St. John’s Wort

• How It Works

  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
    Evidence is lacking to support this use.
  • To treat chronic fatigue
    Some research supports this use, but more is needed.
  • To treat insomnia
    Evidence is lacking 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. Clinical data are lacking.
  • 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.
• 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.
  • Avoid use of St. John’s wort in addition to other prescription antidepressants as it may create a serious condition of excess serotonin in the body.
  • Use of this supplement should also be avoided if taking other supplements such as 5-HTP or SAM-e because these products may also affect serotonin levels.
  • 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 receiving methotrexate: St. John’s wort may increase toxic effects.
  • 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.
  • You are taking SAM-e: Because SAME-e may also affect serotonin levels, the use of multiple herbs that do this should be avoided to reduce risks for excess serotonin in the body, a serious condition.
  • You are taking 5-HTP : Because 5-HTP may also affect serotonin levels, the use of multiple herbs that do this should be avoided to reduce risks for excess serotonin in the body, a serious condition.
• 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
  • Psychosis
• 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.
• Scientific Name

  Hypericum perforatum

• 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. St. John’s Wort was also used by Native Americans for wound healing, snakebites, and diarrhea. Today, it 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 it 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) (76), 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 sustained as well 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⁾. St. John’s wort may enhance the effect of clopidogrel in patients who have undergone percutaneous coronary intervention ⁽¹⁷⁾ but more studies are needed. In another study, St John’s wort was shown to improve glucose tolerance by increasing insulin secretion independently of insulin sensitivity in healthy subjects taking metformin ⁽⁷⁷⁾; and to modulate cortical plasticity in healthy subjects ⁽⁷⁸⁾.

  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 pharmacist before using this product.

• Purported Uses
  • Depression
  • Fatigue
  • Insomnia
  • Pain
  • Premenstrual syndrome
  • Seasonal affective disorder
  • Wound healing
• 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⁾; and exerts neuroprotective effects in PC12 cells via regulating the AKT/GSK-3β signaling to decrease aluminum-induced Aβ production and tau phosphorylation ⁽⁸²⁾.

• Warnings
  • May cause photosensitivity with fair-skinned individuals more at risk ⁽¹⁸⁾ or subacute neuropathy ⁽²⁹⁾ in conjunction with sun exposure or other photosensitizing agents or products.
  • May reduce efficacy of chemotherapy ^{(37) (38) (39)}. May enhance skin toxicity of radiation therapy ⁽⁴⁰⁾.
  • St. John’s wort should be discontinued at least one week before surgery or chemotherapy ^(37) (41).
• Contraindications
  • Pregnant or nursing women ⁽⁴²⁾ or those on oral contraceptives ⁽⁴³⁾ should not consume St. John’s wort.
  • Patients being treated with prescription antidepressants should not consume St. John’s wort as it may create a syndrome of central serotonin excess ⁽⁴⁴⁾.
  • Use of this supplement should also be avoided if taking other supplements such as 5-HTP or SAM-e because these products may also affect serotonin levels.
  • Numerous documented interactions with conventional drugs should preclude its use while undergoing chemotherapy, radiation therapy, antiretroviral therapy, immunosuppressive therapy, and anticoagulant therapy.
• 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⁾.

  Psychosis: A 25-year-old man,  with a history of brief and self-remitting drug-induced psychosis and a positive family history of psychotic depression, experienced florid psychotic symptoms concomitant with self-administration of Hypericum perforatum  ⁽⁸¹⁾.

• Herb-Drug Interactions
  • CYP450 3A4 ⁽⁵⁷⁾ and CYP 2C9 ⁽⁵⁸⁾ substrate drugs: 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 (ie, 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 substrate drugs: 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⁾.
  • Bupropion: Prolonged facial dystonia was reported in a 58-year-old Caucasian woman following use of bupropion along with St. John’s wort ⁽⁵³⁾.
  • Rifampicin: Ambient temperature-dependent allodynia and paresthesia were reported in female subjects following coadministration with St. John’s wort, in sun-exposed areas (back of the hands and perioral and nasal area). Aggravation of symptoms resulted in persistence of paresthesia and phototoxic erythrodermia ⁽⁷⁹⁾.
  • Ambrisentan: St. John’s wort significantly reduced exposure with ambrisentan, but this interaction was deemed not to be clinically relevant ⁽⁸⁰⁾.
• References

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  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.

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  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.

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