St. John's Wort

Health Care Professional Information

Scientific Name
Hypericum perforatum
Common Name

Saint John’s wort, hypericum, goatweed, God’s wonder plant, witches herb

Clinical Summary

St. John’s wort is a perennial herb indigenous to Europe, West Asia, and North Africa, and now prevalent in many parts of the world. The flowering tops are reputed for their medicinal properties and the herb has a centuries-long history as a remedy for headaches, kidney problems, and nerve disorders. It was also used by Native Americans for wound healing, snakebites, and diarrhea. Today, St. John’s wort is used in several European countries as an antidepressant, and to treat anxiety, sleep and seasonal affective disorder. It is marketed as a dietary supplement in the U.S. for depression and other psychological symptoms.

St. John’s wort is one of the most extensively studied herbs, with active constituents hyperforin and hypericin being the focus of most research. Lab studies show that St. John's wort has neuroprotective properties (1) and may relieve neuropathic pain (2). Clinical studies suggest St. John's wort may be as effective as selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (3), fluoxetine (4) (5) and citalopram (6) (7) for mild to moderate depression; it was also shown to be a cost-effective alternative to generic antidepressants (75). Reductions in depression were also sustained with continued use (8). However, data are inconsistent when all types of depression are analyzed (9) (10) and some randomized trials have found St. John's wort ineffective for both major (11) and minor depression (12). A few studies also indicate efficacy of St. John's wort in the management of premenstrual syndrome (13), and vasomotor symptoms in peri- and postmenopausal women (14), but failed to show any benefit for attention-deficit/hyperactivity disorder in children and adolescents (15) and in individuals with stomatodynia (16). Another study suggests that St. John's wort may enhance the effect of clopidogrel in patients who have undergone percutaneous coronary intervention (17) but more studies are needed.

St. John's wort has many documented interactions with conventional drugs through the induction of cytochrome P450 (CYP450) enzymes resulting in reduced efficacy or treatment failure, as well as several associated adverse effects. Its use may also cause photosensitivity (18) and has been associated with increased risk of cataracts (19) (20). Therefore, patients should speak with their physician or pharmacy before using this product.

Purported Uses
  • Depression
  • Fatigue
  • Insomnia
  • Pain
  • Premenstrual syndrome
  • Seasonal affective disorder
  • Wound healing
Constituents
  • Anthraquinones: Napthodianthrones, including hypericin and pseudohypericin
  • Phloroglucinols: Hyperforin, adhyperforin
  • Flavonoids: Hyperin, hyperoside, quercetin, kaempferol, rutin
  • Bioflavonoids: Amenotoflavone
  • Phenols: Caffeic, chlorogenic, para-coumaric, para-hydroxybenzoic acid, hyperfolin
  • Volatile oils: Methyl-2-octane, trace amounts monoterpenes (limonene), and sesquiterpenes (caryophyllene, humulene)
  • Tannins: Proanthocyanidins
    (36)
Mechanism of Action

In vitro studies have shown hypericum to inhibit serotonin, norepinephrine, and dopamine reuptake by neurons (22) (23). Although earlier data suggested monoamine oxidase inhibition, further investigation demonstrated this inhibition to be insignificant in vivo (24). More recently hyperforin, the main constituent associated with serotonin reuptake inhibition, was shown to activate transient receptor potential C6 channels in vitro inducing neurite outgrowth and possibly influencing monoamine uptake (25), and to stimulate the development and function of oligodendrocytes (26). Hypericin suppresses voltage-dependent calcium channel and mitogen-activated protein kinase activity and evokes glutamate release, adding further clues to its function in the brain (27). Hypericin-induced phototoxicity appears to be oxygen-dependent and may involve intracellular pH reduction or mediation by the TNF-related apoptosis inducing ligand receptor system (28). Incidental reporting also suggests that photoactivated hypericin can cause the demyelination of cutaneous axons (29).

Mechanisms by which St. John’s wort induces or modulates different enzymes, altering the pharmacokinetics of corresponding drug substrates, continue to be evaluated. Hyperforin induces CYP 3A4 through activation of the pregnane X receptor (30) and St. John’s wort extract modulates UDP-glucuronosyltransferase (31) and P-glycoprotein (P-gp) activity via protein kinase C (PKC) (32). Analgesic and CNS activity may be due to its bioflavonoid content (21) as well as through inhibition of PKC isoforms and their phosphorylation (2).

The enolized beta-dicarbonyl system contained in hyperforin may play a central role in its antiangiogenic activity, but the chemical and metabolic instability of hyperforin itself has led to the search for more stable derivatives (33). In animal models, hyperforin and its stabilized derivative aristoforin suppress lymphatic endothelial cell growth and lymphangiogenesis by inducing cell cycle arrest or apoptosis (34). Hyperforin also reversed P-gp and breast cancer resistance protein activity in human myeloid leukemia cell lines (35).

Pharmacokinetics

Hypericin: Oral administration peak concentration at approximately 2 hours, elimination half-life approximately 25 hours. Steady state concentrations with three times daily dosing occurred by day 4. Terminal half-life is 42 hours.

Hyperforin: Oral administration peak concentration occurred at approximately 3.5 hours. Elimination half-life is approximately 9 hours. Steady state concentration with 300 mg St. John's wort (standardized to 14.8 mg hyperforin) equal to 100 ng/ml.

Pseudohypericin: Oral administration peak concentration at approximately 30 minutes. Terminal half-life is approximately 23 hours. (36)

Warnings
Contraindications
Adverse Reactions

Common: Headache, nausea, dry mouth, sleepiness, and gastrointestinal upset (5).
Infrequent: Photosensitivity (18), neuropathy (29), increased prothrombin time (21).
Case reports
Acute transplant rejection: Two patients with prior heart transplantation due to end-stage ischemic cardiomyopathy who were maintained on immunosuppressive regimens that included cyclosporin experienced transplant rejection directly linked to the use of St. John’s wort. After discontinuation of the supplement, plasma cyclosporin returned to therapeutic values (45). A subsequent report of 45 kidney or liver transplant recipients also describe rejection episodes or declines in trough levels of cyclosporin (average, 49%) linked to ingestion of St. John’s wort. In many cases, these patients did not inform their healthcare team about their ingestion of this supplement (46).

Cardiovascular collapse: Hypotension without anaphylactic symptoms occurred shortly after induction of general anesthesia was potentially linked to long-term use of St. John’s wort in a patient (47).

Severe drug-induced acute hepatitis: A 61-year-old woman with chronic hepatitis C receiving pegylated interferon α obtained undetectable qualitative hepatitis C virus that persisted after treatment suspension. The patient revealed use of St. John's wort for depressed mood in the preceding 6 weeks. She was hospitalized after continued worsening of liver function tests and tested positive for antinuclear antibodies. Elevated levels slowly declined after methylprednisolone treatment, but a new flare occurred with steroid tapering. Liver function tests returned to baseline levels after 6 months of prednisone treatment. It was determined the combination of pegylated interferon α and St. John's wort resulted in severe acute hepatitis in this patient (48).

Mania: Occurred in 3 patients with underlying bipolar disorder but resolved promptly in 2 patients following discontinuation while the third experienced persistent agitation for several months (36).

Serotonin syndrome: Hypertension, diaphoresis, agitation, dizziness, and weakness with acute onset occurred in 1 patient following 10 days of St. John's wort, but resolved following supportive care and supplement discontinuation (49). In a case series, five elderly patients who combined prescription antidepressants with St. John's wort were clinically diagnosed with central serotonergic syndrome (44).

Erythroderma: Developed 4 days after initiation of St. John's wort affecting both light-exposed and non light-exposed areas of skin, and resolved after 5 weeks with concomitant oral steroids (50).

Hypericin-induced radiation recall dermatitis: A 65-year-old man with completely resected squamous cell carcinoma of the epiglottis who received adjuvant locoregional radiotherapy (RT) developed unusual intensive skin reactions during treatment. The skin was completely bland at follow-up, but half a year later the previously irradiated skin became erythematous. The patient took hypericin for depressive mood during and months after RT without informing the physician. Local application of a steroid cream diminished symptoms that would return after the end of steroid therapy. Symptoms eventually disappeared with the discontinuation of hypericin (40).

Photosensitivity reactions: Three cases of photosensitivity reactions occurred in individuals who used topical and/or oral St. John's wort preparations prior to sun exposure or undergoing phototherapy (18). Although 2 of the 3 cases were complicated by pre-existing disease and therapy, St. John's wort photosensitivity was still the identified cause, and in the patient with pre-existing disease did not entirely resolve.

Subacute toxic neuropathy: A 35-year-old woman who took St. John’s Wort for mild depression developed stinging pain on sun-exposed areas after 4 weeks which worsened during and after sun exposure. Pain was provoked by light touch or air movement. Symptoms began to improve 3 weeks after St. John’s wort was withdrawn, and disappeared after 2 months (29).

Sexual dysfunction: Decreased sexual libido was normalized following discontinuation of St. John's wort (51).

Withdrawal syndrome: Nausea, anorexia, dry retching, dizziness, dry mouth, thirst, cold chills, and extreme fatigue occurred in a patient within 24 hours of stopping intake of St. John's wort after 32 days of treatment (52).

Prolonged facial dystonia: Reported in a 58-year-old Caucasian woman following use of bupropion along with St. John's wort (53).
 

Herb-Drug Interactions

CYP450 3A4 (57) and CYP 2C9 (58) substrates: St. John's wort induces these isoenzymes, affecting the metabolism of certain medications and reducing serum concentrations (59). Drugs metabolized by these enzymes include:

  • HIV protease inhibitors: Blood levels of indinavir and ritonavir can be significantly reduced, resulting in increased HIV viral load and development of viral resistance (60) (61).
  • HIV non-nucleoside reverse transcriptase inhibitors: Increased oral clearance and lowered plasma concentrations of nevirapine possibly resulting in antiretroviral resistance and treatment failure (62).
  • Cyclosporin / Tacrolimus: Blood levels of cyclosporin (45) (46) or tacrolimus (63) (64) can be significantly reduced, resulting in decreased efficacy or acute transplant rejection.
  • Diltiazem / Nifedipine: Blood levels of diltiazem or nifedipine can be reduced, resulting in decreased efficacy (36).
  • Irinotecan: Due to changes in hepatic metabolism caused by St. John's wort, levels of irinotecan metabolite SN-38 may be lowered by as much as 40% for up to 3 weeks following discontinuation of St. John's wort (37).
  • Imatinib: Increased clearance (38) (39).
  • Docetaxel: Subtherapeutic docetaxel concentrations may result when docetaxel is administered to patients who regularly use St. John's wort (65).
  • Warfarin: May increase or decrease activity when administered concomitantly. Internal normalization ratio should be monitored routinely (66).
  • Clopidogrel: May enhance clopidogrel-induced platelet inhibition (17).
  • Triptans: Increased serotonergic effect and possible serotonin syndrome when combined with sumatriptan, naratriptan, rizatriptan, or zolmitriptan (36).
  • SSRIs: Increased serotonergic effect and possible serotonin syndrome when combined with citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline (49).
  • Tricyclic Antidepressants: Increased serotonergic effect and possible serotonin syndrome when combined with nefazodone, amitriptyline, or imipramine. Possible reduction in efficacy of antidepressants due to changes in metabolism (36).
  • Zolpidem: decreased plasma concentration (67).
  • Oral Contraceptives: May reduce blood levels resulting in decreased efficacy (i.e., breakthrough bleeding or pregnancy) (43).
  • Alcohol: May result in increased sedation (36).
  • Alprazolam: May reduce blood levels, resulting in decreased efficacy (57).
  • Dextromethorphan: May reduce blood levels, resulting in decreased efficacy (57).
  • Simvastatin: Increased clearance, resulting in elevated LDL cholesterol (68).
  • Atorvastatin: Increased clearance, resulting in elevated LDL cholesterol (69).
  • Rosuvastatin: Reduces efficacy via increased clearance (70).
  • Oxycodone: Reduces oxycodone plasma concentrations, significantly reducing its effectiveness (71).
  • Gliclazide: Increased clearance (58).
  • Clozapine: Reduces plasma level of clozapine (73).
  • Methotrexate: Increases exposure and toxicity of Methotrexate in rats(74).

    P-gp substrates: St. John's wort induces intestinal P-gp, resulting in decreased absorption and lowered plasma concentrations of certain drugs including digoxin (54), talinolol (55), and fexofenadine (56). It may also produce severe adverse effects in conjunction with pegylated interferon α (48).

    UGT (Uridine 5'-diphospho-glucuronosyltransferase) substrates: St. John's wort modulates UGT enzymes in vitro and may increase the side effects of drugs such as acetaminophen (31).
Literature Summary and Critique
Szegedi A, et al. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 2005;330 (7490):503.
A total of 251 patients with acute major depression were given either 900 mg/day hypericum extract WS 5570 three times a day or 20 mg paroxetine, an SSRI, once a day for six weeks. At two weeks, the doses were increased to 1800 mg/day of hypericum and 40 mg paroxetine for patients who did not respond to the treatments. Researchers found that both the treatment groups showed significant decrease in depression scores. St. John's wort appears to be as effective as paroxetine in the management of severe depression. However, care should be taken while taking St. John's wort as it can interact with other drugs.

Fava M, et al. A double-blind, randomized trial of St John’s wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol. 2005;25:441–447.
St. John’s wort extract vs fluoxetine and placebo was evaluated in this double-blind trial. After single-blind washout, 135 patients with major depressive disorder were randomized to 12 weeks of therapy with St. John’s wort extract 900 mg/d, fluoxetine 20 mg/d, or placebo. HAMD-17 and analysis of covariance (ANCOVA) compared differences in endpoint HAMD-17 scores across the 3 treatment groups, treating baseline HAMD-17 as the covariate. ANCOVA analyses showed lower mean HAMD-17 scores at endpoint for St. John’s wort (n = 45; mean ± SD, 10.2 ± 6.6) vs fluoxetine group (n = 47; 13.3 ± 7.3; p < 0.03) with a trend toward same relative to placebo (n = 43; 12.6 ± 6.4; p = 0.096). There was also a trend toward higher rates of remission with St. John’s wort (38%) compared with fluoxetine (30%) and placebo (21%). Investigators found St. John’s wort to be safe and well tolerated and significantly more effective than fluoxetine with a trend toward superiority over placebo. Authors also conclude that the smaller than planned sample size may account for the lack of statistically significant advantage of St. John’s wort over placebo.

Kasper S, et al. Continuation and long-term maintenance treatment with Hypericum extract WS((R)) 5570 after recovery from an acute episode of moderate depression - A double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol. Nov 2008;18(11):803-813.
To determine the long-term effects of sustained treatment with hypericum extract WS 5570 in 426 individuals with recurrent, moderate depression (defined as Hamilton Depression Rating Scale [HAMD] total score ≥20 and ≥3 previous episodes in 5 years), this double-blind, randomized, placebo-controlled study was performed. Participants were given WS 5570 (3x300 mg/day) or placebo for 26 weeks during which relapse rates, time to relapse, HAMD scores, as well as adverse events were assessed. Time until relapse was significantly greater and HAMD scores were lower in the WS 5570-treated group as compared with the placebo group. Also, there was no difference in adverse events reported between the 2 groups. Thus, in individuals treated for recurrent, moderate depression, WS 5570 maintenance therapy reduced relapse; however, further studies are required to determine if WS 5570 maintenance therapy is comparable to conventional maintenance therapies.

Gastpar M, et al. Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry. 2006;39:66-75.
This double-blind, placebo-controlled, multicentre phase III trial enrolled 388 patients suffering from moderate depression. Participants were randomized to one of 3-arms: hypericum extract 900 mg, citalopram 20 mg, or placebo using a once-daily dosage regimen for 6 weeks. The course of depression was documented using the HAMD, von Zerssen’s Adjective Mood Scale (BfS), and the Clinical Global lmpression (CGI) scales for safety and tolerability. HAMD scores demonstrated statistically significant therapeutic equivalence for hypericum extract vs citalopram (both 10.3 ± 6.4, p < 0.0001) as well as superiority over placebo (13.0 ± 6.9, p < 0.0001). At treatment end, 54.2 % of participants using hypericum extract were deemed therapy responders vs 55.9% citalopram and 39.2% placebo. Significantly more adverse events were documented for citalopram (53.2%, vs hypericum 17.2% and placebo 30%). Investigators concluded that hypericum extract was noninferior to citalopram, significantly superior to placebo, and had better safety and tolerability than citalopram.

Singer A, et al. Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine. 2011;18:739-42.
This reanalysis of the Gastpar et al study (above) evaluated duration of response and relapse/recurrence. In 30 of 154 responders (19.5%), relapse was highest with citalopram (14 of 54), and lowest with hypericum extract (8 of 54) and placebo (8 of 46) groups. No differences in relapse severity were observed. Response duration was longest with hypericum (1817 days, vs citalopram, 1755 days; placebo, 802 days). The authors determined that hypericum extract was more efficient in lowering relapse/recurrence rates of responders and increased response duration compared with citalopram and placebo.

Dosage (Inside MSKCC Only)
This field is only visible to only OneMSK users.
References
  1. Griffith TN, Varela-Nallar L, Dinamarca MC, et al. Neurobiological effects of Hyperforin and its potential in Alzheimer's disease therapy. Curr Med Chem. 2010;17(5):391-406.
  2. Galeotti N, Vivoli E, Bilia AR, et al. St. John's Wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity. Biochem Pharmacol. May 1 2010;79(9):1327-1336.
  3. Szegedi A, Kohnen R, Dienel A, et al. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ. Mar 5 2005;330(7490):503.
  4. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. Mar 2000;15(2):61-68.
  5. Fava M, Alpert J, Nierenberg AA, et al. A Double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol. Oct 2005;25(5):441-447.
  6. Gastpar M, Singer A, Zeller K. Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry. Mar 2006;39(2):66-75.
  7. Singer A, Schmidt M, Hauke W, et al. Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine. Jun 15 2011;18(8-9):739-742.
  8. Kasper S, Volz HP, Moller HJ, et al. Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression—a double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol. Nov 2008;18(11):803-813.
  9. Linde K, Mulrow CD, Berner M, et al. St John's wort for depression. Cochrane Database Syst Rev. 2005(2):CD000448.
  10. Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008(4):CD000448.
  11. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA. Apr 18 2001;285(15):1978-1986.
  12. Rapaport MH, Nierenberg AA, Howland R, et al. The treatment of minor depression with St. John's Wort or citalopram: failure to show benefit over placebo. J Psychiatr Res. Jul 2011;45(7):931-941.
  13. Canning S, Waterman M, Orsi N, et al. The efficacy of Hypericum perforatum (St John's wort) for the treatment of premenstrual syndrome: a randomized, double-blind, placebo-controlled trial. CNS drugs. Mar 2010;24(3):207-225.
  14. Abdali K, Khajehei M, Tabatabaee HR. Effect of St John's wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: a randomized, double-blind, placebo-controlled study. Menopause. Mar 2010;17(2):326-331.
  15. Weber W, Vander Stoep A, McCarty RL, et al. Hypericum perforatum (St John's wort) for attention-deficit/hyperactivity disorder in children and adolescents: a randomized controlled trial. JAMA. Jun 11 2008;299(22):2633-2641.
  16. Sardella A, Lodi G, Demarosi F, et al. Hypericum perforatum extract in burning mouth syndrome: a randomized placebo-controlled study. J Oral Pathol Med. Aug 2008;37(7):395-401.
  17. Lau WC, Welch TD, Shields T, et al. The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol. Jan 2011;57(1):86-93.
  18. Lane-Brown MM. Photosensitivity associated with herbal preparations of St John's wort (Hypericum perforatum). Med J Aust. Mar 20 2000;172(6):302.
  19. He YY, Chignell CF, Miller DS, et al. Phototoxicity in human lens epithelial cells promoted by St. John's Wort. Photochem Photobiol. Nov-Dec 2004;80(3):583-586.
  20. Booth JN, 3rd, McGwin G. The association between self-reported cataracts and St. John's Wort. Curr Eye Res. Oct 2009;34(10):863-866.
  21. Fetrow CW, Avila JR. Professional's Handbook of Complementary & Alternative Medicine. Springhouse, PA Springhouse; 1999.
  22. Neary JT, Bu Y. Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Res. Jan 23 1999;816(2):358-363.
  23. Franklin M, Chi J, McGavin C, et al. Neuroendocrine evidence for dopaminergic actions of hypericum extract (LI 160) in healthy volunteers. Biol Psychiatry. Aug 15 1999;46(4):581-584.
  24. Yu PH. Effect of the Hypericum perforatum extract on serotonin turnover in the mouse brain. Pharmacopsychiatry. Mar 2000;33(2):60-65.
  25. Leuner K, Kazanski V, Muller M, et al. Hyperforin—a key constituent of St. John's wort specifically activates TRPC6 channels. FASEB J. Dec 2007;21(14):4101-4111.
  26. Wang Y, Zhang Y, He J, et al. Hyperforin promotes mitochondrial function and development of oligodendrocytes. J Neurochem. Nov 2011;119(3):555-568.
  27. Chang Y, Wang SJ. Hypericin, the active component of St. John's wort, inhibits glutamate release in the rat cerebrocortical synaptosomes via a mitogen-activated protein kinase-dependent pathway. Eur J Pharmacol. May 25 2010;634(1-3):53-61.
  28. Kiesslich T, Krammer B, Plaetzer K. Cellular mechanisms and prospective applications of hypericin in photodynamic therapy. Curr Med Chem. 2006;13(18):2189-2204.
  29. Bove GM. Acute neuropathy after exposure to sun in a patient treated with St John's Wort. Lancet. Oct 3 1998;352(9134):1121-1122.
  30. Godtel-Armbrust U, Metzger A, Kroll U, et al. Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John's wort. Naunyn Schmiedebergs Arch Pharmacol. Aug 2007;375(6):377-382.
  31. Volak LP, Court MH. Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug-drug interactions between PKC inhibitors and UGT1A6. Xenobiotica. May 2010;40(5):306-318.
  32. Ott M, Huls M, Cornelius MG, et al. St. John's Wort constituents modulate P-glycoprotein transport activity at the blood-brain barrier. Pharm Res. May 2010;27(5):811-822.
  33. Martinez-Poveda B, Verotta L, Bombardelli E, et al. Tetrahydrohyperforin and octahydrohyperforin are two new potent inhibitors of angiogenesis. PloS one. 2010;5(3):e9558.
  34. Rothley M, Schmid A, Thiele W, et al. Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor-induced lymphangiogenesis in vivo. Int J Cancer. Jul 1 2009;125(1):34-42.
  35. Quiney C, Billard C, Faussat AM, et al. Hyperforin inhibits P-gp and BCRP activities in chronic lymphocytic leukaemia cells and myeloid cells. Leuk Lymphoma. Aug 2007;48(8):1587-1599.
  36. Barnes J, Anderson LA, Phillipson JD. St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol. May 2001;53(5):583-600.
  37. Mathijssen RH, Verweij J, de Bruijn P, et al. Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst. Aug 21 2002;94(16):1247-1249.
  38. Frye RF, Fitzgerald SM, Lagattuta TF, et al. Effect of St John's wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther. Oct 2004;76(4):323-329.
  39. Smith P, Bullock JM, Booker BM, et al. The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy. Nov 2004;24(11):1508-1514.
  40. Putnik K, Stadler P, Schafer C, et al. Enhanced radiation sensitivity and radiation recall dermatitis (RRD) after hypericin therapy — case report and review of literature. Radiat Oncol. 2006;1:32.
  41. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. Jul 11 2001;286(2):208-216.
  42. Mischoulon D. Update and critique of natural remedies as antidepressant treatments. Obstet Gynecol Clin North Am. Dec 2009;36(4):789-807, x.
  43. Vlachojannis J, Cameron M, Chrubasik S. Drug interactions with St. John's wort products. Pharmacol Res. Mar 2011;63(3):254-256; author reply 257-258.
  44. Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol. Spring 1999;12(1):7-10.
  45. Ruschitzka F, Meier PJ, Turina M, et al. Acute heart transplant rejection due to Saint John's wort. Lancet. Feb 12 2000;355(9203):548-549.
  46. Breidenbach T, Hoffmann MW, Becker T, et al. Drug interaction of St John's wort with cyclosporin. Lancet. May 27 2000;355(9218):1912.
  47. Irefin S, Sprung J. A possible cause of cardiovascular collapse during anesthesia: long-term use of St. John's Wort. J Clin Anesth. Sep 2000;12(6):498-499.
  48. Piccolo P, Gentile S, Alegiani F, et al. Severe drug induced acute hepatitis associated with use of St John's wort (Hypericum perforatum) during treatment with pegylated interferon alpha. BMJ case reports. 2009;2009.
  49. Parker V, Wong AH, Boon HS, et al. Adverse reactions to St John's Wort. Can J Psychiatry. Feb 2001;46(1):77-79.
  50. Holme SA, Roberts DL. Erythroderma associated with St John's wort. Br J Dermatol. Nov 2000;143(5):1127-1128.
  51. Bhopal JS. St John's wort-induced sexual dysfunction. Can J Psychiatry. Jun 2001;46(5):456-457.
  52. Dean AJ, Moses GM, Vernon JM. Suspected withdrawal syndrome after cessation of St. John's wort. Ann Pharmacother. Jan 2003;37(1):150.
  53. Milton JC, Abdulla A. Prolonged oro-facial dystonia in a 58 year old female following therapy with bupropion and St John's Wort. Br J Clin Pharmacol. Nov 2007;64(5):717-718.
  54. Gurley BJ, Swain A, Williams DK, et al. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res. Jul 2008;52(7):772-779.
  55. Schwarz UI, Hanso H, Oertel R, et al. Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of talinolol. Clin Pharmacol Ther. May 2007;81(5):669-678.
  56. Xie R, Tan LH, Polasek EC, et al. CYP3A and P-glycoprotein activity induction with St. John's Wort in healthy volunteers from 6 ethnic populations. J Clin Pharmacol. Mar 2005;45(3):352-356.
  57. Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA. Sep 17 2003;290(11):1500-1504.
  58. Xu H, Williams KM, Liauw WS, et al. Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol. Apr 2008;153(7):1579-1586.
  59. Imai H, Kotegawa T, Tsutsumi K, et al. The recovery time-course of CYP3A after induction by St John's wort administration. Br J Clin Pharmacol. May 2008;65(5):701-707.
  60. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John's wort. Lancet. Feb 12 2000;355(9203):547-548.
  61. Patel J, Buddha B, Dey S, et al. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: changes in P-gp and CYP3A4 activity. Am J Ther. Jul-Aug 2004;11(4):262-277.
  62. de Maat MM, Hoetelmans RM, Math t RA, et al. Drug interaction between St John's wort and nevirapine. AIDS. Feb 16 2001;15(3):420-421.
  63. Mai I, Stormer E, Bauer S, et al. Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant. Apr 2003;18(4):819-822.
  64. Hebert MF, Park JM, Chen YL, et al. Effects of St. John's wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol. Jan 2004;44(1):89-94.
  65. Komoroski BJ, Parise RA, Egorin MJ, et al. Effect of the St. John's wort constituent hyperforin on docetaxel metabolism by human hepatocyte cultures. Clin Cancer Res. Oct 1 2005;11(19 Pt 1):6972-6979.
  66. Jiang X, Williams KM, Liauw WS, et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. May 2004;57(5):592-599.
  67. Hojo Y, Echizenya M, Ohkubo T, et al. Drug interaction between St John's wort and zolpidem in healthy subjects. J Clin Pharm Ther. Dec 2011;36(6):711-715.
  68. Eggertsen R, Andreasson A, Andren L. Effects of treatment with a commercially available St John's Wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin. Scand J Prim Health Care. Sep 2007;25(3):154-159.
  69. Andren L, Andreasson A, Eggertsen R. Interaction between a commercially available St. John's wort product (Movina) and atorvastatin in patients with hypercholesterolemia. Eur J Clin Pharmacol. Oct 2007;63(10):913-916.
  70. Gordon RY, Becker DJ, Rader DJ. Reduced efficacy of rosuvastatin by St. John's Wort. Am J Med. Feb 2009;122(2):e1-2.
  71. Nieminen TH, Hagelberg NM, Saari TI, et al. St John's wort greatly reduces the concentrations of oral oxycodone. Eur J Pain. Sep 2010;14(8):854-859.
  72. Pizzorno JEJ, Murray MT. Textbook of Natural Medicine. 2nd ed. Edinburgh, UK: Churchill Livingstone; 1999.
  73. Van Strater AC, Bogers JP. Interaction of St John's wort (Hypericum perforatum) with clozapine. Int Clin Psychopharmacol. 2012 Mar;27(2):121-4.
  74. Yang SY, Juang SH, Tsai SY, Chao PD, Hou YC. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats. Toxicol Appl Pharmacol. 2012 Aug 15;263(1):39-43.
  75. Solomon D, Adams J, Graves N. Economic evaluation of St. John's wort (Hypericum perforatum) for the treatment of mild to moderate depression. J Affect Disord. 2013 Jun;148(2-3):228-34.

Consumer Information

How It Works

Bottom Line: St. John's wort can help relieve depression. However, this herb can affect the activity of many drugs, including those used in chemotherapy.

Several animal and human studies have shown that St. John's wort is effective against depression and well tolerated. It may also be useful in treating premenstrual syndrome and in reducing vasomotor symptoms in peri- and postmenopausal women. Compounds known as hypericin and hyperforin may interact with chemicals and counteract processes in the brain that are associated with depression. St. John's wort was also found to have neuroprotective effects in animal studies. More studies are needed.

Purported Uses
  • To treat depression
    Several studies in humans support the use of this herb for depression. Other studies yielded contradicting results.
  • To treat anxiety
    Although many studies support its use in depression, none have studied it to treat anxiety. No clinical evidence supports this use.
  • To treat chronic fatigue
    Some research supports this use, but more is needed.
  • To treat insomnia
    There is not enough evidence to support this use.
  • To reduce the symptoms of premenstrual syndrome (PMS)
    St. John's wort was shown in randomized trials to reduce PMS symptoms.
  • To treat seasonal affective disorder (SAD)
    So far, a few studies show that St. John's wort is not effective for SAD.
  • Topically, for wound healing
    In laboratory studies, St. John's wort acts as an antibiotic and antiviral agent, but there is no proof from clinical trials that it can help wounds heal.
  • To treat human immunodeficiency virus (HIV)
    A small study showed high toxicity and no benefit.
  • To attention-deficit/hyperactivity disorder (ADHD)
    A small study showed that St. John's wort is not effective for ADHD.
Research Evidence

In clinical trials researchers have found that St. John's wort extract can be as effective as several common antidepressant drugs with fewer side effects overall. It has also been shown to lower depression relapse and recurrence. However, there are mixed conclusions when all types of depression are evaluated. Some studies also suggest that St. John's wort can reduce pain and irritability associated with premenstrual syndrome, and hot flashes in peri- and postmenopausal women.

St. John's wort has many documented interactions with conventional drugs that work through similar mechanisms. This can result in reduced effectiveness, unexpected or serious adverse effects, and even treatment failure. Therefore, patients should speak with their physician or pharmacist before using this product, and especially avoid combining this herb with other drugs and treatment regimens.

Patient Warnings
  • This product may cause your skin to be more sensitive to sunlight, leading to sunburn, rash, or redness of the skin.
  • St. John’s wort may reduce the effectiveness of chemotherapy, and also increase the adverse skin effects of radiation therapy.
  • Patients should discontinue use of this product well before surgery, chemotherapy, or radiation therapy.
  • Use of St. John’s wort in addition to other prescription antidepressants may create a serious condition of excess serotonin in the body.
  • Contact your doctor if you experience pain or tingling in the extremities, wounds that will not heal, yellowing of the eyes or skin, or any other unusual symptoms while taking this herb.
Do Not Take If
  • You are pregnant or nursing.
  • You are taking birth control pills (St. John's wort can increase the risk of pregnancy).
  • You are undergoing treatment with UV light (Skin may become more sensitive to light).
  • You are undergoing radiation therapy (St. John’s wort may increase adverse skin effects).
  • You are undergoing chemotherapy (St. John's wort can reduce its effectiveness).
  • You are scheduled for surgery (St. John's wort should be discontinued well before surgery).
  • You are taking blood thinners or undergoing other anticoagulant therapy (St. John's wort may increase or decrease their effect).
  • You are taking medication to treat congestive heart failure or heart rhythm problems (St. John's wort might lessen their effects).
  • You are taking medications for depression and/or anxiety (St. John's wort may have additive effects and lead to serotonin excess, a serious condition).
  • You have bipolar disorder (This herb has caused mania in a few patients with bipolar disorder).
  • You are taking medications for migraines or cluster headaches (St. John's wort may have additive effects and lead to serotonin excess, a serious condition).
  • You are taking drugs for high or low blood pressure (St. John's wort may decrease or increase their effects).
  • You are taking drugs for diabetes (St. John's wort can decrease their effectiveness).
  • You are undergoing immunosuppressive therapy, antiretroviral therapy, or therapy for respiratory diseases (St. John's wort can decrease their effectiveness).
  • You are taking cholesterol lowering drugs (St. John's wort can decrease their effectiveness).
  • You are taking cough suppressants or allergy medications (St. John's wort can decrease their effectiveness).
  • You are taking pain killers (St. John's wort can decrease their effectiveness and increase side effects).
  • You regularly consume alcohol (St. John's wort may result in increased sedation).
  • You are taking Clozapine (St. John's wort can decrease its effectiveness).

St. John's Wort increased exposure and toxic effects of methotrexate in a study of rats.

Side Effects
  • Headache
  • Gastrointestinal upset: nausea, abdominal discomfort, constipation
  • Dizziness, confusion, sedation, sleep disturbances
  • Fatigue
  • Dry mouth
  • Skin sensitivity to sunlight
  • Increase in the amount of time it can take blood to clot
Case reports include incidences of:
  • Prolonged and involuntary facial muscle contractions (twisting and repetitive movements)
  • Intense and widespread reddening of the skin
  • Acute transplant rejection
  • Low blood pressure after general anesthesia
  • Drug-induced acute hepatitis
  • Mania and serotonin syndrome
  • Intense nerve pain
  • Sexual dysfunction
  • Withdrawal symptoms
Special Point
  • Do not use St. John's wort if you are undergoing surgery, chemotherapy or radiation therapy.
  • St. John's wort interferes with the action of many different drugs. Check with your doctor or pharmacist to make sure that other medications you are taking do not interact with St. John's wort.
E-mail your questions and comments to aboutherbs@mskcc.org.