St. John's wort's therapeutic uses

DEFINITION: Natural plant product used to treat specific health conditions.

PRINCIPAL PROPOSED USE: Mild to moderate depression

OTHER PROPOSED USES: Anxiety, attention deficit disorder, burning mouth syndrome, diabetic neuropathy and other forms of neuropathy, eczema, insomnia, menopause, obsessive-compulsive disorder, premenstrual syndrome, seasonal affective disorder, smoking cessation, viral infections

Overview

St. John’s wort is a common perennial herb with many branches and bright yellow flowers that grow 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 Uses

In Germany, other parts of Europe, and the United States, St. John’s wort is 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 clinical depression of mild to moderate intensity. 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.

Research suggests that St. John’s Wort is more effective than a placebo, and some studies have shown it to be approximately as effective as standard drugs with fewer side effects. However, St. John’s wort may interact harmfully with many standard medications. It can limit the effectiveness of prescription medication and potentially combine with other antidepressants to cause a spike in serotonin levels that can be life-threatening.

St. John’s wort has also shown promise for the 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, 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 hyperactivity disorder (ADHD), anxiety, insomnia, menopausal symptoms, premenstrual syndrome (PMS), seasonal affective disorder (SAD), and social phobia. However, scientific evidence of the herb's benefits for these conditions is mixed. 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 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 the combination treatment was significantly more effective than the placebo for both problems. According to a literature review and a meta-analysis, St. John's wort appears to be effective in easing the symptoms of menopause.

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.

St. John's wort also may not aid in smoking cessation. A study of 118 participants failed to find statistically significant differences in nicotine cravings, sleep regulation, or anxiety among individuals quitting smoking by taking a placebo or St. John's wort. However, some small studies found positive results.

Therapeutic Dosages

The typical dosage of St. John’s wort ranges from 300 to 1200 milligrams (mg) per day. Usually, doses are divided and taken two to three times a day of an extract standardized to contain 0.3 percent hypericin. Some products are standardized to hyperforin content (usually 2 to 5 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. A 2018 Journal of Pharmacy and Pharmacology meta-analysis of fifty-nine studies found that taking 1 mg of hyperforin or less daily was associated with fewer major interactions.

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 2009 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. A 2016 systematic review of thirty-five studies concurred with those results. However, the US National Center for Complementary and Integrative Health considers evidence still inconclusive, and the US Food and Drug Administration (FDA) has not approved St. John's wort for prescription medications for depression. For these reasons, patients should not replace other forms of treatment with St. John's wort, and a healthcare provider should always be consulted.

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. John's 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 a high placebo effect and no exact 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 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 who believed it was too unstable to play a major role in the herb’s action. However, subsequent evidence corrected this view. Standard St. John’s wort extract contains between 1 and 6 percent hyperforin (though these supplements are not regulated). Evidence from animal and human studies suggests the active ingredient hyperforin in St. John’s wort raises the levels of neurotransmitters, but other active ingredients may also contribute. In fact, two double-blind trials using a form of St. John’s wort with low hyperforin content found it effective. A 2022 study reported the development of a new class of antidepressant drugs based on hyperforin analysis.

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. Neither of the two small studies assessed in 2018 provided strong evidence for St. John's wort as a chronic pain treatment.

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, particularly fair-skinned individuals, 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, 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, research suggests that regular use of St. John’s wort can increase the risk of sun-induced cataracts and other eye damage. Individuals who take St. John’s wort should avoid extensive sun exposure and wear protective eyewear.

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. 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. Among them are 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), blood thinners (such as warfarin), chemotherapy drugs, oral contraceptives, tricyclic antidepressants, proton pump inhibitors (such as Prilosec), atypical antipsychotics such as olanzapine or clozapine (for schizophrenia), anesthetics, and the heart disease drug ivabradine. Others include certain benzodiazepines, methadone, oxycodone, anticonvulsants, antihypertensives, antihyperlipidemic drugs, calcium channel blockers, diabetes drugs, respiratory drugs, finasteride (used for prostate problems), and antimicrobials.

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 unintended pregnancies.

One study showed that among people taking a cholesterol-lowering medication in the statin family, the 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.)

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 the 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. Although studies suggest St. John's wort was not associated with preterm birth, it may be linked to congenital abnormalities. 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. Despite passing through breast milk, infants exposed to St. John's wort did not appear to experience side effects, and midwives recommend it as a treatment for postpartum depression.

Case reports suggest that, like other antidepressants, St. John’s wort can cause episodes of mania in individuals with or at risk of bipolar disorder (manic-depressive disorder). 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 from the late 1990s suggested that St. John’s might present this risk as well. However, other studies suggested that normal doses of the herb should not cause MAO-like effects. A 2018 study in BioMed Research International found that hypericin inhibited MAO-A slightly, but hyperforin did not. Until this issue is sorted out conclusively, 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 the 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. Based on a small rat study published in the Journal of the Turkish-German Gynecological Association in 2019, daily consumption of St. John's wort could lead to a permanent reduction in the number of ovarian follicles and ultimately to ovarian failure.

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 to stop taking the drug and allow it to wash out of their system before starting St. John’s wort. The individual should consult their doctor regarding how much time is necessary. Individuals taking medication for severe depression should not switch to St. John’s wort. The herb is unlikely to work well enough for such use, and depression could worsen to a dangerous level.

In individuals with cancer, taking St. John’s wort may reduce the efficacy of chemotherapy drugs or increase the risk of skin toxicity resulting from radiation therapy. Those who take St. John’s wort during their care plan activities should avoid it for one week prior to treatments.

Important Interactions

Many types of drugs can interact with St. John’s wort. Individuals taking antidepressants, including monoamine oxidase inhibitors (MAO inhibitors), selective serotonin reuptake inhibitors (SSRIs), or tricyclics, should not take St. John’s wort. The combination can lead to a deadly condition called serotonin syndrome. These medications include citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil), fluoxetine (Prozac), sertraline (Zoloft), amitriptyline (Elavil), imipramine (Tofranil), phenelzine, (Nardil), tranylcypromine (Parnate), and nefazodone (Serzone). To transition to one of these medications after taking St. John’s wort, individuals should allow a several-week gap between medications to ensure all of the herb is eliminated.

Taking allergy drugs called antihistamines, like cetirizine (Zyrtec) and fexofenadine (Allegra) with St. John’s wort causes them to be less effective. It also has the same effect on hormonal birth control methods: the anxiety medication alprazolam (Xanax), the asthma medication theophylline (Elixophylline), and the anticoagulant coumadin (Warfarin).

People 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. The effects of sedatives like diazepam (Valium) and zaleplon (Sonata) are amplified when taking this herb. Stimulants or herbs such as Ritalin, caffeine, or ephedrine (ephedra) might interact adversely with St. John’s wort.

Finally, some people with HIV take St. John’s wort in the false belief that the herb will fight HIV/AIDS. The unintended result may be to reduce the potency of standard anti-HIV drugs.

Other interactions include many medications for migraines, antifungals, statins, calcium channel blockers, antiretroviral medication, immunosuppressants, and over-the-counter cough medicine. Because so many medications can have harmful interactions with St. John’s wort, it is essential to consult a medical professional before adding it to a treatment regimen. People who are pregnant, breastfeeding, or have surgery scheduled within two weeks should not take St. John’s wort.

Bibliography

Bjerkenstedt, L., et al. “Hypericum Extract LI 160 and Fluoxetine in Mild to Moderate Depression: A Randomized, Placebo-Controlled Multi-center Study in Outpatients.” European Archives of Psychiatry and Clinical Neuroscience 255 (2005): 40–47.

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): 441–47.

Hamdaoui, Yamina El, et al. "Analysis of Hyperforin (St. John's Wort) Action at TRPC6 Channel Leads to the Development of a New Class of Antidepressant Drugs." Molecular Psychiatry, vol. 27, 2022, pp. 5070-5085, doi: 10.1038/s41380-022-01804-3.

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): 803–13.

Peterson, Bahtya, and Hoang Nguyen. "St. John's Wort." StatPearls, National Institutes of Health, 16 May 2023, www.ncbi.nlm.nih.gov/books/NBK557465. Accessed 20 Sept. 2024.

Pietrangelo, Ann. "St. John’s Wort: The Benefits and the Dangers." Healthline, 29 Nov. 2023, www.healthline.com/health-news/is-st-johns-wort-safe-080615. Accessed 20 Sept. 2024.

Rowles, Alexandra. “How St. John’s Wort Fights Depression.” Healthline, 26 Mar. 2017, www.healthline.com/nutrition/st-johns-wort. Accessed 4 May 2020.‌

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

"St. John's Wort." National Center for Complementary and Integrative Health, National Institutes of Health, Oct. 2020, nccih.nih.gov/health/st-johns-wort. Accessed 20 Sept. 2024.

“St. John’s Wort.” Reviewed by Eric Hurwitz, Health Library, 27 Mar. 2020, healthlibrary.epnet.com/GetContent.aspx?token=D39207C8-9100-4DC0-9027-9AC6BA11942D&chunkiid=31050#refM1. Accessed 4 May 2020. ‌

"St. John's Wort and Depression: In Depth." National Center for Complementary and Integrative Health, National Institutes of Health, Dec. 2017, nccih.nih.gov/health/stjohnswort/sjw-and-depression.htm. Accessed 20 Sept. 2024.

Uebelhack, R., J. U. Blohmer, et al. “Black Cohosh and St. John’s Wort for Climacteric Complaints.” Obstetrics and Gynecology 107 (2006): 247–55.

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): 265–75.