St. John's Wort
St. John's wort is a common perennial herb of many branches and bright yellow flowers that grows wild in much of the world. Its name derives from the herb's tendency to flower around the feast of St. John. (A wort simply means plant in Old English.) The species name perforatum derives from the watermarking of translucent dots that can be seen when the leaf is held up to the sun.
St. John's wort has a long history of use in treating emotional disorders. During the Middle Ages, St. John's wort was popular for "casting out demons." In the 1800s, the herb was classified as a nervine, or a treatment for "nervous disorders." When pharmaceutical antidepressants were invented, German researchers began to look for similar properties in St. John's wort.
What Is St. John's Wort Used for Today?
Today, St. John's wort is a widely used treatment for depression in Germany, other parts of Europe, and the United States. The evidence-base for its use approaches that of many modern prescription drugs at the time of their first approval.
Most studies of St. John's wort have evaluated individuals with major depression of mild to moderate intensity. This contradictory-sounding language indicates that the level of depression is more severe than simply feeling "blue." However, it is not as severe as the most severe forms of depression. Typical symptoms include depressed mood, lack of energy, sleep problems, anxiety, appetite disturbance, difficulty concentrating, and poor stress tolerance. Irritability can also be a sign of depression.
Taken as a whole, research suggests that St. John's wort is more effective than placebo and approximately as effective as standard drugs. Furthermore, St. John's wort appears to cause fewer side effects than many antidepressants. However, the herb does present one significant safety risk: it interacts harmfully with a great many standard medications. (See Safety Issues for details.)
St. John’s wort has also shown promise for treatment of severe major depression.107,126 Note : St. John's wort alone should never be relied on for the treatment of severe depression. If you or a loved one feels suicidal, unable to cope with daily life, paralyzed by anxiety, incapable of getting out of bed, unable to sleep, or uninterested in eating, see a physician at once. Professional care may be lifesaving.
Besides depression, St. John’s wort has also been tried for many other conditions in which prescription antidepressants are thought useful, such as attention deficit disorder,131anxiety, insomnia,15menopausal symptoms,20premenstrual syndrome (PMS),19,102seasonal affective disorder (SAD),98,99 and social phobia.103 However, there is as yet no convincing evidence that it offers any benefit for these conditions. One substantial double-blind study did find St. John's wort potentially helpful for somatoform disorders (commonly called psychosomatic illnesses).104
Standard antidepressants are also often used for diabetic neuropathy and other forms of neuropathy (nerve pain). However, a small double-blind, placebo-controlled trial failed to find St. John's wort effective for this purpose.16 Another study failed to find St. John's wort helpful for obsessive-compulsive disorder.115
St. John’s wort contains, among other ingredients, the substances hypericin and hyperforin. Early reports suggested that St. John's wort or synthetic hypericin might be useful against viruses such as HIV, but these have not panned out.17 However, there is some evidence hyperforin may be able to fight certain bacteria, including some that are resistant to antibiotics.18 Note : This evidence is far too preliminary to count St. John's wort as an effective antibiotic.
One interesting double-blind study evaluated a combination therapy containing St. John's wort and black cohosh in 301 women with general menopausal symptoms as well as depression.116 The results showed that use of the combination treatment was significantly more effective than placebo for both problems.
In a small placebo-controlled trial, hypericin extract showed no benefit for burning mouth syndrome, a poorly understood condition in which a person experiences ongoing moderate to severe pain in the tongue and/or mouth.129
What Is the Scientific Evidence for St. John's Wort?
There have been two main kinds of studies: those that compared St. John's wort to placebo, and others that compared it to prescription antidepressants. A 2008 detailed review of 29 randomized, placebo controlled trials found that St. Johns wort was consistently more effective than placebo and equally effective to standard antidepressants.133
St. John's Wort Versus Placebo
Studies of St. John's wort (and other antidepressants) use a set of questions called the Hamilton Depression Index (HAM-D). This scale rates the extent of depression, with higher numbers indicating more serious symptoms.
Double-blind, placebo-controlled trials involving a total of more than 1,500 participants with major depression of mild to moderate severity have generally found that use of St. John's wort can significantly reduce HAM-D scores as compared to placebo.21-28,89,105,123 In addition, continued treatment with St. Johns Wort over 6 months may be effective at preventing a relapse of moderate depression in patients who recover from an initial acute episode.132
For example, in a 6-week trial, 375 individuals with average 17-item HAM-D scores of about 22 (indicating major depression of moderate severity) were given either St. John's wort or placebo.89 Individuals taking St. John's wort showed significantly greater improvement than those taking placebo.
Three double-blind, placebo-controlled trials evaluating individuals with a similar level of depression have failed to find St. John’s wort more effective than placebo.27,85,106 However, three studies cannot overturn a body of positive research. Keep in mind that 35% of double-blind studies involving pharmaceutical antidepressants have also failed to find the active agent significantly more effective than placebo.85 As if to illustrate this, in two of the three studies in which St. John’s wort failed to prove effective, a conventional drug (Zoloft in one case, Prozac in the other) also failed to prove effective. The reason for these negative outcomes is not that Zoloft or Prozac does not work. Rather, statistical effects can easily hide the benefits of a drug, especially in a condition like depression where there is as a high placebo effect and no really precise method of measuring symptoms. Thus, unless a whole series of studies find St. John’s wort ineffective, especially trials in which a comparison drug treatment does prove effective, St. John’s wort should still be regarded as probably effective for major depression of mild to moderate severity.
St. John's Wort Versus Medications
At least 8 double-blind trials enrolling a total of more than 1,200 people have compared St. John’s wort to fluoxetine (Prozac), citalopram (Celexa), paroxetine (Paxil) or sertraline (Zoloft).31-33,90,91,107,108,117-118,134 In all of these studies, the herb proved as effective as the drug and generally caused fewer side effects.
In the largest of these trials, a 6-week study of 388 people with major depression of mild-to-moderate severity, St. John's wort proved equally effective as the drug citalopram (Celexa) and more effective than placebo.118 Additionally, Celexa caused a significantly higher rate of side effects than St. John's wort. There were also significantly more side effects in the placebo group than in the St. John's wort group—presumably because treatment of depression reduces physical symptoms of psychological origin.
St. John’s wort has also been compared to older antidepressants, with generally favorable results.34-38
How Does St. John’s Wort Work for Depression?
Like pharmaceutical antidepressants, St. John's wort is thought to raise levels of neurotransmitters in the brain, such as serotonin, norepinephrine, and dopamine.6,7
The active ingredient of St. John’s wort is not known. Extracts of St. John’s wort are most often standardized to the substance hypericin, which has led to the widespread misconception that hypericin is the active ingredient. However, there is no evidence that hypericin itself is an antidepressant. Another ingredient of St. John's wort named hyperforin has shown considerable promise as the most important ingredient. Hyperforin was first identified as a constituent of Hypericum perforatum in 1971 by Russian researchers, but it was incorrectly believed to be too unstable to play a major role in the herb's action.1 However, subsequent evidence corrected this view. It now appears that standard St. John's wort extract contains about 1% to 6% hyperforin.2 Evidence from animal and human studies suggests that it is the hyperforin in St. John’s wort that raises the levels of neurotransmitters.8-10 Nonetheless, there may be other active ingredients in St. John's wort also at work.11,12 In fact, 2 double-blind trials using a form of St. John's wort with low hyperforin content found it effective.13,14 The bottom line remains that more research is necessary to discover just how St. John’s wort acts against depression.
The typical dosage of St. John's wort is 300 mg 3 times a day of an extract standardized to contain 0.3% hypericin. Some products are standardized to hyperforin content (usually 2% to 3%) instead of hypericin. These are usually taken at the same dosage. Two studies found benefits with a single daily dose of 900 mg.118-119
Yet another form of St. John's wort has shown effectiveness in double-blind studies. This form contains little hyperforin and is taken at a dose of 250 mg twice daily.41,42 There is some evidence that this form of St. John's wort may be less likely to interact with medications. (See Drug Interactions.)
If the herb bothers your stomach, take it with food.
Remember that the full effect takes 4 weeks to develop. Do not give up too soon!
St. John's wort taken alone usually does not cause immediate side effects. In a study designed to look for side effects, 3,250 people took St. John's wort for 4 weeks.43 Overall, about 2.4% reported problems. The most common complaints were mild stomach discomfort (0.6%), allergic reactions—primarily rash—(0.5%), tiredness (0.4%), and restlessness (0.3%). Another study followed 313 individuals treated with St. John's wort for 1 year.44 The results showed a similarly low incidence of adverse effects.
In the extensive German experience with St. John's wort as a treatment for depression, there have been no published reports of serious adverse consequences from taking the herb alone.45 Animal studies involving enormous doses of St. John's wort extracts for 26 weeks have not shown any serious effects.46
However, there are a number of potential safety risks with St. John's wort that should be considered. These are outlined in the following sections.
Cows and sheep grazing on St. John's wort have sometimes developed severe and even fatal sensitivity to the sun. In one study, highly sun-sensitive people were given twice the normal dose of the herb.47 The results showed a mild but measurable increase in reaction to ultraviolet radiation. Another trial found that a one-time dose of St. John’s wort containing 2 or 6 times the normal daily dose did not cause an increased tendency to burn, nor did 7 days of treatment at the normal dose.83 However, there is a case report of severe and unexpected burning in an individual who used St. John's wort and then received ultraviolet therapy for psoriasis.48 In addition, two individuals using topical St. John's wort experienced severe reactions to sun exposure.84
The morals of the story are as follows: if you are especially sensitive to the sun, do not exceed the recommended dose of St. John's wort, and continue to take your usual precautions against burning. If you are receiving UV treatment, do not use St. John’s wort at all; and if you apply St. John’s wort to your skin, keep that part of your body away from the sun.
In addition, you might get into problems if you combine St. John's wort with other medications that cause increased sun sensitivity, such as sulfa drugs and the anti-inflammatory medication piroxicam (Feldene). The medications omeprazole (Prilosec) and lansoprazole (Prevacid) may also increase the tendency of St. John's wort to cause photosensitivity.49
Finally, a report suggests that regular use of St. John's wort might also increase the risk of sun-induced cataracts.50 While this is preliminary information, it may make sense to wear sunglasses when outdoors if you are taking this herb on a long-term basis.
Herbal experts have warned for some time that combining St. John's wort with drugs in the Prozac family (SSRIs) might raise serotonin too much and cause a number of serious problems. Recently, case reports of such events have begun to trickle in.51-53 This is a potentially serious risk. Do not combine St. John's wort with prescription antidepressants except on the specific advice of a physician. Since some antidepressants, such as Prozac, linger in the blood for quite some time, you also need to exercise caution when switching from a drug to St. John's wort.
Antimigraine drugs in the triptan family (such as sumatriptan, or Imitrex) and the pain-killing drug tramadol also raise serotonin levels and might interact similarly with St. John's wort.54,55
However, perhaps the biggest concern with St. John's wort is that it appears to decrease the effectiveness of numerous medications, including protease inhibitors and reverse transcriptase inhibitors (for HIV infection), cyclosporine and tacrolimus (for organ transplants), digoxin (for heart disease), statin drugs (used for high cholesterol), warfarin (Coumadin) (a blood thinner), chemotherapy drugs, oral contraceptives, tricyclic antidepressants, protein pump inhibitors (like Prilosec), atypical antipsychotics like olanzapine or clozapine (for schizophrenia), anesthetics, and the new heart disease drug ivabradine.56-67,80,82,87,88,92,93,95,101,109-113,124,125,127,128 In fact, there are theoretical reasons to believe that this herb might reduce the effectiveness or otherwise interact with about 50% of all medications.114 Furthermore, suppose you are taking St. John's wort while your physician is adjusting the dosage of one of your medications to obtain an optimum balance of efficacy and side effects. A problem may then occur if you subsequently stop taking the herb: blood levels of the drug may then rise, with potentially dangerous consequences.
Note that these proposed interactions are not purely academic: they could lead to catastrophic consequences. Indeed, St. John's wort appears to have caused several cases of heart, kidney, and liver transplant rejection by interfering with the action of cyclosporine.
On a less dramatic level, one study showed that among people taking a cholesterol-lowering medication in the statin family, use of St. John’s wort caused cholesterol levels to rise.127 (The same would be expected to occur if you are using red yeast rice to treat high cholesterol, as red yeast rice supplies naturally-occurring statin drugs.)
Finally, some people with HIV take St. John's wort in the false belief that the herb will fight AIDS. The unintended result may be to reduce the potency of standard anti-HIV drugs.
There is some evidence that low-hyperforin St. John's wort may have less potential for drug interactions than other forms of St. John's wort.121-122,125 Nonetheless, we recommend that people taking any oral or injected medication that is critical to their health or wellbeing should entirely avoid using any form of St. John's wort until more is known; if you are already taking the herb, you should not stop taking it until you can simultaneously have your drug levels monitored. On general principles, we also advise avoid using the herb prior to undergoing general anesthesia.
Safety in Special Circumstances
One animal study found no ill effects on the offspring of pregnant mice.69 However, these findings alone are not sufficient to establish St. John's wort as safe for use during pregnancy. Furthermore, the St. John's wort constituent hypericin can accumulate in the nucleus of cells and directly bind to DNA.70 For this reason, pregnant or nursing women should avoid St. John's wort. Furthermore, safety for use by young children or people with severe liver or kidney disease has not been established.
Certain foods contain a substance named tyramine. These foods include aged cheeses, aged or cured meat, sauerkraut, soy sauce, other soy condiments, beer (especially beer on tap), and wine. Drugs in the MAO inhibitor family interact adversely with tyramine, causing severe side effects such as high blood pressure, rapid heart rate, and delirium. One case report suggests that St. John’s might present this risk as well.96 However, other studies suggest that normal doses of St. John’s should not cause MAO-like effects.4,5,97 Until this issue is sorted out, we recommend that individuals taking St. John’s wort avoid tyramine-containing foods. Since MAO inhibitors react adversely with stimulant drugs such as Ritalin, ephedrine (found in the herb ephedra), and caffeine, we also recommend that you avoid combining St. John’s wort with them.
One small study suggests that high doses of St. John's wort might slightly impair mental function.73
One case report associates use of St. John's wort with hair loss.74 The authors note that standard antidepressants may also cause hair loss at times.
One study raised questions about possible antifertility effects of St. John's wort. When high concentrations of St. John's wort were placed in a test tube with hamster sperm and ova, the sperm were damaged and less able to penetrate the ova.75 However, since it is unlikely that this much St. John's wort can actually come in contact with sperm and ova when they are in the body rather than in a test tube, these results may not be meaningful in real life.
In one reported case, St. John’s Wort may have interacted with the menopause drug tibolone to produce severe liver damage.130
Transitioning from Medications to St. John's Wort
If you are taking a prescription drug for mild to moderate depression, switching to St. John's wort may be a reasonable idea if you would prefer taking an herb. To avoid overlapping treatments, the safest approach is to stop taking the drug and allow it to wash out of your system before starting St. John's wort. Consult with your doctor on how much time is necessary.
However, if you are taking medication for severe depression, switching over to St. John's wort is not a good idea. The herb probably will not work well enough, and you may sink into a dangerous depression.
Interactions You Should Know About
If you are taking:
1. Erdelmeier CAJ. Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L.Pharmacopsychiatry. 1998;31(suppl 1):2-6.
2. Schulz V. Hyperforin-Werte keinesfalls nur "Spuren." Dtsch Apoth Ztg. 1998;138:65. Cited by: Chatterjee S, Noldner M, Koch E, et al. Antidepressant activity of Hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry. 1998;31(suppl 1):7-15.
3. Suzuki O, Katsumata Y, Oya M, et al. Inhibition of monoamine oxidase by hypericin. Planta Med. 1984;50:272-274.
4. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatr Neurol. 1994;7(suppl 1):S57-S59.
5. Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatr Neurol. 1994;7(suppl 1):S54-S56.
6. Muller WE, Rossol R. Effects of hypericum extract on the expression of serotonin receptors . J Geriatr Psychiatry Neurol. 1994;7(suppl 1):S63-S64.
7. Muller WE, Kasper S, Volz HP, et al. Hypericum extract (LI160) as an herbal antidepressant. Pharmacopsychiatry. 1997;30(suppl 2):71-134.
8. Muller WE, Singer A, Wonnemann M, et al. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry. 1998;31(suppl 1):16-21.
9. Ghattacharya SK, Chakrabareti A, Chatterjee SS. Activity profiles of two hyperforin-containing hypericum extracts in behavioural models. Pharmacopsychiatry. 1998;31(suppl):22-29.
10. Laakmann G, Schle C, Baghai T, et al. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(suppl):54-59.
11. Dimpfel W, Schober F, Mannel M. Effects of a methanolic extract and a hyperforin-enriched CO2 extract of St. John's wort ( Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG). Pharmacopsychiatry. 1998;31(suppl 1):30-35.
12. Butterweck V, Jurgenliemk G, Nahrstedt A, et al. Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test. Planta Med. 2000;66:3-6.
13. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15:61-68.
14. Schrader E, Meier B, Brattstrom A. Hypericum treatment of mild-moderate depression in a placebo-controlled study: a prospective, double-blind, randomized, placebo-controlled, multicentre study. Hum Psychopharmacol. 1998;13:163-169.
15. Schulz H, Jobert M. The influence of hypericum extract on the sleep EEG in older volunteers [in German; English abstract]. Nervenheilkunde. 1993;12:323-327.
16. Sindrup SH, Madsen C, Bach FW, et al. St. John's wort has no effect on pain in polyneuropathy. Pain. 2001;91:361-365.
17. Gulick R, McAuliffe V, Holden-Wiltse J, et al. Phase I studies of hypericin, the active compound in St. John's wort, as an antiretroviral agent in HIV-infected adults. Ann Intern Med. 1999;130:510-514.
18. Schempp CM, Pelz K, Wittmer A, et al. Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria. Lancet. 1999;353:2129.
19. Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. BJOG. 2000;107:870-876.
20. Grube B, Walper A, Wheatley D. St. John's Wort extract: efficacy for menopausal symptoms of psychological origin. Adv Ther. 1999;16:177-186.
21. Hansgen KD, Vesper J, Ploch M. Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160. J Geriatr Psychiatry Neurol. 1994;7(suppl 1):S15-S18.
22. Laakmann G, Schle C, Baghai T, et al. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(suppl):54-59.
23. Schrader E, Meier B, Brattstrom A. Hypericum treatment of mild-moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo-controlled, multicentre study. Hum Psychopharmacol. 1998;13:163-169.
24. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for depression—An overview and meta-analysis of randomised clinical trials. BMJ. 1996;313:253-258.
25. Ernst E. St. John's wort, an anti-depressant? A systematic, criteria-based review. Phytomedicine. 1995;2:67-71.
26. Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ. 1999;319:1534-1539.
27. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St. John's wort in major depression: a randomized controlled trial. JAMA. 2001;285:1978-1986.
28. Kalb R, Trautmann-Sponsel RD, Kieser M. Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial. Pharmacopsychiatry. 2001;34:96-103.
29. Hansgen KD, Vesper J. Antidepressant efficacy of a high-dose hypericum extract [translated from German]. MMW Munch Med Wochenschr. 1996;138:29-33.
30. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St. John's wort in major depression: a randomized controlled trial. JAMA. 2001;285:1978-1986.
31. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15:61-68.
32. Harrer G, Schmidt U, Kuhn U, et al. Comparison of equivalence between the St. John's wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung. 1999;49:289-296.
33. Brenner R, Azbel V, Madhusoodanan S, et al. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther. 2000;22:411-419.
34. Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ. 1999;319:1534-1539.
35. Vorbach EU, Arnoldt KH, Hubner WD. Efficacy and tolerability of St. John's wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry. 1997;30(suppl 2):81-85.
36. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicians' Guide to Herbal Medicine. 3rd ed. Berlin, Germany: Springer-Verlag; 1998:59.
37. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for depression—An overview and meta-analysis of randomised clinical trials. BMJ. 1996;313:253-258.
38. Ernst E. St. John's wort, an anti-depressant? A systematic, criteria-based review. Phytomedicine. 1995;2:67-71.
40. Sindrup SH, Madsen C, Bach FW, et al. St. John's wort has no effect on pain in polyneuropathy. Pain. 2001;91:361-365.
41. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15:61-68.
42. Woelk H. Comparison of St John's wort and imipramine for treating depression: randomised controlled trial. BMJ. 2000;321:536-539.
43. Woelk H, Burkard G, Grunwald J. Benefits and risks of the hypericum extract LI 160: Drug monitoring study with 3,250 patients. J Geriatr Psychiatr Neurol. 1994;7(suppl 1):S34-S38.
44. Hubner WD, Arnoldt KH. St John's Wort: a one year treatment study [in German; English abstract]. Z Phytother. 2000;21:306-310.
45. De Smet PA, Nolen WA. St. John's wort as an anti-depressant. BMJ. 1996;3:241-242.
46. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physicians' Guide to Herbal Medicine. 3rd ed. Berlin, Germany: Springer-Verlag; 1998:56.
47. Brockmoller J, Reum T, Bauer S, et al. Hypericin and pseudohypericin: Pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry. 1997;30(suppl 2):94-101.
48. Lane-Brown MM. Photosensitivity associated with herbal preparations of St John's wort (Hypericum perforatum) [letter]. Med J Aust. 2000;172:302.
49. Mirossay A, Mirossay L, Tothova J, et al. Potentiation of hypericin and hypocrellin-induced phototoxicity by omeprazole. Phytomedicine. 1999;6:311-317.
50. Roberts J. Presentation: American Society for Photobiology; 1999.
51. DeMott K. St. John's wort tied to serotonin syndrome. Clinical Psychiatry News. 1998;26:28.
52. Gordon JB. SSRIs and St. John's wort: Possible toxicity? Am Fam Physician. 1998;57:950,953.
53. Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol. 1999;12:7-10.
54. Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother. 1997;31:175-177.
55. Hernandez AF, Montero MN, Pla A, et al. Fatal moclobemide overdose or death caused by serotonin syndrome? J Forensic Sci. 1995;40:128-130.
56. Jobst KA, McIntyre M, St. George D, et al. Safety of St John's wort (Hypericum perforatum). Lancet. 2000,355:575.
57. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John's wort. Lancet. 2000;355:548.
58. Ruschitzka F, Meier PJ, Turina M, et al. Acute heart transplant rejection due to Saint John's wort. Lancet. 2000;355:547.
59. Baker RK, Brandt TL, Siegel D, et al. Inhibition of human DNA topoisomerase IIalpha by the naphtha-dianthrone, hypericin. Proc Am Assoc Cancer Res. 1998;39:422.
60. Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther. 1999;66:338-345.
61. Maurer A. Interaction of St. John's wort extract with phenprocoumon [abstract 79]. Eur J Clin Pharmacol. 1999;55:A22.
62. Nebel A, Baker RK, Schneider BJ, et al. Potential metabolic interaction between St. John's wort and theophylline. Ann Pharmacother. 1999;33:502.
63. De Smet PA, Touw DJ. Safety of St. John's wort. Lancet. 2000;355:575-576.
64. Breidenbach TH, Hoffmann MW, Becker TH, et al. Drug interaction of St John's wort with ciclosporin. Lancet. 2000;355:1912.
65. Barone GW, Gurley BJ, Ketel BL, et al. Drug interaction between St. John's wort and cyclosporine. Ann Pharmacother. 2000;34:1013-1016.
66. Dresser GK, Schwarz UI, Wilkinson GR, et al. St. John's wort induces intestinal and hepatic CYP3A4 and P-glycoprotein in healthy volunteers [abstract]. Clin Pharmacol Ther. 2001;69:P23.
67. Abul-Ezz SR, Barone GW, Gurley BJ, et al. Effect of herbal supplements on cyclosporine blood levels and associated acute rejection. Presented at: 33rd Annual Meeting of the American Society of Nephrology, Renal Week 2000; October 11-16, 2000; Toronto, Canada.
68. Jobst KA, McIntyre M, St. George D, et al. Safety of St John's wort (Hypericum perforatum).Lancet. 2000;355:575.
69. Rayburn WF, Gonzalez CL, Christensen HD, et al. Effect of prenatally administered hypericum (St John's wort) on growth and physical maturation of mouse offspring. Am J Obstet Gynecol. 2001;184:191-195.
70. Miskovsky P, Chinsky L, Wheeler GV, et al. Hypericin site specific interactions within polynucleotides used as DNA model compounds. J Biomol Struct Dyn. 1995;13:547-552.
71. Nierenberg AA, Burt T, Matthews J, et al. Mania associated with St. John's wort. Biol Psychiatry. 1999;46:1707-1708.
72. Barbenel DM, Yusufi B, O'Shea D, et al. Mania in a patient receiving testosterone replacement postorchidectomy taking St John's wort and sertraline. J Psychopharmacol. 2000;14:84-86.
73. Ellis KA, Stough C, Vitetta L, et al. An investigation into the acute nootropic effects of Hypericum perforatum L. (St. John's Wort) in healthy human volunteers. Behav Pharmacol. 2001;12:173-182.
74. Parker V, Wong AH, Boon HS, et al. Adverse reactions to St John's Wort. Can J Psychiatry. 2001;46:77-79.
75. Ondrizek RR, Chan PJ, Patton WC, et al. An alternative medicine study of herbal effects on the penetration of zona-free hamster oocytes and the integrity of sperm deoxyribonucleic acid. Fertil Steril. 1999;71:517-522.
76. Suzuki O, Katsumata Y, Oya M, et al. Inhibition of monoamine oxidase by hypericin. Planta Med. 1984;50:272-274.
77. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatr Neurol. 1994;7(suppl 1):S57-S59.
78. Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatr Neurol. 1994;7(suppl 1):S54-S56.
79. Laird RD, Webb M. Psychotic episode during use of St. John's wort. J Herbal Pharmacother. 2001;1:81-87.
80. Mai I, Kruger H, Budde K, et al. Hazardous pharmacokinetic interaction of Saint John's wort ( Hypericum perforatum) with the immunosuppressant cyclosporin. Int J Clin Pharmacol Ther. 2000;38:500-502.
81. Sugimoto Ki K, Ohmori M, Tsuruoka S, et al. Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther. 2001;70:518-524.
82. Roots J, et al. Interaction of a herbal extract from St. John’s wort with amitryptyline and its metabolites [abstract]. Clin Pharmacol Ther. 2000;67:159
83. Schempp CM, et al. Single-dose and steady-state administration of Hypericum perforatum extract (St. John’s Wort) does not influence skin sensitivity to UV radiation, visible light, and solar-simulated radiation. Arch Dermatol. 2001;137:512-513
84. Lane-Brown MM. Photosensitivity associated with herbal preparations of St John's wort ( Hypericum perforatum) [letter]. Med J Aust. 2000;172:302.
85. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287:1807-1814.
86. Hubner WD, Kirste T. Experience with St John's Wort ( Hypericum perforatum) in children under 12 years with symptoms of depression and psychovegetative disturbances. Phytother Res. 2001;15:367-370.
87. de Maat MM, Hoetelmans RM, Mathot RA, et al. Drug interaction between St. John’s wort and nevirapine [letter]. AIDS. 2001;15:420-421.
88. Gorski JC, Hamman MA, Wang Z, et al. The effect of St. John's Wort on the efficacy of oral contraception [abstract MPI-80]. American Society for Clinical Pharmacology and Therapeutics Annual Meeting; March 24-27, 2002; Atlanta, GA.
89. Lecrubier Y, Clerc G, Didi R, et al. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Am J Psychiatry. 2002;159:1361-1366.
90. Behnke K, Jensen GS, Graubaum HJ, et al. Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Adv Ther. 2002;19:43-52.
91. van Gurp G, Meterissian GB, Haiek LN, et al. St John's wort or sertraline? Randomized controlled trial in primary care. Can Fam Physician. 2002;48:905-912.
92. Mathijssen RH, Verweij J, de Bruijn P, et al. Effects of St. John’s Wort on irinotecan metabolism. J Natl Cancer Inst. 2002;94:1247-1249.
93. Hennessy M, Kelleher D, Spiers JP, et al. St. John’s Wort increases expression of P-glycoprotein: implications for drug interactions. Br J Clin Pharmacol. 2002;53:75-82.
94. Schultz V. Clinical trials with hypericum extracts in patients with depression--results, comparisons, conclusions for therapy with antidepressant drugs. Phytomedicine. 2002;9:468-474.
95. Johne A, Schmider J, Brockmoller J, et al. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort (Hypericum perforatum). J Clin Psychopharmacol. 2002;22:46-54.
96. Patel S, Robinson R, Burk M. Hypertensive crisis associated with St. John's Wort. Am J Med. 2002;112:507-508.
97. Bennet DA, Phyun L, Pok JF, et al. Neuropharmacology of St. John’s Wort ( Hypericum). Ann Pharmacother. 1998;32:1201-1208.
98. Martinez B, Kasper S, Ruhrmann S, et al. Hypericum in the treatment of seasonal affective disorders. J Geriatr Psychiatr Neurol. 1994;7(Suppl 1):S29-S33.
99. Wheatley D. Hypericum in seasonal affective disorder (SAD). Curr Med Res Opin. 1999;15:33-37.
100. Schempp M, Hezel S, Simon C. Topical treatment of Atopic dermatitis with Hypericum creamA randomised, placebo-controlled, double-blind half-side comparison study. Hautarzt. 2003;54:248-253.
101. Crowe S, McKeating K, et al. Delayed emergence and St. John's wort. Anesthesiology. 2002;96:1025-1027.
102. Hicks SM, Walker AF, Gallagher J, et al. The significance of "nonsignificance" in randomized controlled studies: a discussion inspired by a double-blinded study on St. John's wort ( Hypericum perforatum L.) for premenstrual symptoms. J Altern Complement Med. 2005;10:925-932.
103. Kobak KA, Taylor LV, Warner G, et al. St. John's wort versus placebo in social phobia: results from a placebo-controlled pilot study. J Clin Psychopharmacol. 2005;25:51-58.
104. Muller T, Mannel M, Murck H, et al. Treatment of somatoform disorders with St. John's wort: a randomized, double-blind and placebo-controlled trial. Psychosom Med. 2004;66:538-547.
105. Uebelhack R, Gruenwald J, Graubaum HJ, et al. Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial. Adv Ther. 2004;21:265-75.
106. Bjerkenstedt L, Edman GV, Alken RG, et al. Hypericum extract LI 160 and fluoxetine in mild to moderate depression, A randomized, placebo-controlled multi-center study in outpatients. Eur Arch Psychiatry Clin Neurosci. 2004 Nov 12. [Epub ahead of print]
107. Szegedi A, Kohnen R, Dienel A, Kieser M. 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 Feb 11. [Epub ahead of print]
108. Bjerkenstedt L, Edman GV, Alken RG, et al. Hypericum extract LI 160 and fluoxetine in mild to moderate depression, A randomized, placebo-controlled multi-center study in outpatients. Eur Arch Psychiatry Clin Neurosci. 2004 Nov 12. [Epub ahead of print]
109. 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. 2004;57:592-599.
110. Mueller SC, Uehleke B, Woehling H, et al. Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin. Clin Pharmacol Ther. 2004;75:546-557.
111. Wang LS, Zhou G, Zhu B, et al. St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther. 2004;75:191-197.
112. 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. 2004;44:89-94.
113. Pfrunder A, Schiesser M, Gerber S, et al. Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol. 2003;56:683-690.
114. 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. 2003;290(11):1500-1504.
115. Kobak KA, Taylor LV, Bystritsky A, et al. St John's wort versus placebo in obsessive-compulsive disorder: results from a double-blind study. Int Clin Psychopharmacol. 2005;20:299-304.
116. Uebelhack R, Blohmer JU, Graubaum HJ, et al. Black cohosh and St. John's wort for climacteric complaints: a randomized trial. Obstet Gynecol. 2006;107:247-255.
117. 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. 2005;25:441-447.
118. 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. 2006;39:66-75.
119. Uebelhack R, Gruenwald J, Graubaum HJ, et al. Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial. Adv Ther. 2004;21:265-275.
120. Murphy PA, Kern SE, Stanczyk FZ, et al. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception. 2005;71:402-408.
121. Mueller SC, Majcher-Peszynska J, Uehleke B, et al. The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose. Eur J Clin Pharmacol. 2005 Dec 10. [Epub ahead of print]
122. Arold G, Donath F, Maurer A, et al. No Relevant Interaction with Alprazolam, Caffeine, Tolbutamide, and Digoxin by Treatment with a Low-Hyperforin St John's Wort Extract. Planta Med. 2005;71:331-337.
123. Kasper S, Anghelescu I, Szegedi A, et al. Superior efficacy of St Johns wort extract WS® 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial. BMC Med. 2006 Jun 23. [Epub ahead of print]
124. Portoles A, Terleira A, Calvo A, et al. Effects of Hypericum perforatum on Ivabradine Pharmacokinetics in Healthy Volunteers: An Open-Label, Pharmacokinetic Interaction Clinical Trial. J Clin Pharmacol. 2006;46:1188-1194.
125. Whitten DL, Myers SP, Hawrelak JA, et al. The effect of St John's wort extracts on CYP3A: a systematic review of prospective clinical trials. Br J Clin Pharmacol. 2006 Sep 29. [Epub ahead of print]
126. Anghelescu IG, Kohnen R, Szegedi A, et al. Comparison of hypericum extract WS® 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression: results from a randomized multicenter study. Pharmacopsychiatry. 2006;39:213-219.
127. 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. 2007 Aug 15. [Epub ahead of print]
128. 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. 2008 Jan 23.
129. Sardella A, Lodi G, Demarosi F, et al. Hypericum perforatum extract in burning mouth syndrome: a randomized placebo-controlled study. J Oral Pathol Med. 2008 Mar 6.
130. Etogo-Asse F, Boemer F, Sempoux C, et al. Acute hepatitis with prolonged cholestasis and disappearance of interlobular bile ducts following tibolone and Hypericum perforatum (St. John's wort). Case of drug interaction? Acta Gastroenterol Belg. 2008;71:36-38.
131. 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. 2008;299:2633-2641.
132. 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. 2008 Aug 9
133. Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008;CD000448.
134. Singer A, Schmidt M, Hauke W, Stade K. 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(8-9):739-742.
135. Lundahl A, Hedeland M, Bondesson U, Knutson L, Lennernas H. The effect of St. John's wort on the pharmacokinetics, metabolism and biliary excretion of finasteride and its metabolites in healthy men. Eur J Pharm Sci. 2009;36(4-5):433-443.
Last reviewed December 2017 by EBSCO CAM Review Board
Last Updated: 4/11/2018
EBSCO Information Services is fully accredited by URAC. URAC is an independent, nonprofit health care accrediting organization dedicated to promoting health care quality through accreditation, certification and commendation.
This content is reviewed regularly and is updated when new and relevant evidence is made available. This information is neither intended nor implied to be a substitute for professional medical advice. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with questions regarding a medical condition.
To send comments or feedback to our Editorial Team regarding the content please email us at firstname.lastname@example.org. Our Health Library Support team will respond to your email request within 2 business days.