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St. John's Wort

Scientific Name(s): Hypericum perforatum L.
Common Name(s): Amber touch-and-heal, Esbericum, Goatweed, Gol-raei, Hofariqoun, Hyperforat, Hyperiforce, John's wort, Kira, Klamath weed, LI 160, Millepertuis, Neuroplant, Psychotonin, Rosin rose, Sedariston, St John's wort, St. John's wort, STEI 300, WS 5573, Ze 117

Clinical Overview

Use

Meta-analyses of quality clinical trials support a place for St. John's wort in the treatment of depression as mono- or adjunctive therapy. Effectiveness is comparable with standard antidepressants, while St. John's wort is associated with fewer and milder adverse reactions compared with conventional antidepressants. Benefit in reducing some climacteric symptoms in women with natural menopause has also been demonstrated. Unintended interactions with other drugs and quality control issues need to be considered prior to use. Limited data are available for several other areas of therapeutic use.

Dosing

Preparations vary greatly in chemical content and quality, and may be standardized regarding quantity of hyperforin (commonly 3% to 5%) or hypericin (commonly 0.3%) constituents. Clinical trials evaluating the efficacy of St. John's wort in depression have commonly used 900 mg of extract daily in 3 divided doses for up to 12 weeks (range, 200 to 1,800 mg/day).

Contraindications

Use with various antineoplastics, anticoagulants, and anti-infectives (including antivirals), as well as boceprevir, cobicistat, telaprevir, and voriconazole is contraindicated.

Pregnancy/Lactation

Avoid use. Hypericin and hyperforin have been detected in breast milk. St. John's wort should be avoided during pregnancy and lactation until further long-term studies demonstrate a lack of toxicity in the developing fetus and breastfeeding infants.

Interactions

St. John's wort has been reported to interact with numerous drugs. Drugs with a narrow therapeutic window should be monitored closely. Patients should be cautioned on the potential for interactions and consult their health care provider before taking St. John's wort with prescription or nonprescription drugs.

Adverse Reactions

Adverse reactions are usually mild. Potential adverse reactions include GI symptoms (eg, dry mouth, dizziness, constipation) and confusion. Photosensitization may also occur. In clinical trials, adverse reactions and discontinuations due to adverse effects were usually less with St. John's wort than with standard antidepressants. Other possible rare adverse reactions include induction of mania and effects on male and female reproductive capabilities. Impaired glucose tolerance has been documented in healthy volunteers.

Toxicology

Information is lacking.

Botany

St. John's wort is a perennial plant native to Europe but found throughout the United States and parts of Canada. It is an aggressive weed that grows in the dry ground of roadsides, meadows, woods, and hedges. It generally reaches a height of 0.3 to 0.61 m, except on the Pacific coast where it has attained heights of 1.5 m.Awang 1991 The plant has oval-shaped leaves and yields golden-yellow flowers that bloom from June to September. The flower petals have black or yellow glandular dots and lines. There are approximately 370 species in the genus Hypericum, which is derived from the Greek words "hyper" and "eikon" meaning "over an apparition," alluding to the plant's ancient use to ward off evil spirits. "Perforatum" refers to the leaf's appearance; when held up to light, the translucent leaf glands resemble perforations.Hahn 1992, Upton 1997 Harvest of the plant for medicinal purposes occurs in July and August, and the plant material must be dried immediately to avoid loss of potency.Bombardelli 1995 The dried herb consists of the plant's flowering tops.Upton 1997

History

St. John's wort has been used as an herbal remedy for its anti-inflammatory and healing properties since the Middle Ages,Bombardelli 1995 with many herbalists, including Hippocrates and Pliny, recording its medicinal properties. It was noted for its wound-healing and diuretic properties, as well as for the treatment of neuralgic conditions such as back pain. In 1633, Gerard's Herbal recorded the plant's use as a balm for burns, and its oil was also popular during this time.Upton 1997 A reddish-colored olive oil extract made from the fresh flowers has been taken internally for the treatment of anxiety but has also been applied externally to relieve inflammation and promote healing.Hahn 1992

St. John's wort has been approved since 1984 by the German Commission E for the treatment of anxiety, depression, and insomnia. Although it fell into disuse for a time, a renewed interest, especially in Western countries, has led to use as a component of numerous preparations for treating anxiety and depression. The plant has been used in traditional medicine as an antidepressant and a diuretic, as well as for gastritis and insomnia.Hahn 1992, Ng 2017, Russo 2014 Topically, it was traditionally used in the management of wounds, bruises, skin ulcers, cuts, burns, contusions, myalgia, and hemorrhoids, and as an antiseptic.Samadi 2010, Yucel 2017 It is now licensed in many European countries and widely prescribed for depression.Ng 2017

Chemistry

Several reports regarding the chemical components in St. John's wort are available.Butterweck 2007, Mauri 2000, Schmitt 2006, Wurglics 2006 More than 150 constituents have been identified that interact in synergistic, additive, and antagonistic manners to produce a variety of actions. The most commonly described constituents are naphthodianthrones, flavonoids, phloroglucinols, and essential oils. The naphthodianthrones (hypericin, pseudohypericin) and the phloroglucinols (hyperforin, adhyperforin) are the most characterized.Russo 2014

Naphthodianthrons occur in St. John's wort in concentrations of less than 0.1% to 0.15%. The anthraquinone derivatives hypericin and pseudohypericin (also emodin-anthranol and cyclo-pseudohypericin) are the best known components of the plant. Isohypericin and protohypericin are also present. The reddish dianthrone pigment hypericin (Hypericum red) ranges from 0.02% to 2.5%, depending on harvesting period, drying process, and storage.Bombardelli 1995, Newall 1996 Hypericin content varies widely among growing regions, and concentrations are contingent on plant part, with flowers, buds, top leaves, and secondary stems yielding the highest percents.Upton 1997 Microscopic evaluation revealed that hypericin accumulates in secretory cell globules within these plant structures.Liu 1999 Numerous reports concerning high-performance liquid chromatography analysis of hypericin in St. John's wort exist.Balogh 1999, Chi 1999, Fourneron 1999, Michelitsch 2000, Mulinacci 1999, Sirvent 2000, Stochmal 1998, Tateo 1998 Liposoluble pigments from the plant, including hypericin, carotenoids, and chlorophylls, have also been reported.Omarova 1998 A review of the chemistry of phenanthroperylene quinones from hypericin reveals photosensory pigments.Falk 1999

Flavonoid concentrations in St. John's wort occur at less than 12% in flowers and approximately 7% in leaves/stalksUpton 1997 and include kaempferol, quercetin, quercitrin, isoquercitrin, amentoflavone, luteolin, myricetin, hyperin, hyperoside, rutin, miquelianin, and astilbin.Bombardelli 1995, Butterweck 2000, Newall 1996, Upton 1997 The proanthocyanidins (approximately 12% of aerial parts) are certain forms of catechin and epicatechin.Upton 1997

Hyperforin and adhyperforin are in the phloroglucinol class of compounds.Erdelmeier 1998, Hahn 1992, Upton 1997 Hyperforin appears in St. John's wort in concentrations of 2% to 4%, and its isolation, purity, and stability have been studied.Orth 1999 The recovery of hyperforin in plasma has been measured.Chi 1999 The related structure furohyperforin, an oxygenated analog of hyperforin, has been isolated from the plant,Verotta 1999 as have other hyperforin analogs.Verotta 2000 The essential oil component of St. John's wort is between 0.05% and 0.9%.Hahn 1992, Upton 1997 It consists of mono- and sesquiterpenes, mainly 2-methyl-octane (16% to more than 30%), n-nonane, alpha- and beta-pinene, alpha-terpineol, geraniol, and traces of myrecene, limonene, and caryophyllene, as well as others.Bombardelli 1995, Newall 1996, Upton 1997

Other compounds present in St. John's wort include xanthones (1.28 mg per 100 g) and tannins (3% to 16%). One study reports that tannin content in extracts is influenced by parameters such as temperature of maceration.Rafajlovska 1998 Phenol constituents include caffeic, chlorogenic, and p-coumaric acids, and hyperfolin. Other plant constituents include acids (eg, nicotinic, myristic, palmitic, stearic), carotenoids, choline, pectin, hydrocarbons, and long-chain alcohols. Amino acids include cysteine, gamma-aminobutyric acid (GABA), glutamine, leucine, lysine, and others.Bombardelli 1995, Hahn 1992, Newall 1996, Upton 1997

St. John's wort products are not regulated by the US Food and Drug Administration because they are classified as dietary supplements.Congress 1994 Several reports evaluating commercial preparations of St. John's wort have found inconsistencies in active ingredients, such as potency variations of labeled hypericin concentrations (from 47% to 165%),Constantine 1998 different concentrations of major components among brands,Liu 1999 and marked deviations in hyperforin and adhyperforin amounts in certain preparations.Melzer 1998 Several reports address these issues, with various proposed standardization methods.Khwaja 1999, Kurth 1998, Mason 1999, Schempp 1999

Uses and Pharmacology

Animal and human studies have elucidated the pharmacokinetic differences among the structurally similar components hypericin, pseudohypericin, and hyperforin. Bioavailability of these constituents after oral administration is low and ranges from approximately 15% to 20%. Penetration of the blood-brain barrier is similarly low with only about 5% of hypericin likely to reach the brain; hypericin's half-life in the brain appears to be a few weeks.Russo 2014 Time to peak plasma levels (Cmax) ranges from 30 minutes to 3 hours for pseudohypericin, from 4.6 to 8.1 hours for hypericin, and about 2.8 to 3.6 hours for hyperforin after single doses of St. John's wort (range, 300 to 1,800 mg [approximately 0.3% of hypericins]).Hammer 2014, Russo 2014 Steady-state levels of hypericin are reached at 4 days, with a prolonged plasma half-life of about 25 hours due to hypericin's high affinity for albumin and lipoprotein. Hyperforin exhibits linear pharmacokinetics at doses up to 600 mg, after which plasma levels tend to be lower than expected. After repeat doses of 900 mg/day of extract, hyperforin steady-state levels of about 100 ng/mL have been reported, with a half-life of 9 hours.Russo 2014

St. John's wort, particularly hyperforin, has been shown in vitro and in vivo to inhibit monoamine oxidase type A (MAO-A) and MAO-B as well as the reuptake of norepinephrine, dopamine, and serotonin. It has a strong affinity for GABA, glutamate, and adenosine receptors.Sood 2010 It induces the cytochrome P450 (CYP-450) system, the uridine diphosphate glucuronosyltransferase (UGT) isozyme, and P-glycoprotein.Kummer 2016, Markert 2015, Pereira 2013 Downregulation of beta-adrenergic receptors has also been documented.Russo 2014 The major coactive constituents shown to mediate the broad-spectrum inhibition of neurotransmitter reuptake are hypericin, hyperforin, quercetin, and kaempferol.Chrubasik-Hausmann 2018

Bioactivities of the various constituents in St. John's wort are a result not only of their bioavailability but also of the complex interactions of the constituents themselves, some of which are light dependent. This complexity also highlights the challenge of interpreting existing data.Hammer 2014

Anti-inflammatory activity

Animal and in vitro data

In vitro studies revealed that St. John's wort at low concentrations is capable of increasing immunity, but at high concentrations can suppress immunity.Cabrelle 2008, Evstifeeva 1996, Fidan 2008, Mukerjee 2008 A number of signaling pathways elicited by compounds in Hypericum have been identified in human and animal cell cultures and in vivo in animal models. Quercetin, amentoflavone, hyperforin, and hypericin have been shown to individually reduce nuclear factor kappa B, tumor necrosis factor alpha (TNF-alpha), cyclooxygenase-2, p38, and other key factors in inflammatory signaling pathways. Combining the individual compounds altered the resulting activities, reflecting apparent interactions among the constituents of St. John's wort when combined. Additionally, bioactivities of some compounds were dependent on light, whereas others were light independent. These interactions appear to provide a balance of both pro- and anti-inflammatory activities, as well as phototoxic and photoprotective actions. Pseudohypericin was a necessary element in the anti-inflammatory process, as it was required for the reduction in prostaglandin E2.Hammer 2014 Similarly, St. John's wort ethanolic extract inhibited the increase in neutrophil recruitment and the inflammatory biomarkers interleukin 1beta (IL-1beta) and TNF-alpha as well as the decrease in glutathione that was induced by acetaminophen toxicity in mice. Subsequently, AST and ALT levels were also decreased. A dose-dependent reduction in acetaminophen-induced lethality was also observed.Hohmann 2015

Antimicrobial activity

In vitro data

Antibacterial activity has been described.Barbagallo 1987, Bejaoui 2017 Extracts of H. perforatum and Hypericum humifusum containing differing amounts of hypericin (60 mg/g and 90 mg/g, respectively) and hyperforin (8.5 mg/g and 30 mg/g, respectively) exhibited very strong inhibitory and bactericidal activity against several gram-positive and gram-negative bacteria as well as Candida albicans. Strongest minimum inhibitory concentrations (MICs) (200 to 250 mcg/mL) were observed against Enterococcus faecium, Staphylococcus aureus, and Staphylococcus epidermidis by H. humifusum extract and against C. albicans by H. perforatum extract. The lowest minimum bactericidal concentrations (350 mcg/mL) were observed for S. epidermidis, Bacillus subtilis, and C. albicans, and were fairly comparable between the 2 extracts. Weakest effects were seen for Salmonella typhimurium and 2 strains of Pseudomonas aeruginosa.Bejaoui 2017

Antiviral/HIV activity

Antiviral activity has been reported for influenza, herpes simplex types 1 and 2 (HSV-1, HSV-2), Sindbis virus, poliovirus, retrovirus infection in vitro and in vivo, murine cytomegalovirus, and hepatitis C.Bombardelli 1995, Jacobson 2001, Müller 2004, Newall 1996, Upton 1997 Hypericin and pseudohypericin exert unique effective antiviral actions, possibly because of nonspecific associations with cellular and viral membranes. Hypericin and pseudohypericin inhibit a variety of encapsulated viruses, including HIV.Upton 1997

In vitro data

3-Hydroxy lauric acid obtained from H. perforatum exhibited light-independent, anti-HIV activity in an in vitro experiment.Maury 2009

Clinical data

Clinical trials of St. John's wort use in HIV are limited by the prevalence of interactions between St. John's wort and standard HIV therapy. In 1999, a phase 1 study evaluating hypericin's effects in 30 patients concluded that hypericin had no antiretroviral activity, with phototoxicity being observed.Gulick 1999

Antiviral activity may involve a photoactivation process, as exposure of hypericin to fluorescent light markedly increases antiviral activity.Bombardelli 1995, Maury 2009 An example of this was demonstrated in a case series in which an approximate 50% improvement was observed in acyclovir-recalcitrant herpes skin lesions treated with a phototherapy protocol that included H. perforatum (10% extract containing 1% w/v hypericin and 0.5% w/v chlorophyll) as the photosensitizer compared to phototherapy with red laser therapy alone. Patients ranged in age from 7 to 77 years and presented with HSV-1, HSV-2, or combination-type lesions.Tardivo 2012

Cancer

In vitro data

The cytocidal activity of hyperforin and its effect on tumor growth inhibition have been demonstrated against human cell lines.Business Wire 1998, Hostanska 2003, Lorusso 2009, Schmitt 2006, Stavropoulos 2006

Clopidogrel nonresponders

Clinical data

Platelet response improved significantly subsequent to administration of St. John's wort versus placebo in clopidogrel nonresponders with stable angina who underwent elective percutaneous coronary intervention (PCI). In a small, open-label, randomized clinical trial (N=23), known clopidogrel nonresponders were randomized 2:1 to receive St. John's wort 300 mg 3 times daily or placebo, in addition to dual antiplatelet therapy (aspirin 80 mg and clopidogrel 75 mg), for 2 weeks after PCI. Platelet response improved significantly when measured as P2Y12 reaction units to clopidogrel but not when measured as thrombin receptor activating peptide units to thrombin receptor activating peptide or as aspirin reaction units or arachidonic acid units to aspirin, which indicated a selective interaction of St. John's wort with the clopidogrel pathway.Trana 2013

Crigler-Najjar syndrome

Clinical data

A case of reduced hyperbilirubinemia, decreased fatigue, and improved quality of life has been reported in a patient with congenital Crigler-Najjar syndrome type II. The patient was administered 2 regimens given 18 months apart of Hypericum dry extract 300 mg 3 times daily for 8 weeks.Kummer 2016

Depression/CNS-related conditions

Clinical data

Meta-analyses, including Cochrane meta-analyses, of quality clinical trials have been conducted to examine effects of St. John's wort in comparison with placebo and antidepressant therapy for treatment of depression.Kasper 2008, Linde 2000, Linde 2005, Linde 2015, Magni 2013, Rahimi 2009 In some studies of mild, moderate, and majorLinde 2000, Seifritz 2016 depression, St. John's wort was more effective than placebo and similarly effective as standard antidepressants.Kasper 2008, Linde 2000, Linde 2005, Linde 2015, Rahimi 2009, Sarris 2007, Seifritz 2016, Thachil 2007 Adverse effects are lower for St. John's wort than for standard antidepressants.Asher 2017, Knüppel 2004, Linde 2000, Qaseem 2016, Rahimi 2009, Thachil 2007 A previous Cochrane review found insufficient evidence to support a place in therapy for St. John's wort in treating major depressionLinde 2005; however, more recent trials and analysis of participants meeting criteria for major depression have led to a somewhat more positive, but cautious, recommendation for Hypericum.Linde 2000, Qaseem 2016 Issues raised in the meta-analyses include the heterogeneity of older clinical trials, the wide variation and quality of Hypericum preparations, use of comparatively low doses of pharmaceutical antidepressants, and the emergence of more favorable trials.Asher 2017, Linde 2000, Linde 2005, Qaseem 2016, Sarris 2007 Limited evidence is available for use in depression in adolescentsCharrois 2007, Sarris 2007, Walter 1999 or the elderly, or for patients with comorbid conditions such as Alzheimer diseaseChatterjee 1999 or anxiety.Sarris 2009 However, one analysis of 4 studies (N=1,058) that used a stabilized dry extract of H. perforatum, WS 5570, showed a significant improvement in depression scores (P<0.01) compared to placebo in younger patients (younger than 60 years) as well as older patients (60 years of age and older).Kasper 2015

More recent meta-analyses examining the benefits and risks of St. John's wort compared to selective serotonin reuptake inhibitors (SSRIs), specifically in patients with major depressive disorder (MDD), found no statistically significant difference in response, remission, and depression scores between the 2 treatments. As in earlier studies, the risks of treatment were significantly higher for SSRIs than St. John's wort, as was treatment discontinuation due to adverse events.Asher 2017, Magni 2013, Ng 2017, Purgato 2014 St. John's wort was also shown in head-to-head comparisons in network meta-analyses to have superior efficacy in MDD when compared to exercise and omega-3 fatty acids.Asher 2017 Commercial extracts used were mostly standardized to hypericin 0.12% to 0.3% and hyperforin 2% to 5%; doses ranged from 300 to 1,800 mg/day given over 4 to 12 weeks. Two meta-analyses evaluating data on SSRIs as a group included 12 randomized controlled trials (RCTs) (N=1,806)Asher 2017 and 27 RCTs (N=3,808), repsectively.Ng 2017 Overall, the strength of evidence was considered low by one paper because of the moderate to low doses of comparator antidepressants used in the studies.Asher 2017

Further studies have shown St. John's wort to be effective in the acute treatment of mild depression at a range of dosages (600 to 1,200 mg daily),Kasper 2008 while long-term studies describe clinical advantage over placebo with regard to time to relapse and overall relapse rates when St. John's wort 900 mg daily was administered over 26 and 52 weeks.Brattström 2009, Kasper 2008 Unintended drug-herb interactions with St. John's wort may compromise the efficacy of other drugs; however, St John's wort as adjunctive therapy has been used clinically to reduce the dose needed for pharmaceutical antidepressants.Izzo 2016, Ravindran 2016 Additionally, as in clinical trials with pharmaceutical antidepressants, a significant placebo effect and similar placebo response pattern occurs in MDD trials with St. John's wort, such that nonresponders will likely exhibit no clinical response early in the trial (ie, within the first 4 weeks) and placebo responders will experience a clinical response within the first 2 weeks of the trial.Sarris 2013

Guidelines discussing the use of St. John's wort in MDD have been published. The American Psychiatric Association practice guideline for the treatment of patients with MDD recognizes that while modest evidence supports the use of St. John's wort, data are conflicting and insufficient to make a recommendation for its use in the treatment of MDD. In addition, careful attention to drug-drug interactions is needed with St. John's wort. However, the guidelines also state that in patients who prefer complementary and alternative therapies, St. John's wort may be considered.Gelenberg 2010 The Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of MDD in adults (2016) recommend St. John's wort as first-line monotherapy in mild to moderate MDD based on level 1 evidence (defined as at least 2 RCTs with adequate sample sizes, preferably placebo-controlled, and/or meta-analysis with narrow confidence interval). St. John's wort is recommended as second-line adjunctive therapy in moderate and higher-severity MDD, based on level 2 data (defined as at least 1 RCT with adequate sample size and/or meta-analysis with wide confidence intervals).Ravindran 2016 The American College of Physicians clinical practice guideline for treatment of adults with MDD report no significant difference in response or remission (low-quality evidence) but better tolerability (moderate-quality evidence) with St. John's wort monotherapy compared to low-dose second-generation antidepressants. Due to the lack of rigorous standardization of product purity and potency in the United States, data were deemed insufficient to recommend a place in therapy for St. John's wort in the treatment of MDD.Qaseem 2016

Based on efficacy in depression, Hypericum extracts have been recommended as appropriate therapy in mild or moderate depression with bipolar disorder as an alternative to standard antidepressant therapy.Andreescu 2008 A trial (N=54) evaluating the efficacy of 900 mg of Hypericum extract daily in adolescents with attention-deficit/hyperactivity disorder and a subsequent systematic review found no difference compared with placebo at 8 weeksSarris 2011, Weber 2008 and no difference using the same dosage in burning mouth syndrome.Sardella 2008 St. John's wort 600 mg/day performed better than placebo in 6 primary outcome measures in patients with somatoform disorders.Müller 2004 Equivocal results have been demonstrated for Hypericum extracts in the management of premenstrual symptoms, which may be reflective of the different dosages used.Hicks 2004, Stevinson 2000 Improvement in total, behavioral, and physical symptoms in women diagnosed with premenstrual syndrome (PMS) has been demonstrated with Hypericum compared to placebo in double-blind RCTs that include a small crossover pilot study (N=36) and a larger prospective trial (N=170).Canning 2010, Ghazanfarpour 2011

Seasonal affective disorder, a type of depression in which symptoms occur in fall/winter and resolve in spring/summer, improved with St. John's wort in combination with light therapy.Martinez 1994 In an open-label trial, statistically but not clinically significant improvements in several target behaviors in 3 young autistic males (19 to 22 years of age) were documented after 4 weeks of St. John's wort 20 mg/day. The patients were resistant to previous treatment with neuroleptics or methylphenidate.Niederhofer 2009

The Scottish Intercollegiate Guidelines Network (SIGN) guidelines on the management of perinatal mood disorders (2012) state that St John's wort and other alternative medicines should not be used during pregnancy and lactation based on lack of evidence specific to use in perinatal mood disorders, the risk of drug interactions, and lack of regulation for such products.SIGN 2012

Irritable bowel syndrome

Clinical data

Equivocal results have been reported by 2 studies using St. John's wort 900 mg/day in patients with irritable bowel syndrome (IBS).Saito 2010, Wan 2010 In a small pilot study (N=30), 8 weeks of treatment with St. John's wort significantly improved psychological well-being, with improved scores on anxiety and depression scales (P<0.05). Autonomic response to physical stimuli was also significantly improved (P<0.01), but not to psychological stressors. Symptom improvement was reported for pain, bloating, and overall severity (P<0.05).Wan 2010 However, in another study, placebo provided significantly better responses in overall symptom severity and diarrhea, and provided adequate relief in a 12-week double-blind RCT that enrolled 70 symptomatic adults with IBS.Saito 2010

Menopausal symptoms

Clinical data

A systematic review and meta-analysis assessing safety and efficacy of St. John's wort preparations in women who experienced natural menopause identified 9 studies (N=6,983) that met inclusion criteria, 6 of which were included in the efficacy meta-analysis (N=717). Interventions included H. perforatum as monotherapy (3 studies) as well as in combination with chaste tree or black cohosh. The meta-analysis revealed a significant improvement with St. John's wort in climacteric scale scores overall (standard mean difference, –1.08; 95% CI, –1.38 to –0.77; P<0.0001), with moderate heterogeneity, and in hot flush scores (standard mean difference, –0.64; 95% CI, –0.78 to –0.5; P<0.0001), with no heterogeneity. In addition to the overall improvement in hot flushes, hot flush severity, duration, and frequency also improved significantly (P<0.0001 each). However, no significant difference was found in depression scores. The 4 trials included in the safety analysis showed no difference between treatment and placebo.Liu 2014

The Society of Obstetricians and Gynaecologists of Canada revised clinical practice guidelines on managing menopause (2014) recommend that complementary and alternative medicine that has demonstrated efficacy for mild menopausal symptoms, including St. John's wort for healthy mood balance and associated sleep disturbances, may be offered (level I-B evidence).Reid 2014 Another Canadian organization, the Committee on the Evolution of Practices in Oncology (CEPO), recommends against the use of St. John's wort for managing hot flashes in breast cancer survivors (level II evidence [ie, evidence demonstrated by small randomized trials with uncertain results), as no benefit was shown over placebo; however, the single study reviewed did report significant improvements in sleep and quality-of-life measures in the St. John's wort group (900 mg/day for 3 months).L'Espérance 2013

Restless legs syndrome

Clinical data

St. John's wort was investigated in an open-label pilot study in 21 patients with restless legs syndrome. All 17 patients who reported at least a 70% improvement in symptom severity scores and improved sleep during the 10-day induction phase opted to enter the 3-month continuation phase. During phase 1, a St. John's wort 300 mg standardized extract was taken daily. However, during phase 2, a dose of 300 mg was recommended to be taken daily for 4 to 5 days, stopped until symptoms recurred, and then continued as needed for the duration of the study. After 3 months, median severity score had improved significantly from 24 (±5.1) at baseline to 4.1 (±1) (P<0.0001). The St. John's wort regimen was taken for a median of 40 days during the 3-month period, with symptom-free periods ranging from 2 to 7 days (median, 3 days). No adverse effects were reported.Pereira 2013

Skin conditions

Clinical data

A double-blind, placebo-controlled trial conducted in 11 healthy volunteers demonstrated the ability of an H. perforatum extract cream (1.5%) rich in hyperforin to significantly improve protection of irradiated skin from radicals (80.6% reduction in radicals) compared to untreated skin; the placebo cream led to a 55.7% reduction in radical production.Arndt 2013 Of the 8 trials included in a systematic review investigating topical herbal medicines for atopic eczema, one small double-blind, randomized, placebo-controlled trial published in 2003 assessed the safety and efficacy of a hyperforin topical cream in 21 patients (12 to 59 years of age). After 4 weeks, the topical H. perforatum cream significantly improved the intensity of eczema (ie, erythema, papulation, crust, excoriation, lichenification, scaling) as well as reduced S. aureus skin colonization compared to placebo. A few nonserious adverse events were reported. Risk of bias was low across all domains.Thandar 2017 In a small pilot study (N=10), both St. John's wort and vehicle alone significantly improved erythema, scaling, and thickness in plaques of patients with mild psoriasis. Application of St. John's wort resulted in greater reduction in erythema scores, scaling scores, and thickness scores, with improvement in scaling being the most pronounced; on a 3-point scale, a mean difference of –1.8 and –0.3 was observed for treatment and vehicle, respectively. No between-group comparative statistics were provided.Najafizadeh 2012

Substance dependence/smoking cessation

Animal data

A limited number of animal studies exist evaluating the role of Hypericum extracts in reducing craving and symptoms of withdrawal from morphine, ethanol, and stimulant substances (eg, nicotine, caffeine, amphetamine). Decreased self-administration of ethanol and withdrawal syndrome have been demonstrated in rodents, as well as no increased ethanol intake after periods of deprivation.De Vry 1999, Ebrahimie 2015, Uzbay 2008, Uzbay 2008

Clinical data

A Cochrane review of antidepressants for smoking cessation also examined evidence for herbal products, including St. John's wort. The evidence for St. John's wort suggests that it is not significantly better than placebo for this indication (2 studies, N=261; relative risk [RR], 0.81; 95% CI, 0.26 to 2.53).Hughes 2014 Clinical trials have produced equivocal results regarding a role in smoking cessation, with one small trial (N=24) without a control group showing efficacy in cessation rates with Hypericum at 12 weeksLawvere 2006 and others showing no difference from placebo.Camfield 2013, Parsons 2009, Uzbay 2008 A larger randomized, blinded, placebo-controlled, dose-ranging study similarly found no difference in smoking cessation rates, mean cigarettes smoked per day, withdrawal symptoms, or tobacco cravings in the St. John's wort 900 mg/day or 1,800 mg/day groups compared to placebo. Of the 118 cigarette smokers enrolled in the 12-week study, 43% withdrew before study end and were smoking during their last study visit.Sood 2010 Differences in study populations, dosing, and formulation of preparations make comparisons difficult. Further quality studies are needed with larger numbers of subjects.

Wound healing

Topical and internal use of St. John's wort has been reported to provide effective wound healing. It stimulates fibroblast motility, collagen production, and keratinocyte differentiation, as well as possesses antimicrobial and anti-inflammatory effects. Hyperforin, hypericin, and derivatives of these constituents have been effective in treating skin ulcers, abrasions, burns, scratches, decubitus, and surgical wounds.

Clinical data

In a case report, the oily extract of St. John's wort was used to facilitate healing of decubitus ulceration.Yucel 2017 St. John's wort was also observed to provide significantly more benefit to wound healing and scar formation in women who underwent cesarean section compared to placebo and untreated controls (P<0.001).Samadi 2010

Other uses

Hypericin has been shown to inhibit T-type calcium channel activityShan 2000 and has a cellular protective effect.Breyer 2007, Menegazzi 2008

Dosing

Preparations vary greatly in chemical content and quality, and may be standardized regarding hyperforin (commonly 2% to 5%) or hypericin (commonly 0.12% to 0.3%) content.Asher 2017, Linde 2005, Ng 2017, Wurglics 2006 Doses used for a variety of indications in clinical studies most commonly ranged from 300 mg/day to 1,800 mg/day.

Depression

Clinical trials evaluating the efficacy of St. John's wort in depression have commonly used 900 mg of extract daily in 3 divided doses for periods of up to 12 weeks (range, 200 to 1,800 mg/day).Kasper 2008, Linde 2000, Papakostas 2007

Skin conditions and wounds

Two studies used a topical hypericum cream containing hypericin 1% and 1.5%.Arndt 2013, Tardivo 2012

Pregnancy / Lactation

The use of St. John's wort in perinatal depression has been considered; however, insufficient data exist to support its use.Freeman 2009 There is a lack of systematic evidence on the safety of Hypericum in pregnancy or lactation.Dugoua 2006, Freeman 2009 A small study of case-matched infants born to mothers consuming St. John's wort during pregnancy found an increase in colic, drowsiness, and lethargy.Dugoua 2006

Studies in rats suggest the preparation may have teratogenic and toxic effects,Gregoretti 2004, Lee 2003, Russo 2014 while other studies suggest no changes in cognitive development or long-term behavior.Dugoua 2006 Emmenagogue and abortifacient effects due to uterine stimulant action have been suggested,Brinker 1998, Ernst 2002, Rotblatt 2002, Shipochliev 1981 but evidence is weak.Dugoua 2006

In 2 separate studies, the rates of major postnatal malformations (eg, hypospadias, bilateral hip dislocation, heart septum defect, obstructed ureter) in children of women exposed to St. John's wort while pregnant were 5% and 8.1%. A total of 5 cases of malformation were reported in 75 exposed live births; comparatively, malformations expected in the general population range from 3% to 5%. The differences reported in the studies were not statistically significantly different compared to women taking prescription antidepressants (4%) or those who were otherwise healthy and/or not exposed (0%). However, the hypericum-exposed sample sizes were small (N=38 and N=37), and caution is warranted in interpreting these results.Kolding 2015, Russo 2014 Case reports exist of low levels of hypericin and hyperforin detected in breast milk, but not in the breastfeeding infants.Freeman 2009, Klier 2006

St. John's wort should be avoided during pregnancy and lactation until further long-term studies demonstrate a lack of toxicity in the developing fetus and breastfeeding newborn.Freeman 2009, Kalra 2005

SIGN guidelines on the management of perinatal mood disorders (2012) state that St John's wort and other alternative medicines should not be used during pregnancy and lactation based on a lack of evidence specific to use in pregnancy or lactation, the risk of drug interactions, and lack of regulation for such products.SIGN 2012

Support for use of St. John's wort in surgical wound healing has been demonstrated in women who underwent caesarean section.Izzo 2016

Interactions

Drug interactions with St. John's wort are highly variable and often difficult to predict based solely on the St. John's wort dose because of the complex interactions among hypericum constituents in any particular product or doseform.Chrubasik-Hausmann 2018, Hammer 2014, Mueller 2004 Additionally, single-dose compared to long-term administration (ie, at least 10 days) of St. John's wort in drug interaction studies has been shown to have opposite effects on the pharmacokinetics of coadministered substrate drugs.Borrelli 2009

St. John's wort enhances the expression of the CYP-450 system, apparently as a result of binding to the nuclear pregnane X receptor (PXR). Hyperforin appears to be the specific receptor ligand and it is hyperforin content, not hypericin, that seems to most consistently determine the extent of the drug interaction, with 1 mg/day suggested as the critical cut-off dose for clinically significant interactions.Chrubasik-Hausmann 2018, Kummer 2016, Pereira 2013 UGT isozyme induction is also mediated by PXR, so drugs metabolized by UGT have the potential to be affected by St. John's wort. The expression of P-glycoprotein (P-gp) is also stimulated by St. John's wort. Induction of both the intestinal and hepatic CYP3A4 has been observed.Arold 2005, Kummer 2016, Markert 2015, Pereira 2013 Studies with voriconazole indicate that St. John's wort may be a stronger inducer of CYP2C19 and CYP2C9 than CYP3A4. Clinical studies have also reported induction of CYP2E1. However, the Food and Drug Administration reportedly classifies St. John's wort as a strong inducer (80% or greater decrease in area under the curve [AUC]) of CYP3A4 and a weak inducer (20% to 50% decrease in AUC) of CYP2C9.Berry-Bibee 2016, Li 2017, Markert 2015, Russo 2014 The extent of induction of CYP3A4 and P-gp appears to be comparable among ethnic groups (ie, African American, white, Chinese, Hispanic, Indian, Malay).Russo 2014 Organic anion-transporting polypepetides (OATPs) do not appear to be affected.Li 2017, Markert 2015

Afatinib: P-gp/ABCB1 inducers may decrease the serum concentration of afatinib. Consider therapy modification.Gilotrif November 2013

Aminolevulinic acid (systemic): Photosensitizing agents may enhance the photosensitizing effect of aminolevulinic acid (systemic). Avoid combination.Alacare March 2015, Ameluz May 2016, Drucker 2011, Gleolan June 2017, Ladner 2001, Lankerani 2004, Levulan March 2010, Naldi 1999

Aminolevulinic acid (topical): Photosensitizing agents may enhance the photosensitizing effect of aminolevulinic acid (topical). Monitor therapy.Alacare March 2015, Ameluz May 2016, Drucker 2011, Ladner 2001, Lankerani 2004, Levulan March 2010, Naldi 1999

Ambrisentan: St. John's wort may decrease the serum concentration of ambrisentan. Monitor therapy.Markert 2015

Amphetamines: Amphetamines may enhance the adverse/toxic effect of serotonin modulators. The risk of serotonin syndrome may be increased. Monitor therapy.Parrott 2002, Prior 2002, Sloviter 1978,

Antiemetics (5-HT3 antagonists): Antiemetics (5-HT3 antagonists) may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Monitor therapy.Altman 2010, Boyer 2005, Gener 2010, George 2011, Gollapudy 2012, Sorscher 2002, Stanford 1999, Stanford 2010, Turkel 2001

Antihepaciviral combination products: CYP3A4 inducers (moderate) may decrease the serum concentration of antihepaciviral combination products. Avoid combination.Technivie July 2015, Viekira Pak July 2015

Antiparkinson agents (monoamine oxidase inhibitor [MAOI]): Antiparkinson agents (MAOIs) may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Consider therapy modification.Azilect May 2014, Dingemanse 1996, Duval 2013, Emsam March 2015, Fernandes 2011, Garcia-Monco 1995, Gitlin 1997, Hilli 2009, Hinds 2000, Jermain 1992, Laine 1997, Lefebvre 1995, Montastruc 1993, Panisset 2015, Richard 1997, Ritter 1997, Smith 2015, Suchowsersky 1990, Toyama 1994, Waters 1994, Wu 2009, Xadago March 2017, Zelapar July 2014, Zomberg 1991

Antipsychotic agents: Serotonin modulators may enhance the adverse/toxic effect of antipsychotic agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic agents may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Monitor therapy.Chopra 2004, Duggal 2005, Fisher 2002, Gambassi 2006, Karki 2003, Kaufman 2006, Kim 2007, Kohen 2007, Kontaxakis 2003, Kontaxakis 2003, Marlowe 2006, Matsumoto 2005, Stevens 2008, Verre 2008

Apixaban: St. John's wort may decrease the serum concentration of apixaban. Avoid combination.Eliquis December 2012

Artemether: St. John's wort may decrease serum concentrations of the active metabolite(s) of artemether. Specifically, dihydroartemisinin concentrations may be reduced. St John's wort may decrease the serum concentration of artemether. Avoid combination.Byakika-Kibwika 2012, Coartem April 2013, Huang 2012, Kredo 2011

Asunaprevir: CYP3A4 inducers (moderate) may decrease the serum concentration of asunaprevir. Avoid combination.Sunvepra March 2016

Atazanavir: St. John's wort may decrease the serum concentration of atazanavir. Avoid combination.Reyataz June 2014

Axitinib: St. John's wort may decrease the serum concentration of axitinib. Avoid combination.Inlyta January 2012, Pithavala 2010

Bedaquiline: CYP3A4 inducers (moderate) may decrease the serum concentration of bedaquiline. Avoid combination.Dooley 2012, Sirturo May 2015, Svensson 2013

Benzodiazepines (metabolized by oxidation): St. John's wort may increase the metabolism of benzodiazepines (metabolized by oxidation). Monitor therapy.Chrubasik-Hausmann 2018, Markowitz 2000, Markowitz 2003

Bictegravir: St. John's wort may decrease the serum concentration of bictegravir. Avoid combination.Biktarvy February 2018

Boceprevir: St. John's wort may decrease the serum concentration and AUC of boceprevir. Additionally, boceprevir may increase serum concentrations of hypericin (the active component of St. John's wort). Avoid combination. This combination is contraindicated in boceprevir prescribing information but was determined to be clinically insignificant in a phase 1, open-label trial (N=17).Jackson 2014, Victrelis May 2011

In healthy adults, coadministration of St. John's wort and boceprevir reduced the steady-state AUC of boceprevir by 9% and increased hypericin AUC by 23%, Cmax by 32%, and C8 by 37%. These changes were determined to be clinically insignificant.Jackson 2014

Bortezomib: St. John's wort may decrease the serum concentration of bortezomib. Avoid combination.Butterweck 2007

Bosutinib: St. John's wort may decrease the serum concentration of bosutinib. Avoid combination.Bosulif September 2012

Brentuximab vedotin: P-gp/ABCB1 Inducers may decrease the serum concentration of brentuximab vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy.Adcentris September 2013, Han 2013

Brexpiprazole: St. John's wort may decrease the serum concentration of brexpiprazole. Consider therapy modification.Rexulti July 2015

Brigatinib: St. John's wort may decrease the serum concentration of brigatinib.Alunbrig April 2017

Bupropion: St. John's wort may decrease the serum concentration of bupropion. Consider therapy modification.Chrubasik-Hausmann 2018

Cabozantinib: St. John's wort may decrease the serum concentration of cabozantinib. Avoid combination.Cometriq December 2012

Canagliflozin: St. John's wort may decrease the serum concentration of canagliflozin.Invokana May 2014

Cannabis: St. John's wort may decrease the serum concentration of cannabis.Sativex February 2014, Watanabe 2007

Cardiac glycosides: St. John's wort may decrease the serum concentration of cardiac glycosides. Monitor therapy.Izzo 2016, Johne 1999, Mueller 2004

Carisoprodol: St. John's wort may increase serum concentrations of the active metabolite(s) of carisoprodol. Specifically, meprobamate concentrations may be increased. St. John's wort may decrease the serum concentration of carisoprodol. Monitor therapy.Soma February 2013

Celiprolol: P-gp/ABCB1 inducers may decrease the serum concentration of celiprolol. Monitor therapy.Lilja 2004, Selectol July 2017

Ceritinib: St. John's wort may decrease the serum concentration of ceritinib. Avoid combination.Zykadia April 2014

Clarithromycin: CYP3A4 inducers (moderate) may increase serum concentrations of the active metabolite(s) of clarithromycin. CYP3A4 inducers (moderate) may decrease the serum concentration of clarithromycin. Consider therapy modification.Biaxin May 2011, Hafner 1998, Kakuda 2014

CloZAPine: St John's wort may decrease the serum concentration of clozapine. Avoid combination.Clozaril June 2014, Jerling 1994, Joos 1998, Junghan 1993, Langbehn 2000, Miller 1991, Muller 1988, Peritogiannis 2007, Raitasuo 1994, Tiihonen 1995, Van Strater 2012

Cobicistat: St. John's wort may decrease the serum concentration of cobicistat. Avoid combination.Stribild August 2012

Cobimetinib: CYP3A4 inducers (moderate) may decrease the serum concentration of cobimetinib. Avoid combination.Cotellic November 2015

Codeine: CYP3A4 inducers (moderate) may decrease serum concentrations of the active metabolite(s) of codeine. Monitor therapy.Acetaminophen November 2017, Caraco 1997

Copanlisib: St John's wort may decrease the serum concentration of copanlisib. Avoid combination.Aliqopa September 2017, Dresser 2003, Piscitelli 2000, Sugimoto 2001, Wang 2001

Crizotinib: St. John's wort may decrease the serum concentration of crizotinib. Avoid combination.Xalkori August 2011

Cyclosporine (systemic): St. John's wort may decrease the serum concentration of cyclosporine (systemic); cases of organ rejection have been documented. Consider therapy modification.Ahmed 2001, Alscher 2003, Barone 2000, Barone 2001, Bauer 2003, Breidenbach 2000, Breidenbach 2000, Dresser 2003, Durr 2000, Izzo 2016, Karliova 2000, Mai 2000, Mai 2004, Mandelbaum 2000, Moschella 2001, Ruschitzka 2000, Turton-Weeks 2001, Yue 2000

CYP3A4 substrates: St. John's wort (a CYP3A4 inducer) may increase the metabolism of CYP3A4 substrates and reduce their effectiveness. St John's wort may decrease the serum concentration of CYP3A4 substrates. Consider therapy modification.Bjornsson 2003, Di 2008, FDA 2013, Izzo 2009, Zhou 2008

Dabigatran etexilate: P-gp/ABCB1 inducers may decrease the serum concentration of dabigatran etexilate. Avoid combination.Pradax June 2008, Pradaxa October 2010

Dabrafenib: St John's wort may decrease the serum concentration of dabrafenib. Consider therapy modification.Tafinlar May 2013

Daclatasvir: St John's wort may decrease the serum concentration of daclatasvir. Avoid combination.Daklinza July 2015

Dapoxetine: Dapoxetine may enhance the adverse/toxic effect of serotonin modulators. Avoid combination.Dunkley 2003, Priligy December 2013, Sternbach 1991

Dasatinib: St. John's wort may decrease the serum concentration of dasatinib. Avoid combination.Eley 2006, Sprycel October 2010

Deflazacort: CYP3A4 inducers (moderate) may decrease serum concentrations of the active metabolite(s) of deflazacort. Avoid combination.Emflaza February 2017

Dextromethorphan: St. John's wort may decrease the serum concentration of dextromethorphan. Consider therapy modification.Russo 2014

Dienogest: St. John's wort may decrease the serum concentration of dienogest. Avoid combination.Natazia May 2010

Digoxin: St. John's wort may decrease the serum concentration of digoxin. Monitor therapy.Arold 2005, Johne 1999, Mueller 2004

Docetaxel: St. John's wort may increase clearance and decrease AUC. Avoid combination.Goey 2014

Dolutegravir: St. John's wort may decrease the serum concentration of dolutegravir. Avoid combination.Tivicay June 2015

Doxorubicin (conventional): St. John's wort may decrease the serum concentration of doxorubicin (conventional). Consider therapy modification.Adriamycin July 2012, Bartlett 1994, Callies 2003, Christen 1993, Doxorubicin October 2013, Erlichman 1993, Hor 2008, McCaffrey 2013, Rushing 1994, Sandanaraj 2008, Sandler 2004, Sella 1994, Sonneveld 2001, Tidefelt 1994, Toffoli 2004, Vaccher 2001

Dronedarone: St. John's wort may decrease the serum concentration of dronedarone. Avoid combination.Multaq June 2009

Efavirenz: St. John's wort may decrease the serum concentration of efavirenz. Avoid combination.Sustiva March 2008

Elbasvir: St John's wort may decrease the serum concentration of elbasvir. Avoid combination.Zepatier January 2016

Eliglustat: St. John's wort may decrease the serum concentration of eliglustat. Avoid combination.Cerdelga August 2014

Elvitegravir: St. John's wort may decrease the serum concentration of elvitegravir. Avoid combination.Genvoya November 2015, Stribild July 2015, Vitekta July 2015

Encorafenib: CYP3A4 inducers (moderate) may decrease the serum concentration of encorafenib. Avoid combination.Braftovi June 2018

Enzalutamide: St. John's wort may decrease the serum concentration of enzalutamide. Avoid combination.Xtandi August 2012

Erlotinib: St. John's wort may decrease the serum concentration of erlotinib. Consider therapy modification.Hamilton 2014, Pillai 2013, Tarceva April 2014

Erythromycin: St. John's wort may decrease the serum concentration of erythromycin. Avoid combination.Russo 2014

Esomeprazole: St. John's wort may decrease the serum concentration of esomeprazole. Avoid combination.Nexium June 2011, Wang 2004

Estriol (systemic): CYP3A4 inducers (moderate) may decrease the serum concentration of estriol (systemic). Monitor therapy.Ovestin September 2015

Estriol (topical): CYP3A4 inducers (moderate) may decrease the serum concentration of estriol (topical). Monitor therapy.Ovestin September 2015

Estrogen derivatives (contraceptive): St. John's wort may decrease the therapeutic effect of estrogen derivatives (contraceptive). Contraceptive failure is possible. Consider therapy modification.Berry-Bibee 2016, Hall 2003, Izzo 2016, Pfrunder 2003, Schwarz 2003, Yue 2000

Everolimus: St. John's wort may decrease the serum concentration of everolimus. Avoid combination.Afinitor October 2010, Zortress March 2010

Exemestane: St. John's wort may decrease the serum concentration of exemestane. Consider therapy modification.Aromasin March 2011

Flibanserin: CYP3A4 inducers (moderate) may decrease the serum concentration of flibanserin. Avoid combination.Addyi August 2015

Fentanyl: St. John's wort may decrease the serum concentration of fentanyl. Monitor therapy.Actiq June 2012, Duragesic April 2014, Kharasch 2004, Morii 2007, Takane 2005

Fexofenadine: St. John's wort taken for several days may decrease the serum concentration of Fexofenadine. Monitor and consider therapy modification.Borrelli 2009, Izzo 2016

Glecaprevir and pibrentasvir: St. John's wort may decrease the serum concentration of glecaprevir and pibrentasvir. Avoid combination.Mavyret August 2017

Gliclazide: St. John's wort may decrease the serum concentration of gliclazide. Monitor therapy.Diamicron July 2016, Xu 2008

Glucocorticoids (oral): St. John's wort may decrease the serum concentration of glucocorticoids (oral). Monitor therapy.Russo 2014

Grazoprevir: St. John's wort may decrease the serum concentration of grazoprevir. Avoid combination.Zepatier January 2016

Guanfacine: St. John's wort may decrease the serum concentration of guanfacine.Intuniv February 2013

HMG-CoA reductase inhibitors: St. John's wort may increase the metabolism and reduce efficacy of HMG-CoA reductase inhibitors. Consider therapy modification.Russo 2014, Sugimoto 2001

Ibrutinib: St. John's wort may decrease the serum concentration of ibrutinib. Avoid combination.de Jong 2015, de Zwart 2016, Imbruvica August 2017

Ibuprofen: St. John's wort may decrease the serum concentration of ibuprofen. Consider therapy modification.Russo 2014

Idelalisib: St. John's wort may decrease the serum concentration of idelalisib. Avoid combination.Zydelig July 2014

Ifosfamide: CYP3A4 inducers (moderate) may decrease serum concentrations of the active metabolite(s) of ifosfamide. CYP3A4 inducers (moderate) may increase serum concentrations of the active metabolite(s) of ifosfamide. Monitor therapy.Chang 1997, Ifex March 2012, Kerbusch 2001

Imatinib: St. John's wort may increase the metabolism of imatinib. Consider therapy modification.Smith 2004

Integrase inhibitors: St. John's wort may decrease the serum concentration of integrase inhibitors. Avoid combination.Jalloh 2017, Stribild August 2012

Irinotecan products: St. John's wort may diminish the therapeutic effect of irinotecan. St. John's wort may decrease serum concentrations of the active metabolite(s) of irinotecan products. Specifically, concentrations of SN-38 may be reduced. St John's wort may decrease the serum concentration of irinotecan products. Avoid combination.Camptosar December 2014, Mathijssen 2002, Onivyde October 2015

Isavuconazonium sulfate: St John's wort may decrease serum concentrations of the active metabolite(s) of isavuconazonium sulfate. Specifically, St John's wort may decrease isavuconazole serum concentrations. Avoid combination.Cresemba March 2015

Ivabradine: St. John's wort may decrease the serum concentration of ivabradine. Avoid combination.Portolés 2006, Procoralan August 2010

Ivacaftor: St. John's wort may decrease the serum concentration of ivacaftor. Avoid combination.Kalydeco January 2012

Ixazomib: St John's wort may decrease the serum concentration of ixazomib. Avoid combination.Ninlaro November 2015

Ixabepilone: St. John's wort may decrease the serum concentration of ixabepilone. Avoid combination.Ixempra May 2010

Ketamine (oral): St. John's wort may decrease the serum concentration of ketamine (oral). Monitor therapy.Peltoniemi 2012

Lapatinib: St. John's wort may decrease the serum concentration of lapatinib. Avoid combination.Smith 2009, Tykerb August 2011

Ledipasvir: P-gp/ABCB1 inducers may decrease the serum concentration of ledipasvir. Avoid combination.Harvoni October 2014

Linagliptin: P-gp/ABCB1 inducers may decrease the serum concentration of linagliptin. Consider therapy modification.Tradjenta May 2011

Linezolid: Linezolid may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Consider therapy modification.Bergeron 2005, Bernard 2003, Clark 2006, DeBellis 2005, Go 2010, Hachem 2003, Hendershot 2001, Jones 2004, Lavery 2001, Lawrence 2006, Lorenz 2008, Mason 2008, McClean 2011, Miller 2011, Morales 2005, Packer 2007, Sola 2006, Steinberg 2007, Strouse 2006, Tahir 2004, Taylor 2006, Thomas 2004, Wigen 2002, Zyvox June 2015

Lumefantrine: St. John's wort may decrease the serum concentration of lumefantrine. Avoid combination.Byakika-Kibwika 2012, Coartem April 2013, Huang 2012, Kredo 2011

Lurasidone: St. John's wort may decrease the serum concentration of lurasidone. Avoid combination.Latuda January 2017

Macimorelin: St. John's wort may decrease the serum concentration of macimorelin. Avoid combination.Macrelin December 2017

Maraviroc: St. John's wort may decrease the serum concentration of maraviroc. Avoid combination.Selzentry August 2007

Meperidine: St. John's wort may decrease the serum concentration of meperidine. Consider therapy modification.Russo 2014

Metaxalone: Metaxalone may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Monitor therapy.Bosak 2014, Martini 2015, Skelaxin March 2018, Surmaitis 2015

Metformin: St John's wort may decrease the renal clearance of metformin. Improved glucose response may occur that has been shown to result from an acute increase in insulin response, which is independent of the glucose-lowering action of metformin.Stage 2015

Methadone: St. John's wort may decrease the serum concentration of methadone. Monitor therapy.Izzo 2016

Methylene blue: Methylene blue may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Avoid combination.Bach 2004, Grubb 2012, Hanna 2014, Harvey 2010, Hencken 2016, Heritier Barras 2010, Izdes 2014, Kartha 2006, Khan 2007, Khavandi 2008, Larson 2015, Majithia 2006, Martindale 2003, Martino 2016, Mathew 2006, McDonnell 2012, Methylene blue September 2014, Ng 2008, Nicolaou 2016, Pollack 2009, Provayblue April 2014, Ramsay 2007, Rowley 2009, Schwiebert 2009, Shanmugam 2008, Smith 2015, Stanford 1999, Stanford 2010, Sweet 2007, Top 2014

Methylphenidate: Methylphenidate may enhance the adverse/toxic effect of serotonin modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy.Ishii 2008, Metadate February 2017, Park 2010, Turkoglu 2015

Metoclopramide: Serotonin modulators may enhance the adverse/toxic effect of metoclopramide. This may manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy.Chopra 2004, Fisher 2002, Gambassi 2006, Karki 2003, Kaufman 2006, Kim 2007, Kohen 2007, Kontaxakis 2003, Kontaxakis 2003, Marlowe 2006, Matsumoto 2005, Metozolv ODT October 2011, Stevens 2008, Verre 2008

Midostaurin: St John's wort may decrease the serum concentration of midostaurin. Avoid combination.Dutreix 2013, Rydapt April 2017

Mifepristone: St. John's wort may decrease the serum concentration of mifepristone. Avoid combination.Korlym February 2012, Mifeprex April 2009

Naloxegol: St. John's wort may decrease the serum concentration of naloxegol. Avoid combination.Movantik September 2014

Neratinib: CYP3A4 inducers (moderate) may decrease the serum concentration of neratinib. Avoid combination.Nerlynx July 2017

Nifedipine: St. John's wort may decrease the serum concentration of nifedipine. Consider therapy modification.Izzo 2016, Russo 2014

Nilotinib: St. John's wort may decrease the serum concentration of nilotinib. Avoid combination.Tanaka 2011, Tasigna October 2017

NiMODipine: St. John's wort may decrease the serum concentration of nimodipine. Avoid combination.Nimodipine April 2015

Nintedanib: Combined inducers of CYP3A4 and P-gp may decrease the serum concentration of nintedanib. Avoid combination.Ofev October 2014

Nisoldipine: CYP3A4 inducers (moderate) may decrease the serum concentration of nisoldipine. Avoid combination.Michelucci 1996, Sular March 2014

Olaparib: CYP3A4 inducers (moderate) may decrease the serum concentration of olaparib. Avoid combination.Dirix 2016, Lynparza January 2018

Omeprazole: St. John's wort may decrease the serum concentration of omeprazole. Avoid combination.Prilosec June 2011, Wang 2004

Opioid analgesics: Opioid analgesics may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Monitor therapy.Abadie 2015, Ailawadhi 2007, Alkhatib 2010, Altman 2007, Asch 1988, Brown 1996, Bush 2006, Das 2008, Davis 2013, Dougherty 2002, Egberts 1997, El-Okdi 2014, Falls 2014, FDA 2016, Filter 2007, Fluoxetine 2004, Gillman 1995, Gillman 2005, Gnanadesigan 2005, Gollapudy 2012, Guo 2009, Hansen 1990, Hillman 2015, Houlihan 2004, Hunter 2006, Insler 1994, Isenberg 2008, John 2007, Karunatilake 2006, Kesavan 1999, Kirschner 2010, Kitson 2005, Lamberg 2014, Lange-Asschenfeldt 2002, Lantz 1998, Larson 2015, Lee 2009, Mahlberg 2004, Marechal 2011, Martinez 2008, Mason 1997, Mateo-Carrasco 2015, Meyer 1981, Mittino 2004, Noble 1992, Ozkardesler 2008, Peacock 2011, Pedavally 2014, Rang 2008, Robles 2015, Rosebraugh 2001, Roy 2003, Shahani 2012, Shakoor 2014, Song 2013, Tashakori 2010, Tissot 2003, Venlafaxine 2004, Vizcaychipi 2007, Zornberg 1991

Osimertinib: St. John's wort may decrease the serum concentration of osimertinib. Avoid combination.Tagrisso August 2016

Oxycodone: St. John's wort may decrease the serum concentration of oxycodone. Monitor therapy.Nieminen 2010

Palbociclib: St. John's wort may decrease the serum concentration of palbociclib. Avoid combination.Dresser 2003, Ibrance February 2016, Imai 2008, Sugimoto 2001, Wang 2001

Paliperidone: St. John's wort may decrease the serum concentration of paliperidone. Consider therapy modification.Invega April 2014, Invega Sustenna November 2014, Invega Trinza May 2015, Ono 2002, Spina 2000, Vermeulen 2007, Yasui-Furukori 2013

Pantoprazole: St. John's wort may decrease the serum concentration of pantoprazole. Consider therapy modification.Russo 2014

Perampanel: St. John's wort may decrease the serum concentration of perampanel. Consider therapy modification.Fycompa October 2012

P-gp/ABCB1 substrates: P-gp/ABCB1 inducers may decrease the serum concentration of P-gp/ABCB1 substrates. P-gp inducers may also further limit the distribution of P-gp substrates to specific cells/tissues/organs where P-gp is present in large amounts (eg, brain, T-lymphocytes, testes). Monitor therapy.Albermann 2005, Callaghan 2008, Gurley 2008, Ho 2005, Kim 2002, Kivistö 2004, Leslie 2005, Mueller 2004, Teng 2008

Pimavanserin: St. John's wort may decrease the serum concentration of pimavanserin. Monitor therapy.Nuplazid April 2016]

Piperaquine: St. John's wort may decrease the serum concentration of piperaquine. Avoid combination.Eurartesim September 2017

Pitolisant: St. John's wort may decrease the serum concentration of pitolisant. Monitor therapy.Wakix March 2017, Wakix March 2017

Pomalidomide: P-gp/ABCB1 inducers may decrease the serum concentration of pomalidomide. Avoid combination.Pomalyst February 2013

Ponatinib: St. John's wort may decrease the serum concentration of ponatinib. Avoid combination.Iclusig December 2012

Porfimer: Photosensitizing agents may enhance the photosensitizing effect of porfimer. Monitor therapy.Drucker 2011, Lankerani 2004, Naldi 1999, Photofrin June 2011

Progestins (contraceptive): St. John's wort may decrease the therapeutic effect of progestins (contraceptive). Contraceptive failure is possible. Consider therapy modification.Berry-Bibee 2016, Yue 2000

Propafenone: St. John's wort may decrease the serum concentration of propafenone. Monitor therapy.Castel 1990, Dilger 1999, Dilger 2000, Rythmol December 2014

Protease inhibitors: St. John's wort may increase the metabolism of protease inhibitors. Avoid combination.Aptivus April 2011, Crixivan October 2009, Invirase January 2010, Jalloh 2017, Kaletra February 2011, Lexiva September 2009, Norvir November 2009, Piscitelli 2000, Prezista February 2008, Reyataz January 2010

Quetiapine: Quetiapine may enhance the serotonergic effect of St John's wort. This could result in serotonin syndrome. St John's wort may decrease the serum concentration of quetiapine. Consider therapy modification.Bakken 2011, Grimm 2006, Hasselstrom 2004, Seroquel April 2013, Seroquel XR April 2013, Wong 2001

Radotinib: St. John's wort may decrease the serum concentration of radotinib. Consider therapy modification.Supect 2014

Ranolazine: St. John's wort may decrease the serum concentration of ranolazine. Avoid combination.Ranexa July 2011

Regorafenib: St. John's wort may decrease the serum concentration of regorafenib. Avoid combination.Stivarga September 2012

Reverse transcriptase inhibitors (non-nucleoside): St. John's wort may decrease the serum concentration of reverse transcriptase inhibitors (non-nucleoside). Specifically, St. John's wort may increase the metabolism of reverse transcriptase inhibitors (non-nucleoside). Avoid combination.de Maat 2001, Edurant May 2011, Intelence September 2009, Jalloh 2017, Rescriptor May 2008, Sustiva September 2009, Viramune May 2011

Ribociclib: St. John's wort may decrease the serum concentration of ribociclib. Avoid combination.Kisqali March 2017

Rivaroxaban: St. John's wort may decrease the serum concentration of rivaroxaban. Avoid combination.Xarelto July 2011

Romidepsin: St. John's wort may decrease the serum concentration of romidepsin. Avoid combination.Istodax June 2013

Serotonin modulators: Serotonin modulators may enhance the adverse/toxic effect of other serotonin modulators. The development of serotonin syndrome may occur. Consider therapy modification.Dunkley 2003, Izzo 2016, Milton 2007

Simeprevir: St. John's wort may decrease the serum concentration of simeprevir. Avoid combination.Olysio November 2013

Sofosbuvir: P-gp/ABCB1 inducers may decrease the serum concentration of sofosbuvir. Avoid combination.Harvoni November 2015, Sovaldi December 2013

Sonidegib: CYP3A4 inducers (moderate) may decrease the serum concentration of sonidegib. Avoid combination.Odomzo July 2015

Sorafenib: St. John's wort may decrease the serum concentration of sorafenib. Avoid combination.Nexavar October 2011

Sunitinib: St. John's wort may decrease the serum concentration of sunitinib. Avoid combination.Sutent May 2011

Tacrolimus (systemic): St. John's wort may decrease the serum concentration of tacrolimus (systemic). Consider therapy modification.Mai 2003

Tedizolid: Tedizolid may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Monitor therapy.Boyer 2005, Clark 2006, DeBellis 2005, Flanagan 2013, Lavery 2001, Lawrence 2006, Sivextro June 2014, Wigen 2002

Telaprevir: St. John's wort may decrease the serum concentration of telaprevir. Avoid combination.Incivek May 2011

Tenofovir alafenamide: St John's wort may decrease the serum concentration of tenofovir alafenamide. Avoid combination.Descovy April 2016, Genvoya November 2015, Odefsey March 2016

Theophylline: St. John's wort may decrease the serum concentration of theophylline. Monitor therapy.Russo 2014

Thiopental: St. John's wort may enhance the CNS depressant effect of thiopental. Monitor therapy.Thiopental January 2014

Tipranavir: St. John's wort may decrease the serum concentration of tipranavir. Avoid combination.Aptivus October 2007

Tolbutamide: St John's wort may increase the hypoglycemic effects of tolbutamide. Consider therapy modification.Russo 2014

Tolvaptan: St. John's wort may decrease the serum concentration of tolvaptan. Avoid combination.Samsca February 2012, Shoaf 2012

Trabectedin: St. John's wort may decrease the serum concentration of trabectedin. Avoid combination.Machiels 2014, Yondelis July 2014

Tricyclic antidepressants: St. John's wort may increase the metabolism and decrease the serum concentration of tricyclic antidepressants. The risk of serotonin syndrome may theoretically be increased. Consider therapy modification.Izzo 2016, Johne 2002

Ulipristal: St. John's wort may decrease the serum concentration of ulipristal. Avoid combination.Ella June 2014 Fibristal June 2013]

Valbenazine: St. John's wort may decrease the serum concentration of valbenazine. Avoid combination.Ingrezza April 2017

Vandetanib: St. John's wort may decrease the serum concentration of vandetanib. Avoid combination.Martin 2011, Vandetanib April 2011

Velpatasvir: CYP3A4 inducers (moderate) may decrease the serum concentration of velpatasvir. Avoid combination.Epclusa June 2016, Mogalian 2016

Venetoclax: CYP3A4 inducers (moderate) may decrease the serum concentration of venetoclax. Avoid combination.Venclexta April 2016

Verapamil: St. John's wort may decrease the serum concentration of verapamil. Consider therapy modification.Izzo 2016, Russo 2014

Verteporfin: Photosensitizing agents may enhance the photosensitizing effect of verteporfin. Monitor therapy.Drucker 2011, Lankerani 2004, Naldi 1999, Visudyne June 2012

Vincristine (liposomal): St. John's wort may decrease the serum concentration of vincristine (liposomal). Avoid combination.Marqibo August 2012, Villikka 1999

Vinflunine: St. John's wort may decrease the serum concentration of vinflunine. Avoid combination.Javlor September 2014, Zhao 2007

Vitamin K antagonists: St. John's wort may increase the metabolism of vitamin K antagonists. Risk of clotting may be increased. Consider therapy modification.De Smet 2000, Izzo 2016, Jiang 2004, Xalkori August 2011

Vorapaxar: St. John's wort may decrease the serum concentration of vorapaxar. Avoid combination.Kosoglou 2013, Zontivity May 2014

Voriconazole: St. John's wort may decrease the serum concentration of voriconazole. Avoid combination.Rengelshausen 2005, Vfend March 2008

Zolpidem: St. John's wort may decrease the serum concentration of zolpidem. Consider therapy modification.Hojo 2011, Izzo 2016,

Medications for heart failure

St John's wort interacts significantly with digoxin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, amiodarone, and warfarin; avoid use in patients with heart failure.Page 2016

Other interaction data

Some studies have reported insignificant pharmacokinetic drug interactions with natural products. Limited information, a lack of consistent use of standardized product formulations, as well as potentially high interpatient variability in clinical response warrants cautious interpretation and/or application of these data in practice.

A low-hyperforin (3.5 mg) St. John's wort extract induced less than a 12% change in the median AUCs of alprazolam, caffeine, tolbutamide, and digoxin; these interactions were deemed to be clinically insignificant interactions.Arold 2005

Adverse Reactions

A systematic review of current evidence concluded that Hypericum extracts are well tolerated and safe, aside from the potential for unintended interactions with other drugs.Clauson 2008,, Knüppel 2004, Schulz 2006, Stevinson 1999 A number of studies report no serious adverse effects, and in a review of clinical trials, St. John's wort was associated with fewer and milder adverse reactions compared with conventional antidepressants.Stevinson 1999 Adverse effects from H. perforatum were rare and mild. The most frequently described adverse reactions in clinical trials were GI complaints (eg, dry mouth, nausea, change in bowel habits), itching, rash, photosensitization, fatigue, dizziness, confusion, jitteriness, restlessness, insomnia, sedation, sleep disorders, and headache, most of which are attributed to hypericin and pseudohypericin content.Knüppel 2004, Qaseem 2016, Russo 2014, Schulz 2006, Stevinson 1999 Induction of mania has been associated with St. John's wort.Moses 2000, Nierenberg 1999 The volatile oil of St. John's wort is an irritant.Newall 1996 A case report also associated use of St. John's wort with hyponatremia that resulted from syndrome of inappropriate secretion of antidiuretic hormone (SIADH), which has been reported with all classes of synthetic antidepressants.Jones 2014 The contribution of St. John's wort consumption could not be ruled out in a case of development of an extremely rare form of hepatocellular carcinoma in a patient with chronic alcoholism.Lampri 2014

One case report describes acute neuropathy after sun exposure in a patient using St. John's wort.Bove 1998 When ingested, hypericin can induce photosensitization characterized by inflammation of the skin and mucous membranes (including human keratinocytes and lens epithelial cells) following exposure to light, which generates reactive oxidative species that damage axonal membranes directly and activates a calcium-ion channel (transient receptor potential cation channel A1, TRPA1) expressed on peripheral sensory neurons. Pseudohypericin and hyperforin also act as photoirritants.Araya 1981, Beattie 2005, Bernd 1999, He 2004, Hohmann 2016, Kümper 1989, Schempp 1999 However, most reports of photosensitivity have been limited to patients taking excessive doses of H. perforatum, primarily to treat HIV.Murray 1997 For example, both IV (eg, 0.5 mg/kg twice weekly) and oral dosing (eg, 0.5 mg/kg/day) of H. perforatum caused phototoxicity in 30 patients with HIV, with 16 of 30 discontinuing treatment for this reason.Jacobson 2001 Adverse phototoxic neurological effects have also been shown to have a gender-specific association. Specifically 5 of 6 females, but 0 of 6 males, developed dermatologic and neurologic symptoms on sun-exposed areas of the back of the hands and perioral and nasal areas within 6 days of increasing the dose of St. John's wort from 300 mg to 600 mg (3 times daily). Gender specificity for neuropathic effects has also been noted in the German Federal Institute for Drugs and Medical Devices. Gender differences in the dermal expression of interleukins may be involved in this differential response.Hohmann 2016 An interaction of constituents, as found in the whole plant, has been shown to reduce the toxicity of hypericum extracts.Hammer 2014

Long-term treatment (up to 21 days) with St. John's wort significantly increased 2-hour plasma glucose levels (by approximately 40%), total glucose AUC (by 18%), and incremental blood glucose AUC (by 48%) in 10 healthy men. This effect was not only sustained but increased at 6 weeks following the last dose (240 to 294 mg of dry extract and 900 mcg total hypericin twice daily). Six weeks after the last dose, total glucose AUC increased by an additional 17% and incrementally by an additional 31%. Insulin disposition indices suggest that St. John's wort reduces glucose-stimulated insulin secretion during the oral glucose tolerance test.Stage 2016

Toxicology

Limited information on genotoxicity exists. Potent inhibition of sperm motility was observed in vitro.Ondrizek 1999

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