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,131 anxiety, insomnia,15 menopausal symptoms,20 premenstrual syndrome (PMS),19,102 seasonal 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 haven’t 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.
Based on weak evidence that hypericin might have anti-inflammatory properties, St. John’s wort cream has been tried as a treatment for eczema, with some promising results.100
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 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.
- A double-blind, placebo-controlled trial of 54 people with diabetic neuropathy or other forms of neuropathy (pain, numbness and/or tingling caused by injury to nerves) did not find St. John’s wort effective for this purpose.40
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. Don’t 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, 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.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.
The herb also appears to decrease the effectiveness of oral contraceptives120 and by doing so is thought to have caused unwanted pregnancies.68,88
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.
Like other antidepressants, case reports suggest that St. John’s wort can cause episodes of mania in individuals with bipolar disorder (manic-depressive disease).71,72
There is also one report of St. John’s wort causing temporary psychosis in a person with Alzheimer’s disease.79
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 won’t work well enough, and you may sink into a dangerous depression.
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.
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