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Depression and St. John's Wort

St. John’s Wort is a flower supplement that is reported to relieve emotional symptoms of depression, including feelings of sadness, helplessness, hopelessness, and anxiety. It has also shown to reduce physical symptoms of depression, including headache and exhaustion. It is a popular alternative to pharmaceutical treatments because of its relative safety in comparison.

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Effect of St. John's Wort on Depression

St. John’s Wort works as a monoamine (MAO) inhibitor, preventing MAOs from breaking down certain neurotransmitters in the brain. Therefore, it increases the amount and time of mood elevating neurotransmitters, norepinephrine and dopamine, existing in between the synapses of the brain. It also works to increase the amount of serotonin in the brain, which helps regulates a person’s mood.

St. Johns Wort also works to activate gamma-aminobutyric (GABA) receptors in the brain, inhibiting reuptake. Increased GABA activity slows down brain processes, which can lead to feelings of relaxation. This may help with depressive symptoms of restlessness, and increase concentration and the ability to fall asleep.

Read more details about St. John's Wort.

Research Evidence on St. John's Wort

A meta-analysis of 23 randomized trials involving 1757 patients with mild to moderate symptoms of depression found improvement after 4-8 weeks of being treated with St. John’s Wort1. In some of those trials, St. John’s Wort was just as effective to tricylclic antidepressant medications in relieving symptoms of depression, and with fewer side effects. However, research is mixed. In Germany, studies have shown that St. John’s Wort is more effective than pharmaceutical medications, causing the herb to become the most prescribed treatment for depression in the country2. In the US, another study was done that found that St. John’s Wort effectiveness in treating depression was equal to the placebo effect, in which people feel better mostly because they think they should 3.

How to Use St. John's Wort

St. John’s Wort has been shown to be effective in treating mild to moderate forms of depression. Start with a daily dosage of 600-900 mg, split between breakfast and lunch. After the first week, increase to 900-1800 mg daily if necessary. Doses need to be taken for at least three weeks to show improvement. Sometimes the herb will not take full effect until after two months of treatment4. St. John’s Wort can be bought in tea, oil, or pill form. Check the product’s ingredients for 3-5% hyperforin, which is the main active compound in the plant and necessary for treatment effectiveness.

Safety Issues

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. 1 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. 2 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. 3 Animal studies involving enormous doses of St. John's wort extracts for 26 weeks have not shown any serious effects. 4 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. 5 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. 6 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. 7 In addition, two individuals using topical St. John's wort experienced severe reactions to sun exposure. 8 The morals of the story are as follows: if you are especially sensitive to the sun, don't 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. 9 Finally, a report suggests that regular use of St. John's wort might also increase the risk of sun-induced cataracts. 10 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.

Drug Interactions

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. 11 12 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. 13 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. 14 In fact, there are theoretical reasons to believe that this herb might reduce the effectiveness or otherwise interact with about 50% of all medications. 15 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 stoptaking 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.

The herb also appears to decrease the effectiveness of oral contraceptives 16 and by doing so is thought to have caused unwanted pregnancies. 17 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. 18 (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. 19 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. 20 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. 21 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.

Like other antidepressants, case reports suggest that St. John's wort can cause episodes of mania in individuals with bipolar disorder (manic-depressive disease). 22 There is also one report of St. John's wort causing temporary psychosis in a person with Alzheimer's disease . 23

Other Concerns

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. 24 However, other studies suggest that normal doses of St. John’s should not cause MAO-like effects. 25 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. 26 One case report associates use of St. John's wort with hair loss. 27 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. 28 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. 29

Interactions You Should Know About

If you are taking:

  • Antidepressant drugs, including MAO inhibitors , SSRIs , and tricyclics , or possibly the drugs tramadol or sumatriptan (Imitrex): Do not take St. John's wort at the same time. Actually, you need to let the medication flush out of your system for a while (perhaps weeks, depending on the drug) before you start the herb.
  • Digoxin , cyclosporine and tacrolimus, protease inhibitors or reverse transcriptase inhibitors , oral contraceptives , tricyclic antidepressants , warfarin (Coumadin) , statin drugs , theophylline , chemotherapy drugs, newer antipsychotic medications (such as olanzapine and clozapine ), anesthetics, or, indeed, any critical medication: St. John's wort might cause the drug to be less effective. Furthermore, if you are already taking St. John's wort and your physician adjusts your medication dosage to achieve proper blood levels, suddenly stopping St. John's wort could cause the level of the drug in your body to rebound to dangerously high levels.
  • Medications that cause sun sensitivity such as sulfa drugs and the anti-inflammatory medication piroxicam (Feldene) , as well as omeprazole (Prilosec) or lansoprazole (Prevacid) : Keep in mind that St. John's wort might have an additive effect.
  • Stimulant drugs or herbs such as Ritalin, caffeine, or ephedrine ( ephedra ): It is possible that St. John’s wort might interact adversely with them.

Other Uses

St. John’s Wort is also used for seasonal affective disorder, premenstrual syndrome, anxiety, and sleep disorders.


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(1) 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. British Medical Journal 2005 Mar;330: 503-7.

(2) St. John’s Wort for Major Depression: German study shows herb as effective as antidepressants for major depression. http://

(3) Effect of Hypericum perforatum (St. John's wort) in major depressive disorder: a randomized controlled trial. Journal of the American Medical Association, 2002; 287(14): 1807-1814.)

(4) Scott S. Handbook of Complementary and Alternative Therapies in Mental Health. Elsevier Inc 2002

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