What are St. John's wort's therapeutic uses?

Overview

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 time of the feast of St. John. (“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
light.

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
nineteenth century, the herb was classified as a nervine, or a treatment for
so-called nervous disorders. When pharmaceutical antidepressants were invented, German researchers began to
look for similar properties in St. John’s wort.

Therapeutic Dosages

The typical dosage of St. John’s wort is 300 milligrams (mg) three times a day of an extract standardized to contain 0.3 percent hypericin. Some products are standardized to hyperforin content (usually 2 percent to 3 percent) instead of hypericin. These are usually taken at the same dosage. Two studies found benefits with a single daily dose of 900 mg.

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. There is some evidence that this form of St. John’s wort may be less likely than other forms to interact with medications.

Therapeutic Uses

In Germany, other parts of Europe, and the United States, St. John’s wort is now a
widely used treatment for depression. 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 rises to greater severity 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.

St. John’s wort has also shown promise for treatment of severe major depression. St. John’s wort alone should never be relied on for the treatment of severe depression. Persons who are feeling suicidal or who are unable to cope with daily life or who are paralyzed by anxiety, incapable of getting out of bed, unable to sleep, or uninterested in eating should consult a physician or other health practitioner.

St. John’s wort has been tried in the treatment of many other conditions in which
prescription antidepressants are thought useful, such as attention deficit
disorder, anxiety, insomnia, menopausal symptoms, premenstrual syndrome (PMS),
seasonal affective disorder (SAD), and social phobia. However, there is 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).

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. Another study failed to find St. John’s wort helpful for obsessive-compulsive disorder.

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 (human immunodeficiency virus), but
these have not panned out. However, there is some evidence that hyperforin may be
able to fight certain bacteria, including some that are resistant to
antibiotics. This evidence is far too preliminary for any
conclusions to be drawn regarding the effectiveness of St. John’s wort as an
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.

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. 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 or mouth, or both.

Scientific Evidence

Depression. Two main kinds of studies have examined the use of St. John’s wort for depression: those that compared St. John’s wort to placebo and others that compared it to prescription antidepressants. A 2008 detailed review of twenty-nine randomized, placebo-controlled trials found that St. John’s wort was consistently more effective than placebo and just as effective as standard antidepressants.

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
fifteen hundred 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 compared with placebo. In addition, continued treatment with St. Johns wort
over six months may be effective at preventing a relapse of moderate depression in
patients who recover from an initial acute episode. For example, in a six-week
trial, 375 persons with average seventeen-item HAM-D scores of about 22
(indicating major depression of moderate severity) were given either St. John’s
wort or placebo. Persons 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 failed to find St. John’s wort more effective than placebo. However, three studies cannot overturn a body of positive research. It should be noted that 35 percent of double-blind studies involving pharmaceutical antidepressants have also failed to find the active agent significantly more effective than placebo. 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 such as 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 eight double-blind trials enrolling a total of more than twelve hundred people have compared St. John’s wort with fluoxetine (Prozac), citalopram (Celexa), paroxetine (Paxil), or sertraline (Zoloft). 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 six-week study of 388 people with major depression of mild to moderate severity, St. John’s wort proved just as effective as the drug citalopram (Celexa) and more effective than placebo. 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 also has been compared with older antidepressants, with generally favorable results.

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. 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, 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. However, subsequent evidence corrected this view. It now appears that standard St. John’s wort extract contains about 1 percent to 6 percent hyperforin. Evidence from animal and human studies suggests that it is the hyperforin in St. John’s wort that raises the levels of neurotransmitters. Nonetheless, there may be other active ingredients in St. John’s wort also at work. In fact, two double-blind trials using a form of St. John’s wort with low hyperforin content found it effective. More research is necessary to discover just how St. John’s wort acts against depression.

Polyneuropathy. A double-blind, placebo-controlled trial of fifty-four people with diabetic neuropathy or other forms of neuropathy (pain, numbness, or tingling caused by injury to nerves) did not find St. John’s wort effective for this purpose.

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 four weeks. Overall, about 2.4 percent reported problems. The most common complaints were mild stomach discomfort (0.6 percent); allergic reactions, primarily rash, (0.5 percent); tiredness (0.4 percent); and restlessness (0.3 percent). Another study followed 313 individuals treated with St. John’s wort for one year. 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. Animal studies involving enormous doses of St. John’s wort extracts for twenty-six weeks have not shown any serious effects.

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.

Photosensitivity. 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. The
results showed a mild but measurable increase in reaction to ultraviolet (UV)
radiation. Another trial found that a one-time dose of St.
John’s wort containing two or six times the normal daily dose did not cause an
increased tendency to burn, nor did seven days of treatment at the normal dose.
However, there is a case report of severe and unexpected burning in an individual
who used St. John’s wort and then received UV therapy for psoriasis. In addition,
two individuals using topical St. John’s wort experienced severe reactions to sun
exposure.

Persons who are especially sensitive to the sun should not exceed the recommended dose of St. John’s wort and should continue to take the usual precautions against burning. Individuals receiving UV treatment should not use St. John’s wort at all, and those who apply St. John’s wort to the skin should keep those parts of their bodies shielded from the sun.

In addition, combining St. John’s wort with other medications that cause increased
sun sensitivity, such as sulfa drugs and the anti-inflammatory
medication piroxicam (Feldene), may lead to problems. The medications omeprazole
(Prilosec) and lansoprazole (Prevacid) may also increase the tendency of St.
John’s wort to cause photosensitivity.

Finally, a report suggests that regular use of St. John’s wort might also increase the risk of sun-induced cataracts. Although this information is preliminary, it would be prudent for persons taking the herb on a long-term basis to wear sunglasses when outdoors.

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. This is a potentially serious
risk. St. John’s wort should not be combined with prescription antidepressants
except on the specific advice of a physician. Because some antidepressants, such
as Prozac, linger in the blood for quite some time, persons who
have been taking such drugs should exercise caution when switching from these 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.

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 (such as Prilosec),
atypical
antipsychotics such as olanzapine or clozapine (for
schizophrenia), anesthetics, and the new heart disease drug ivabradine. In fact,
there are theoretical reasons to believe that this herb might reduce the
effectiveness of, or otherwise interact with, about 50 percent of all medications.
Problems could arise, for instance, if a person is taking St. John’s wort while
also working with a physician to adjust the dosage of a particular medication to
obtain an optimum balance of efficacy and side effects. If the person subsequently
stops 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 contraceptives and by doing so is thought to have led to
unwanted pregnancies.

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. (The same would be expected to occur if a person were 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. Nonetheless, it is recommended that people taking any oral or injected medication that is critical to their health or well-being entirely avoid using any form of St. John’s wort until more is known; those who are already taking the herb should not stop taking it until they can simultaneously have their drug levels monitored. It is also recommended that persons who are soon to undergo general anesthesia avoid use of the herb.

Safety in special circumstances. One animal study found no ill effects of St. John’s wort on the offspring of pregnant mice. However, these findings alone are not sufficient to establish the herb 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. 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.

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

Other concerns. Certain foods contain a substance called
tyramine. These foods include aged cheeses, aged or cured meats, 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. However,
other studies suggest that normal doses of the herb should not cause MAO-like
effects. Until this issue is sorted out, it is recommended 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, St. John’s wort should not be combined with these.

One small study suggests that high doses of St. John’s wort might slightly impair mental function. Another case report associates use of St. John’s wort with hair loss; 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. However, since it is unlikely that such a large amount of 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.

Transitioning from medications to St. John’s wort. For persons who are taking a prescription drug for mild to moderate depression, switching to St. John’s wort may be a reasonable idea if they prefer taking an herb. To avoid overlapping treatments, the safest approach is for an individual to stop taking the drug and allow it to wash out of his or her system before starting St. John’s wort. The individual should consult with his or her doctor regarding how much time is necessary.

For persons taking medication for severe depression, however, switching over to St. John’s wort is not a good idea. The herb is unlikely to work well enough for such a use, and depression could worsen to a dangerous level.

Important Interactions

Persons who are taking antidepressant drugs, including MAO inhibitors, SSRIs, and tricyclics, or possibly the drugs tramadol or sumatriptan (Imitrex), should not take St. John’s wort at the same time. To switch from such medications to St. John’s wort, individuals should let the medications flush out of their systems for a while (perhaps weeks, depending on the drug) before they start taking the herb.

Individuals who are taking 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 should be aware that St. John’s wort might cause such drugs to be less effective. Those who have been taking St. John’s wort while adjusting medication dosages to achieve proper blood levels should not suddenly stop St. John’s wort, as this could cause the drugs in the body to rebound to dangerously high levels.

Persons who are taking medications that cause sun sensitivity, such as sulfa drugs
and the anti-inflammatory medication piroxicam (Feldene), as well as omeprazole
(Prilosec) or lansoprazole (Prevacid), should keep in mind that St. John’s wort
might have an additive effect. Those who are taking stimulant drugs or herbs such
as Ritalin, caffeine, or ephedrine
(ephedra) should be aware that St. John’s wort might interact adversely with these
substances.

Bibliography

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Fava, M., et al. “A Double-Blind, Randomized Trial of St. John’s Wort, Fluoxetine, and Placebo in Major Depressive Disorder.” Journal of Clinical Psychopharmacology 25 (2005): 441-447.

Hebert, M. F., et al. “Effects of St. John’s Wort Hypericum perforatum on Tacrolimus Pharmacokinetics in Healthy Volunteers.” Journal of Clinical Pharmacology 44 (2004): 89-94.

Kasper, S., et al. “Continuation and Long-Term Maintenance Treatment with Hypericum Extract WS 5570 After Recovery from an Acute Episode of Moderate Depression.” European Neuropsychopharmacology 18 (2008): 803-813.

Sardella, A., et al. “Hypericum perforatum Extract in Burning Mouth Syndrome.” Journal of Oral Pathology and Medicine 37(2008): 395-401.

Uebelhack, R., J. U. Blohmer, et al. “Black Cohosh and St. John’s Wort for Climacteric Complaints.” Obstetrics and Gynecology 107 (2006): 247-255.

Uebelhack, R., J. Gruenwald, et al. “Efficacy and Tolerability of Hypericum Extract STW 3-VI in Patients with Moderate Depression.” Advances in Therapy 21 (2004): 265-275.