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
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
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
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
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
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
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
3-Hydroxy lauric acid obtained from H. perforatum exhibited light-independent, anti-HIV activity in an in vitro experiment.Maury 2009
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
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
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
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
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
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
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
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
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
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.
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.
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
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.
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
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
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
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
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,
Antihepaciviral combination products: CYP3A4 inducers (moderate) may decrease the serum concentration of antihepaciviral combination products. Avoid combination.Technivie July 2015, Viekira Pak July 2015
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
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
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
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
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
Crizotinib: St. John's wort may decrease the serum concentration of crizotinib. Avoid combination.Xalkori August 2011
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Midostaurin: St John's wort may decrease the serum concentration of midostaurin. Avoid combination.Dutreix 2013, Rydapt April 2017
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
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
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
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
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
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
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
Telaprevir: St. John's wort may decrease the serum concentration of telaprevir. Avoid combination.Incivek May 2011
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
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,
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
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
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
Limited information on genotoxicity exists. Potent inhibition of sperm motility was observed in vitro.Ondrizek 1999
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