- St. John’s Wort and Depression: In Depth
- What’s the Bottom Line?
- About St. John’s Wort
- About Depression
- What the Science Says About the Effectiveness of St. John’s Wort for Depression
- What the Science Says About the Safety and Side Effects of St. John’s Wort for Depression
- NCCIH-Funded Research
- More to Consider
- Everything You Should Know Before Trying St. John’s Wort for Depression
- What is St. John’s wort?
- When did it become so popular in the US?
- Is there scientific evidence that St. John’s wort works for depression?
- Does it help with severe depression?
- Is St. John’s wort helpful for other things?
- What’s a typical dosage of St. John’s wort for depression?
- What are the dangers—if any—of taking St. John’s wort?
- St. John’s wort for treating depression.
- St. John’s Wort and Anxiety: The Good and the Bad
- Questions and Answers: A Trial of St. John’s Wort (Hypericum perforatum) for the Treatment of Major Depression
- About the Trial
- 7. How many people participated in the trial, and what were their characteristics?
- 8. How were participants selected?
- 9. What are some of the primary characteristics of this trial?
- 10. What are the main results of this trial?
- 11. Why did sertraline have no greater effect than placebo?
- 12. What is sertraline?
- 13. Why was sertraline used in the trial?
- 14. Who provided the extracts and drugs used in the trial?
- 15. What dose of St. John’s wort was used in the NIH study?
- 16. What dose of sertraline was used in the NIH study?
- 17. What were the most common side effects for St. John’s wort or sertraline in the study?
- 18. Who conducted the study?
- 19. Who else was involved in the NIH St. John’s wort trial?
- 20. Where did the study take place?
- 21. How long did it take to complete the trial?
- Conclusion and Future Research
- For Additional Reading
St. John’s Wort and Depression: In Depth
What’s the Bottom Line?
How much do we know about St. John’s wort for depression?
- We know a fair amount about the short-term effects of St. John’s wort on depression but less about its long-term effects.
What do we know about the effectiveness of St. John’s wort for depression?
- St. John’s wort isn’t consistently effective for depression. Do not use it to replace conventional care or to postpone seeing your health care provider.
What do we know about the safety of St. John’s wort for depression?
- St. John’s wort limits the effectiveness of many prescription medicines.
- Combining St. John’s wort and certain antidepressants can lead to a potentially life-threatening increase in your body’s levels of serotonin, a chemical produced by nerve cells.
- Don’t try to treat depression on your own. Depression can become severe if you don’t get effective, professional help. For some people, depression can increase the risk of suicide. Talk to your health care provider if you or someone you know may be depressed.
About St. John’s Wort
- St. John’s wort (Hypericum perforatum), a plant that grows in the wild, has been used for centuries for mental health conditions. It’s widely prescribed for depression in Europe.
- St. John’s wort is sold as a dietary supplement in the United States, where the standards for selling supplements are less strict than the standards for prescription or over-the-counter drugs.
For more information, see the National Center for Complementary and Integrative Health (NCCIH) Web page about St. John’s wort.
Depression (major depressive disorder or clinical depression) is a common but serious mood disorder. It causes severe symptoms that affect how you feel, think, and handle daily activities, such as sleeping, eating, or working. In 2015, almost 7 percent of U.S. adults had at least one episode of major depression in the past year. Symptoms of depression vary but can include
- Feeling sad or anxious often or all the time
- Not wanting to do activities that used to be fun
- Feeling irritable‚ easily frustrated‚ or restless
- Having problems with sleep and feeling tired
- Eating more or less than usual or having no appetite
- Experiencing pain that doesn’t improve with treatment
- Having trouble concentrating, remembering details, or making decisions
- Feeling guilty, worthless, or helpless
- Thinking about suicide or hurting yourself.
Antidepressants and certain types of psychotherapy help treat depression.
For more information on depression, visit the National Institute of Mental Health (NIMH) Web page on depression.
What the Science Says About the Effectiveness of St. John’s Wort for Depression
The results of studies on the effectiveness of St. John’s wort for depression are mixed.
- In a 12-week, 2011 clinical trial with 73 participants, neither St. John’s wort nor a standard antidepressant medication called citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased symptoms of minor depression better than a placebo. The study was funded by NCCIH and NIMH.
- In a 26-week clinical trial with 124 participants, St. John’s wort, a standard antidepressant (sertraline, an SSRI), and a placebo were similarly effective in treating major depression of moderate severity. NCCIH and NIMH funded this 2012 analysis of data collected in 2002.
- A 2008 review of 29 international studies suggested that St. John’s wort may be better than a placebo and as effective as different standard prescription antidepressants for major depression of mild to moderate severity. St. John’s wort also appeared to have fewer side effects than standard antidepressants. The studies conducted in German-speaking countries—where St. John’s wort has a long history of use by medical professionals—reported more positive results than those done in other countries, including the United States.
- St. John’s wort was no more effective than placebo in treating major depression of moderate severity, an NCCIH- and NIMH-funded study of 340 participants reported in 2002.
The Placebo Effect
- The placebo effect is when patients’ health improves because they think that an intervention—a pill, procedure, or injection, for example—will help. In a clinical trial of St. John’s wort for major depression, what participants guessed they were taking may have affected their recovery from depression more than what they actually received. A health care provider’s style in talking with patients also may have a positive effect on patient health that is separate from the treatment.
What the Science Says About the Safety and Side Effects of St. John’s Wort for Depression
- Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. Symptoms occur within minutes to hours, and may include agitation, diarrhea, fast heartbeat, high blood pressure, hallucinations, increased body temperature, and more.
- There are case reports of St. John’s wort having dangerous side effects, such as worsening of psychotic symptoms in people with bipolar disorder or schizophrenia.
- Taking St. John’s wort can weaken many prescription medicines, such as:
- Birth control pills
- Cyclosporine, used to prevent the body from rejecting transplanted organs
- Digoxin, a heart medication
- Oxycodone, a pain medicine
- Some HIV drugs, including indinavir
- Some cancer medications, including irinotecan
- Warfarin, an anticoagulant (blood thinner).
- Other side effects of St. John’s wort are usually minor and uncommon. They may include upset stomach, dry mouth, headache, fatigue, dizziness, confusion, sexual dysfunction, or sensitivity to sunlight. Also, St. John’s wort is a stimulant and may worsen feelings of anxiety in some people.
NCCIH is studying the potential drug interactions of different herbs, including St. John’s wort.
More to Consider
- Depression can be a serious illness and lead to an increased risk of suicide. If you or someone you know may have depression, talk to a health care provider. Don’t try to treat depression on your own.
- Do not use St. John’s wort to replace conventional care or to postpone seeing a health care provider about a mental health problem.
- Dietary supplements can cause medical problems if you use them incorrectly or in large amounts. Some may interact with medications you take. Your health care provider can advise you.
- Many dietary supplements haven’t been tested in pregnant women, nursing mothers, or children. We have little safety information on St. John’s wort for pregnant women or children. Talk with health care providers if you’re pregnant or nursing or are considering giving a dietary supplement to a child. To learn more, see NCCIH’s fact sheet Using Dietary Supplements Wisely.
- Take charge of your health—talk with your health care providers about any complementary health approaches you use. Together, you can make shared, well-informed decisions.
Everything You Should Know Before Trying St. John’s Wort for Depression
Dubbed “nature’s antidepressant,” the herb St. John’s wort is a popular alternative to antidepressants for people with mild to moderate depression. Herbalists say this ancient herb also has other important uses—involving pain, wound healing, and more—that too often fly under the radar. With large numbers of adulterated herbs on the market, though, you may not always get what you’re expecting. Here’s everything you need to know if you’re considering taking the supplement:
What is St. John’s wort?
The term wort means a plant used as a food or medicine. St. John’s Wort (SJW) is an herb that grows naturally around the world. Herbalists have long used the stems, leaves, buds, and fruit as a natural remedy. Other names for this herb are Hypericum perforatum (which is its official name), goatweed, Klamath weed, racecourse weed, and tipton weed. You can find St. John’s wort in health-food stores and pharmacies in the form of tinctures, fluid extracts, powders, oil infusions, or teas.
When did it become so popular in the US?
Although SJW has long been part of European folk medicine, according to the American Botanical Council (ABC), it was relatively obscure until the late 1990s, when the first European studies documented its effectiveness for treating mild to moderate depression. SJW is now big business, with the ABC noting that US sales reached $57 million in 2015.
Is there scientific evidence that St. John’s wort works for depression?
When researchers at the Rand Corporation, a nonprofit global policy think tank, looked at 35 studies using the herb for mild-to-moderate depression they found that, for their participants, SJW was just as effective as taking an antidepressant. Their review, published in the journal Systematic Reviews in 2016, also revealed that in studies pitting SJW against a placebo, SJW came out ahead. Even better, side effects were significantly lower for people on SJW than a medication. They had fewer GI or neurological problems, and lower rates of sexual concerns.
“St. John’s wort is valuable in the treatment of mild to moderate outpatient depression,” says Richard P. Brown, associate professor of clinical psychiatry at Columbia University in New York, who notes it is the most frequently prescribed “antidepressant” in Germany.
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Still, the number of patients examined in the aforementioned studies was relatively small, says the review’s coauthor Eric Apaydin, a policy researcher at Rand, in Santa Monica, Calif. What’s more, Apaydin says, “since it’s not a drug, the dosage and strain is not the same across all these studies, so it’s hard to know what the true effect is. There still needs to be more research.”
Does it help with severe depression?
Not enough quality studies have examined SJW for major depression for experts to suggest using it for this condition. “We don’t know if it’s beneficial for severe depression or if it isn’t, but it’s not recommended for that because we don’t have the evidence,” Apaydin says. In any event, if you have severe depression, you should see a psychiatrist and not rely on an over-the-counter herb.
Is St. John’s wort helpful for other things?
According to the ABC, lotions and oils containing SJW can be spread on the skin to treat bug bites, sunburns, wounds, and even hemorrhoids. Oils or tinctures taken internally help some people with inflammatory bowel problems. Tiny pilot studies or case reports have also shown SJW might be effective for premenstrual dysphoric disorder (PMDD), psoriasis, and atopic dermatitis.
It can also quell painful nerve pain for many. When Melanie St. Ours, 35, developed a stabbing pain in her tooth three years ago, her dentist suggested bonding the area to protect the nerve. As an herbalist in suburban Baltimore, Maryland, and the author of The Simple Guide to Natural Health, St. Ours knew that SJW is in a category of herbs called “nervines,” which are believed to impact the nervous system. She stopped by a store after leaving the dentist and picked up a tincture for $12.
For her, it was even more effective than she expected. As soon as she got home, she mixed a quarter-teaspoon of the tincture with a few ounces of water, swishing the mixture around her mouth before swallowing. Within ten minutes, she could feel the pain lessening. By the end of the week after regularly taking the product, all the pain had subsided. She has not gone back to the dentist for the bonding. Keep in mind that clinical trials have not verified this effect of SJW, although there are a few animal studies that suggest it, so a placebo effect could be at least partially at play.
What’s a typical dosage of St. John’s wort for depression?
You’ll want a product that is “standardized” (meaning it has a certain amount of the most active ingredient), since this is what the researchers use.
According to the Department of Veterans Affairs, which commissioned the Rand study in advance of updating its practice guidelines, people with mild depression who want to try the herb should look for an extract standardized to 0.3 percent hypericin. A good starting dose, the VA says, is 300 mg three times daily, increasing if there are no problematic side effects up to 1200 mg a day.
What are the dangers—if any—of taking St. John’s wort?
Probably the biggest side effect of SJW is that it can interact with many common medications. For this reason, the Mayo Clinic warns that it should not be taken by anyone on birth control pills (it can decrease their effectiveness). Mayo also cautions people on blood-thinning drugs, chemotherapy, HIV/AIDS medications, and medicine to prevent organ rejection after a transplant that problematic interactions can occur.
You should also not take SJW if you are on an antidepressant. The combination can cause serious complications, including a life-threatening condition known as serotonin syndrome. There are a few cases of people experiencing anxiety from taking the herb.
These cautions, along with side-effects like sun-provoked rashes, are the main reason some psychiatrists are wary. “Of any herb I could prescribe, St John’s Wort is the one with the most herb-drug interactions,” says Lila Massoumi, clinical associate professor of psychiatry at Michigan State University and the chair of the American Psychiatric Association Caucus on Complementary & Integrative Psychiatry, who says she does not generally recommend SJW to her patients.
The problem with doctored or incorrectly labeled SJW has become serious, the ABC says. Before the drug became so popular, it was gathered from the wild. Once demand outpaced this supply, commercial farms in Asia and other countries began to cultivate it. Over the years, some of these imported herbs have come under question. It’s thought that some are simply mislabeled. But other SJW products have been found to have food coloring and other unwanted additives designed to confuse laboratory tests. What these products actually are is anyone’s guess.
Added coloring is especially problematic, because herbalists like St. Ours use the look of a tincture as one way to evaluate SJW’s potency. The best herbs are picked when the flowers peak in summer, St. Ours says. “If it is a deep ruby color, that tells you the plant was picked at the right time and processed in the right way.” With color-spiked products on the market, this may not always be true.
If you have tried SJW in the past and didn’t find it effective, you may want to buy from another, more reputable, company before deciding the herb does not work for you. “It is crucial to select a high quality brand, such as those that have been tested in scientific studies,” Brown advises.
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St. John’s wort for treating depression.
Depression is characterised by depressed mood and/or loss of interest or pleasure in nearly all activities and a variety of other symptoms for periods longer than two weeks. Extracts of St. John’s wort (botanical name Hypericum perforatum L.) are prescribed widely for the treatment of depression.
We have reviewed 29 studies in 5489 patients with depression that compared treatment with extracts of St. John’s wort for 4 to 12 weeks with placebo treatment or standard antidepressants. The studies came from a variety of countries, tested several different St. John’s wort extracts, and mostly included patients suffering from mild to moderately severe symptoms. Overall, the St. John’s wort extracts tested in the trials were superior to placebo, similarly effective as standard antidepressants, and had fewer side effects than standard antidepressants. However, findings were more favourable to St. John’s wort extracts in studies from German-speaking countries where these products have a long tradition and are often prescribed by physicians, while in studies from other countries St. John’s wort extracts seemed less effective. This differences could be due to the inclusion of patients with slightly different types of depression, but it cannot be ruled out that some smaller studies from German-speaking countries were flawed and reported overoptimistic results.
Patients suffering from depressive symptoms who wish to use a St. John’s wort product should consult a health professional. Using a St. John’s wort extract might be justified, but important issues should be taken into account: St. John’s wort products available on the market vary to a great extent. The results of this review apply only to the preparations tested in the studies included, and possibly to extracts with similar characteristics. Side effects of St. John’s wort extracts are usually minor and uncommon. However, the effects of other drugs might be significantly compromised.
St. John’s Wort and Anxiety: The Good and the Bad
A lot of the research surrounding St. John’s wort is for its use in treating depression. However, depression and anxiety are closely linked. An estimated 50 percent of people with depression also suffer from some form of anxiety disorder, according to the Anxiety and Depression Association of America.
St. John’s wort is thought to work by keeping the brain from using up neurotransmitters like serotonin, dopamine, GABA, and norepinephrine. As a result, the neurotransmitters are more effectively used in the brain. This can have an antidepressant and overall feel-good effect in the brain. As a result, a person could experience fewer bouts of anxiety.
Anxiety medications, such as benzodiazepines (including Xanax and Ativan), work on GABA transmitters in the brain. Therefore, many researchers believe that St. John’s wort could have anxiety-relieving effects due to its effects on GABA transmitters.
St. John’s wort is perhaps best known in its treatment for mild-to-moderate depression. A 2017 meta-analysis of 27 clinical trials published in the Journal of Affective Disorders concluded that St. John’s wort had a similar level of effectiveness as selective serotonin reuptake inhibitors (SSRIs) in treating mild-to-moderate depression.
The researchers noted the studies were all short-term, ranging from 4- to 12-weeks in length. Therefore, less is known about how effective St. John’s wort is long-term, compared to antidepressant medications. Some people prefer to take St. John’s wort over antidepressants because it typically causes fewer side effects.
Dosages differed between studies. Participants in one study from the National Institutes of Health regarding depression, took an average of 1,300 milligrams of St. John’s wort per day. The highest dose participants took was 1,800 milligrams, while the starting dose was usually 900 milligrams per day, with people taking 300 milligrams 3 times a day.
Unfortunately, there aren’t many long-term human studies related specifically to anxiety and St. John’s wort. A lot of the connections made between St. John’s wort and treating anxiety are because doctors know the effects St. John’s wort has on the brain. Most of these connections, however, are theoretical.
More human studies are needed but a 2017 study on rats showed that St. John’s wort reversed anxiety and depression in rats and improved their response to stress. A 2019 small human study of 48 people, found that taking St. John’s wort helped them respond more positively to negative signals. They also found that St. John’s wort did not change memory function.
A smaller study from 2008 published in the journal Human Psychopharmacology: Clinical and Experimental found that taking St. John’s wort didn’t help reduce anxiety.
The study asked 28 adults with depression and anxiety to take either a placebo or St. John’s wort and the herb kava. At the study’s conclusion, the participants reported improvements in depression symptoms, but not anxiety.
Questions and Answers: A Trial of St. John’s Wort (Hypericum perforatum) for the Treatment of Major Depression
2. Does St. John’s wort have side effects or interact with prescription medications?
The most common side effects of St. John’s wort include dry mouth, dizziness, gastrointestinal symptoms, increased sensitivity to sunlight, and fatigue. Research from the National Institutes of Health (NIH) reveals that St. John’s wort may reduce the effectiveness of several drugs by speeding up activity in a key pathway responsible for their breakdown. The end result is that blood levels of these drugs decrease because the body breaks them down faster making the drugs less effective. St. John’s wort especially affects indinavir, a protease inhibitor used to treat HIV infection. It may also affect cyclosporine, a drug used to help prevent organ transplant rejection, and other drugs that work through this same pathway in the body, such as birth control pills and medications for heart disease and depression. The U.S. Food and Drug Administration (FDA) issued a Public Health Advisory on February 10, 2000, warning physicians of these potential adverse interactions and advising them to alert their patients.
3. What was the St. John’s wort extract used in this trial?
The St. John’s wort extract used in this study was LI-160, manufactured by Lichtwer Pharma, AG (Berlin, Germany). It was selected because it is a well-characterized and well-studied extract of St. John’s wort that had published literature supporting its possible efficacy in treating depression. The entire supply of St. John’s wort extract used in the study came from one batch and was standardized to between 0.12 and 0.28 percent hypericin. Hypericin is thought to be one of the primary active ingredients in St. John’s wort.
4. What is major depression?
Major depressive disorder, also known as major depression, is the most common type of depressive illness. Symptoms usually develop over days, weeks, or months. They can cause distress and/or interfere with the ability to work, study, sleep, eat, and enjoy once-pleasurable activities. The description of a person experiencing a major depressive episode, as found in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), is that of someone who may feel sad, irritable, hopeless, discouraged, tired, worthless, or guilty much of the time. The person also often cannot think clearly, concentrate, or make decisions. This depressed mood lasts most of the day nearly every day for a period of at least 2 weeks. Untreated, the depression can last for 6 months or longer. Other than depressed mood and/or loss of interest or pleasure, symptoms include at least four of the following:
- Significant weight gain or loss
- Disturbance of normal sleeping patterns (insomnia, hypersomnia)
- Agitation or unusual slowness
- Fatigue or loss of energy nearly every day
- Feelings of worthlessness or guilt
- Diminished ability to think or concentrate
- Recurrent thoughts of death or suicide
Major depression can vary in degree from mild to moderate to severe. In mild cases, there may be some significant distress or interference with daily activities at work, at home, and in social life. In moderate depression, problems and impairments in these areas are more pronounced. If the depression is severe, the person may lose completely the ability to function.
5. Are there proven treatments for major depression?
Fortunately, major depression can be successfully treated. Treatments that have been scientifically proven include a variety of antidepressant medications approved by the FDA and certain psychotherapies, such as cognitive-behavioral therapy and interpersonal therapy. A first step toward getting treatment for depression is a complete physical examination and evaluation by a doctor. The physician can rule out medical conditions, such as a viral infection or thyroid disorder, that can cause the same symptoms as depression.
6. Why did NIH fund a trial of St. John’s wort?
There is considerable public interest in the possibility that St. John’s wort may be an effective treatment for depression. These claims are based on findings from research studies conducted in Europe; however, these studies had several limitations. According to the researchers who led this NIH study, important issues have been raised regarding the existing studies, including: limited information about the use of St. John’s wort in clinically defined major depression; lack of placebo-controlled trials that have included a separate, selective serotonin reuptake inhibitor (SSRI) antidepressant arm; and absence of data regarding long-term use of the extract. In addition, there were concerns that many of the studies had smaller numbers of participants.
Because of the growth in Americans’ use of St. John’s wort in recent years and the need to answer important remaining questions about the herb’s efficacy and long-term use for depression, NIH launched a large study of St. John’s wort in 1997. This 4-year, $6 million study was sponsored by the National Center for Complementary and Alternative Medicine (NCCAM), the National Institute of Mental Health (NIMH), and the NIH Office of Dietary Supplements (ODS). The main purpose of the trial was to determine whether a well-standardized extract of St. John’s wort is effective in the treatment of adults suffering from major depression of moderate severity.
About the Trial
7. How many people participated in the trial, and what were their characteristics?
There were 340 participants in the trial. The average age of participants entering the study was approximately 42 years. Nearly two-thirds were female (65.9 percent). The ethnic composition of the group was approximately 76 percent White, 10 percent Black/African American, 8 percent Hispanic, and 6 percent “other.”
8. How were participants selected?
Eligible participants were men and women ages 18 and older with depression who were confirmed prior to entering the study as having a diagnosis of major depressive disorder as defined by the DSM-IV. In addition, to be eligible, participants had to have at least a moderate level of depressive symptoms as measured by the Hamilton Depression Scale (HAM-D), and at least a moderate level of functional impairment from depression on the Global Assessment of Functioning Scale (GAF) of the DSM-IV. Individuals with severe symptoms who were in need of hospitalization, at high risk for suicide, or having any signs of psychosis (such as hallucinations or delusions) were excluded. These eligibility criteria provided a well-defined group of participants that would represent adults with major depression whose symptoms were significant, though not completely incapacitating.
9. What are some of the primary characteristics of this trial?
This trial had three treatment arms. Participants were assigned at random to one of three treatments for an initial 8 weeks: St. John’s wort, an SSRI antidepressant medication—sertraline (Zoloft), or placebo (inactive pills that looked exactly like St. John’s wort or sertraline tablets). This was a double-blind study, meaning neither the participants nor the clinical staff knew which treatments were being assigned. Participants who responded well to their assigned treatment could continue on it for an additional 4 months during the trial’s second, or continuation, phase. This phase allowed researchers to gather additional data on the safety and longer-term effects of the treatments. This was the first trial to include a long-term followup phase studying the use of St. John’s wort. Participants had regular followup visits to monitor symptoms and any side effects. If participants experienced significant worsening of depression, suicidality, or psychosis, they were withdrawn from the study; offered FDA-approved treatment with at least three followup visits, based on need; and referred to a psychiatrist not involved in the study for care.
To determine the efficacy of St. John’s wort for major depression, the group of participants assigned to St. John’s wort was compared to the group assigned to placebo during the first 8 weeks of treatment. Two primary outcomes were measured:
- Improvements in the HAM-D total score, indicated by a reduction to normal levels in score;
- Complete response to treatment, the percentage of participants essentially free of symptoms of depression, also called “in remission”
A complete response was determined by both a reduction in the HAM-D score and the clinician’s overall estimate of improvement, as measured by the Clinical Global Impressions-Improvement Scale (CGI-I). In addition to the tests already mentioned, several secondary measures of efficacy were used, including clinician-rated and patient-self-administered scales.
10. What are the main results of this trial?
The trial found no statistically significant difference between St. John’s wort and placebo on improvement in HAM-D scores or percentage of complete responses. The percentage of participants in remission from major depression at the end of the 8-week initial treatment phase was approximately 24 percent for St. John’s wort and about 32 percent for placebo. Overall, the percentage of participants who improved either partially or completely was about 38 percent for St. John’s wort and 43 percent for placebo. These findings suggest that St. John’s wort is not effective for the treatment of major depression in adults with a moderate level of symptoms. This conclusion is supported by another recently reported placebo-controlled study (Shelton, et al., 2001).
The study also found no significant difference between sertraline and placebo on either primary outcome, with about 25 percent of the participants on sertraline reaching remission as compared to about 32 percent on placebo. The rate of response overall was about 49 percent for sertraline and 43 percent for placebo, but this difference was not statistically significant. At the same time, additional planned analyses of the data did show that sertraline was superior to placebo on other secondary tests of efficacy, such as the CGI-I alone. The results of the sertraline versus placebo comparison indicate that the sensitivity of this study to antidepressant effects was limited. In other words, even two treatments (sertraline and placebo) previously proven to differ in efficacy for major depression were found not to differ on the primary measures used in this study.
11. Why did sertraline have no greater effect than placebo?
The authors offer possible explanations as to why sertraline was not superior to placebo overall in this study. First, it is known that 35 percent of studies of approved, active antidepressants do not show greater efficacy of the antidepressant over placebo. Second, it is possible that the dose range for sertraline of 50 to 100 milligrams (mg) per day during the first 8 weeks, chosen to ensure effective treatment while minimizing side effects, may not have been adequate despite extensive discussions among study designers to find the best possible dose range.
12. What is sertraline?
Sertraline is an FDA-approved antidepressant of the type known as a selective serotonin reuptake inhibitor (SSRI). Serotonin is a neurotransmitter, a chemical messenger in the brain, that is thought to be in low supply in individuals suffering from depression. An SSRI, such as sertraline, works by blocking the reuptake of serotonin in the nerve cells in the brain, thus making more serotonin available for proper brain function.
13. Why was sertraline used in the trial?
Sertraline was included in this trial to provide a third “active” control arm to aid in assessing the trial’s overall validity. That is, whether the study measured antidepressant effects and not the impact of unrelated factors, such as the effect of a patient withdrawing from the study before the treatment could work. By having a third trial arm with sertraline and comparing it to placebo, the researchers could also measure how sensitive the trial was to detecting any antidepressant effects of St. John’s wort. If sertraline would prove superior to placebo in this study, as expected, then the study’s ability to detect antidepressant effects would be confirmed. In addition, the researchers chose to use an SSRI because there is a lack of placebo-controlled trials of St. John’s wort that included an SSRI arm.
14. Who provided the extracts and drugs used in the trial?
Lichtwer Pharma donated the St. John’s wort extract in tablet form together with matched placebo. Pfizer Inc. donated the supply of sertraline and its matching placebo.
15. What dose of St. John’s wort was used in the NIH study?
The starting dose of St. John’s wort was 900 mg per day (given in 300 mg tablets, three times a day). That dose could be increased up to 1,500 mg per day in the first 6 weeks of the study until the end of the first phase of the trial at 8 weeks. During the second phase of the trial, after 8 weeks, the dose could be increased to 1,800 mg per day. The average dose of St. John’s wort in the initial 8 weeks of the study was about 1,300 mg per day.
16. What dose of sertraline was used in the NIH study?
The average dose of sertraline in this study was 75 mg per day. The starting dose was 50 mg per day and could be increased to 100 mg per day in the first phase of the study. During the second, or continuation, phase of the trial the dose could be increased to 150 mg per day. The range of dosages was comparable to that used in clinical practice.
17. What were the most common side effects for St. John’s wort or sertraline in the study?
St. John’s wort was generally well tolerated. However, people who were taking the extract did experience more sexual dysfunction, general swelling, and urinary frequency than those taking placebo. Side effects for those taking sertraline included sexual dysfunction, sweating, nausea, and diarrhea.
18. Who conducted the study?
The principal investigator for this study was Jonathan R.T. Davidson, M.D., professor of psychiatry and director of the Anxiety and Traumatic Stress Program at Duke University Medical Center, Durham, North Carolina. Dr. Davidson is an expert in clinical research on conventional as well as complementary and alternative medical treatments for mood and anxiety disorders. Dr. Davidson and his collaborators in the Department of Psychiatry and Behavioral Sciences, the Duke Clinical Research Institute, and the Research Triangle Institute, coordinated the entire study.
19. Who else was involved in the NIH St. John’s wort trial?
The scientific aspects of the study were monitored by NIMH and NCCAM staff with the input of an independent group of advisors who were consulted regularly on the protocol and study progress before and during the course of the project. This group included the following: four professors of psychiatry at different universities with specific expertise in the treatment of depression; a professor of pharmacology with expertise in clinical research, pharmacokinetics, and metabolism; a professor of statistics; an expert in botanical medicinal products; and an advocate for people with depression. The study’s safety and data quality were monitored on a quarterly basis by the NIMH Data and Safety Monitoring Board, a group including experts in clinical studies and patient representatives. In addition, this study was monitored by the FDA under an Investigational New Drug application filed by Lichtwer Pharma.
20. Where did the study take place?
The study took place in 12 community and academic psychiatric research centers across the United States. The sites and lead investigators were as follows:
21. How long did it take to complete the trial?
Recruitment of participants took place from December 1998 to June 2000. Analysis of results was completed in 2001, and the paper was submitted for publication in late 2001.
Conclusion and Future Research
22. Should St. John’s wort be used for major depression?
At this time, it is not known what role St. John’s wort should play in the management of depression. The results of this study indicate that St. John’s wort is not effective in treating major depression of moderate severity.
23. Will NIH conduct more research on St. John’s wort?
NCCAM, NIMH, and ODS are planning to conduct a study of the efficacy and safety of St. John’s wort for the treatment of minor depression.
For Additional Reading
The Coordinating Center for the St. John’s wort trial was led by Dr. Davidson and his colleagues at the Duke University Medical Center Department of Psychiatry and Behavioral Sciences, the Duke Clinical Research Institute, and the Research Triangle Institute. For more Duke University Medical Center news visit http://corporate.dukemedicine.org/news_and_publications.
NCCAM is dedicated to exploring complementary and alternative healing practices in the context of rigorous science, training complementary and alternative medicine (CAM) researchers, and disseminating authoritative information to the public and professionals. For additional information on CAM, contact the NCCAM Clearinghouse:
Toll-free in the U.S.: 1-888-644-6226
TTY (for deaf and hard-of-hearing callers): 1-866-464-3615
The NCCAM Clearinghouse provides information about CAM, including St. John’s wort, and about NCCAM.
The National Institute of Mental Health is committed to reducing the burden of mental illness through research on mental disorders and the underlying basic science of brain and behavior. For more information about depression or other mental health disorders visit www.nimh.nih.gov.
The Office of Dietary Supplements, whose mission is to explore the potential role of dietary supplements to improve health care, promotes the scientific study of dietary supplements through conducting and coordinating scientific research and compiling and disseminating research results. For more information visit dietary-supplements.info.nih.gov.