotal reports to lead to second degree burns, resulting in scarring, after exposure to direct sunlight [53].

There is a single case report of supraventricular tachycardia associated with St. John’s wort [54].

In addition, in an in vitro study, high concentrations of St. John's wort had adverse effects upon oocytes and was mutagenic to sperm cells, leading to concerns that use may lead to decreased fertility [55].

Contraindicated in pregnancy and lactation — The use of St. John's wort should be avoided during pregnancy and lactation since high-quality data demonstrating safety are lacking.

One small study compared birth outcomes between 54 pregnancies exposed to St. John's wort, 54 exposed to conventional antidepressants, and 54 healthy, non-exposed pregnancies [56]. Major fetal malformations were found in 5.3, 4.3, and 0 percent, respectively, with the rate of fetal malformations in the St. John's wort exposed group not significantly higher than the 3 to 5 percent expected in the general population.

A German claims-based data analysis compared outcomes for 496 pregnancies exposed to St. John's wort, 420 with exposure during the first trimester [57]. Among the 18 infants born with major malformations, 17 had exposure in the first trimester (relative risk [RR] 3.56, 95% CI 0.48-26.17). Although underpowered and limited by methodologic problems, this finding raises concern over the use of St. John's wort in pregnancy.

In animal models, uterotonic effects have been reported [58]. In studies of St. John's wort in rodents, methodological weaknesses (including lack of product characterization, inadequate determination of appropriate equivalent human dose, and lack of blinding) preclude any reliable conclusions regarding safety in human pregnancy [59].

Discontinue preoperatively — In a review of herb use in the perioperative period, it was suggested that, because of the various drug interactions with St. John's wort, it should be discontinued at least five days prior to a planned surgical procedure [60]. (See "Perioperative medication management", section on 'Herbal medications'.)

DRUG INTERACTIONS — Interactions between St. John's wort and medications are the most common source of adverse effects related to the use of these preparations [9]. Adverse interactions between St. John's wort and certain medications were among the first herb-drug interactions reported [10]. These reports contributed to the growing recognition among clinicians of the potential for adverse herb-drug interactions and the need to ask all patients about nonprescription herb and supplement use. Specific interactions of St. John's wort with other medications may be determined using the drug interactions program included in UpToDate. This program can be accessed from the UpToDate online search page or through the individual drug information topics in the section on drug interactions.

Treatment failures with a wide variety of agents including warfarin, antiretrovirals (for the treatment of HIV disease), antifungals, topical beta blockers for glaucoma, immunosuppressive agents for prevention of graft rejection, narcotics, digoxin, and hormonal contraceptives have been associated with the concomitant use of St. John's wort due to significant induction of cytochrome P (CYP) 1A2, 2C19, 2C9, and 3A4, as well as intestinal P-glycoprotein/multidrug efflux pump (MDR)-1 drug transporters [12-22,61-67].

Use of St. John's wort should be avoided in combination with antidepressants to avoid the potential for the serotonin syndrome [68]. Several cases of serotonin excess (agitation, hyperthermia, diaphoresis, tachycardia, and neuromuscular disturbances including rigidity) have been reported in older adults taking St. John's wort and selective serotonin reuptake inhibitors (SSRIs) together [69].

Examples of significant interactions between St. John's wort and other medications include:

●There was a report of two cases of acute heart transplant rejection from a reduction in cyclosporine levels due to concomitant St. John's wort [11].

●There are case reports of breakthrough bleeding and undesired pregnancy in females taking oral contraceptive pills, presumably due to lowering of ethinylestradiol concentrations [21].

Avoidance of foods containing tyramine while taking St. John's wort is unnecessary due to St. John's wort's limited monoamine oxidase (MAO) inhibitory activity [26,70]. However, although St. John's wort is not suggested for the treatment of depression (see 'Depression' above), for patients who plan to switch from an SSRI or MAO inhibitor to St. John's wort, there should be a period of drug abstinence; we advise a three- to seven-day wash-out period prior to switching from an SSRI to St. John's wort and a three-week wash-out period prior to switching from an MAO inhibitor to St. John's wort. (See "Switching antidepressant medications in adults", section on 'Between SSRIs' and "Switching antidepressant medications in adults", section on 'Switching to or from MAOIs'.)

ADMINISTRATION — The majority of studies of St. John's wort utilized extracts standardized to either 0.3% hypericin or 5% hyperforin in a dosage of 300 to 400 mg three times per day [6,7,71,72]. Caution should be employed with long-term use of hypericum extracts due to a lack of studies beyond 8 to 12 weeks.

Good Manufacturing Practices for the dietary supplement industry have been established by the US Food and Drug Administration (FDA) and were phased in from 2008 to 2010 [73] (see "Overview of herbal medicine and dietary supplements"). However, no studies have demonstrated a positive impact on product standardization and quality. The resultant uncertainty in the quality of available products is another reason supporting the recommendation against the use of St. John's wort.

Patients in the United States who choose to use St. John's wort should purchase products that display a seal of approval by one of three independent organizations that offer quality testing: US Pharmacopeia, ConsumerLab.com, and NSF International. Product manufacturers voluntarily submit and pay for their products to be independently evaluated by these organizations for good manufacturing practices, accurate labeling of ingredients, and absence of harmful levels of contaminants. It is important to recognize, however, that a seal of approval does not ensure that a supplement product is effective or safe for all patients.

SUMMARY AND RECOMMENDATIONS

●Counseling patients – Patients considering the use of St. John's wort should be counseled and cautioned regarding limited evidence of efficacy, the variability in commercially available products, the lack of regulation in St. John's wort products in the United States, and the potential for herb-drug interactions. Given these limitations, we inform patients that St. John's wort is not an established or well-supported treatment for any indication, including depression and menopause. (See 'Limited evidence of efficacy for most conditions' above.)

●Avoid in pregnancy, lactation, and preoperatively – St. John's wort should not be used during pregnancy or lactation and should be discontinued at least five days preoperatively in patients undergoing a planned surgical procedure. (See 'Contraindicated in pregnancy and lactation' above and 'Discontinue preoperatively' above.)

●Herb-drug interactions – St. John's wort has the potential for multiple herb-drug interactions through induction of the cytochrome P (CYP) 3A4 and P-glycoprotein systems. Concurrent use of St. John's wort and medications metabolized by these systems should be avoided. Additionally, there have been reports of serotonin syndrome in patients taking St. John's wort concurrently with selective serotonin reuptake inhibitors (SSRI) antidepressants. (See 'Drug interactions' above.)

●Lack of standardization – The variability in quality and contents of available St. John's wort supplements is an additional concern. For patients who choose to use it, they should select products that meet specific quality criteria according to independent laboratory testing. (See 'Administration' above.)