St John’s Wort

What is St. John’s Wort

St. John’s wort also known as Hypericum perforatum, is a plant with yellow flowers from family Hypericaceae that grows in the wild, whose medicinal uses were first recorded in ancient Greece 1. The dried Hypericum perforatum herb consisting mainly of the flowering tops, including leaves, unopened buds and flowers is the part used pharmaceutically 2. The flowering tops of St. John’s wort are used to prepare teas, tablets, and capsules containing concentrated extracts. Liquid extracts and topical preparations are also used. Several pharmacological activities, including anti-depressant, antiviral, and antibacterial effects, have been documented for extracts of St John’s wort and its constituents 3. Although Hypericum perforatum produces several bioactive compounds, its importance is mainly linked to two molecules highly relevant for the pharmaceutical industry: the prenylated phloroglucinol hyperforin and the naphtodianthrone hypericin 4. While the antidepressant properties of Hypericum perforatum extracts are linked to the presence of hyperforin, another major component, the naphtodianthrone hypericin has been identified as a promising anticancer agent and a potential treatment against neurodegenerative diseases including Alzheimers’s disease 5. Besides St. John’s wort use as a potential antidepressant, hyperforin is also considered a powerful antibacterial compound, effective against all gram-positive bacteria and penicillin-resistant and methicillin-resistant (MRSA) Staphylococcus aureus 6.

However, consumers need to be aware of serious concerns about its safety and effectiveness. St. John’s wort interacts with many medications, making the medications less effective. St. John’s wort may cause serious interactions with prescription drugs, herbs, or supplements. Therefore, people using any medications should consult their healthcare providers, including a pharmacist, prior to starting therapy 7.

Historically, St. John’s wort has been used for a variety of conditions, including depression, kidney and lung ailments, insomnia, and depression, and to aid wound healing.

Currently, St. John’s wort is most often used as a dietary supplement for depression 8, 9. In the United States, the Food and Drug Administration (FDA) has not approved its use as an over-the-counter or prescription medicine for depression.

People also use it as a dietary supplement for other conditions, including menopausal symptoms, attention-deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder. It is used topically for wound healing.

The most common modern-day use of St. John’s wort is for depression. Studies have shown St. John’s wort may be equally effective as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitor (SSRI) antidepressants for mild to moderate depression 9. However, the results of studies on the effectiveness of St. John’s wort for depression are mixed 10.

There has been extensive research on St. John’s wort, especially on its use for depression and on its interactions with medications. Conditions such as ADHD, irritable bowel syndrome, and quitting smoking, current evidence indicates that St. John’s wort is not helpful. For others, such as menopausal symptoms, premenstrual syndrome, and obsessive-compulsive disorder, the evidence is inconclusive.

It has been clearly shown that St. John’s wort can interact in dangerous, sometimes life-threatening ways with a variety of medicines.

What Do We Know About St. John’s wort Safety ?

  • St. John’s wort can weaken the effects of many medicines, including crucially important medicines such as Antidepressants, Birth control pills, Cyclosporine, which prevents the body from rejecting transplanted organs, Digoxin, a heart medication, Some HIV drugs including indinavir, Some cancer medications including irinotecan, Warfarin, an anticoagulant (blood thinner)
  • Serotonin is a brain chemical targeted by antidepressants. Combining St. John’s wort and certain antidepressants can lead to a potentially life-threatening increase in serotonin levels—a condition called serotonin syndrome. Symptoms range from tremor and diarrhea to very dangerous confusion, muscle stiffness, drop in body temperature, and even death 11.
  • Psychosis is a rare but possible side effect of taking St. John’s wort, particularly in people who have or are at risk for mental health disorders, including bipolar disorder 11.
  • St. John’s wort may cause increased sensitivity to sunlight. Other side effects can include anxiety, dry mouth, dizziness, gastrointestinal symptoms, fatigue, headache, or sexual dysfunction.

St. John’s Wort bioactive compounds

Hypericum perforatum contains several classes of biologically active compounds. The composition of extracts from St. John’s wort or Hypericum perforatum has been studied extensively and many secondary metabolites including rutin, hyperforin, hyperoside, quercitrin, isoquercitrin, quercetin, hypericin, and chlorogenic acid, have been identified 12. Nevertheless, two compounds have emerged as the most important for the pharmaceutical industry: hyperforin and hypericin 4.

Hyperforin is a prenylated phloroglucinol derivative that constitutes the most abundant lipophilic component of the hydroalcoholic extracts of Hypericum perforatum 13. The antidepressant and neuro-active effects for which St. John’s wort extracts are known could eventually be attributed to the presence of this particular component and pure hyperforin alone can reproduce most of them 14. Many antidepressants rely on the capacity to inhibit the uptake of important neurotransmitters like serotonin, dopamine (DA), or noradrenaline (norepinephrine) 15. Hyperforin constitutes a natural synaptosomal inhibitor of neurotransmitter uptake. Its efficiency is comparable to that of tricyclic antidepressants (TCA) or serotonin specific inhibitors (SSRI) but without the side-effects typical for these drugs 16.

Unlike many other anti-depressants, hyperforin can inhibit the synaptosomal uptake of the amino acid transmitters, gamma-aminobutyric acid (GABA), and L-glutamate 17. This is due to its mode of action that instead of being based on the competitive interactions for the transporter binding sites, relies on the increase of intracellular Na+ known to be critical for the regulation of neurotransmitter uptake 17. These characteristics confer to hyperforin the status of a broad-spectrum uptake inhibitor of neurotransmitters, whose effects have been reported in several behavioral studies on rats and humans 18.

St. John’s wort extracts are also the main source of natural hypericin. The naphtodianthrone hypericin is regarded as an efficient anticancer compound that induces an apoptotic response after specifically binding to melanoma cancer cells 19. The successful application of hypericin in cancer photodynamic therapy (PDT) takes advantage of the properties of hypericin as one of the most powerful photosensitizers known in nature 20. When exposed to light, hypericin can induce an apoptotic signal. This involves the formation of reactive oxygen species (ROS) that eventually lead to the killing of the tumor 21. Hypericin therapy also induces an increase in cytokine levels, leading to an inflammatory response and the activation of immune cells 22. This mechanism is known as Immunogenic Cell Death. Hypericin is classified as a type II immunogenic cell death inducer 23 since the apoptotic response it induces is triggered at the level of the endoplasmic reticulum. Molecules capable of inducing such immunogenic cell death responses are classified as “damage-associated molecular patterns” (DAMPs) and have become a new avenue of treatment for cancer 23. Hypericin is the most potent natural Immunogenic Cell Death inducer known to date, and its properties are being explored to find even more effective analogues.

The antiviral properties of hypericin were shown against a large number of viruses including HIV, influenza virus A, herpes simplex, bovine diarrhea virus, hepatitis C, duck reovirus, and bronchitis virus 24, 25, 26. Hypericin seems to be particularly effective against enveloped viruses by targeting and modifying viral proteins 27. This effect is enhanced by light, which not only inactivates the virus, but can also prevent fusion of the virus with the cell membrane of the host 28.

It is important to note that other compounds produced by Hypericum perforatum are also regarded as bioactive compounds. These include phenolic derivatives such as tannins and xanthones. Further examples include the flavonoids quercetin, hyperoside, rutin and isoquercitrin. Concentrations of flavonoids can range between 7 to 12% in flowers 29. Flavonoids confer strong antioxidative properties to St. John’s wort extracts. When in high concentrations, these extracts can be referred to as Flavonoids-rich extracts of Hypericum perforatum. They are proposed to reduce the effects of oxidative stress that acts upon such processes as aging, carcinogenesis, diabetes, and many other clinical conditions 30. Flavonoids like quercitin, kaemferol, and biapigenin also have gastro and neuroprotective functions due to their capacity of inhibiting the peroxidation of mitochondrial membranes. By maintaining mitochondrial transmembrane electric potential, the overload of calcium uptake in the mitochondrion is avoided 31.

Interest in St. John’s wort extracts has gone beyond the antidepressant, anti-cancer and antiviral applications after it was discovered that these extracts can reduce both memory impairment and beta-amyloid (β-amyloid) fibril deposition in the brain of APP-transgenic mice 5. These results are compliant with in vitro (test tube) studies showing that hypericin can interfere and significantly inhibit the formation of β-amyloid fibrils by associating with the precursors of these fibrils 32. At high concentrations, hypericin can alter cell membrane permeability and induce anomalous functioning in the affected cells 33. Rats treated with St. John’s wort extracts also showed an increased expression of the ABCC1 transporter which is involved in the clearance of brain tissues from the β-amyloid plaques 5. Since this effect is independent of hyperforin it suggests an additional role for hypericin 5.

In light of these recent studies, it is likely that there will be an increased pharmaceutical demand for both hyperforin and hypericin 4. Since large-scale synthetic production is prohibitively expensive, St. John’s wort extracts remain the main source of these two compounds.

St. John’s Wort Uses

Extracts of Saint John’s Wort St. John’s wort have been used for centuries to treat anxiety, depression, sciatica, or even wounds 34. Externally, oily preparations of the Hypericum perforatum plant may be applied to treat minor burns, wounds, skin inflammation, and nerve pain 35. Internally, it is indicated for the treatment of anxiety and mild to moderately severe depression 36 competing for status as a standard antidepressant therapy and being the only herbal alternative to synthetic antidepressants 37. In recent years, St. John’s wort extracts have been used mainly for their antidepressant properties. While St. John’s wort extracts are commonly sold as mild antidepressants, reports on their efficiency are contradictory, with some studies finding no enhanced effect over placebo treatments 38. In addition, there are reports regarding the existence of local bias being observed in German-speaking countries 39. Besides its use as a potential antidepressant, hyperforin is also considered a powerful antibacterial compound, effective against all gram-positive bacteria and penicillin-resistant and methicillin-resistant (MRSA) Staphylococcus aureus 40.

  • It is important to note that in the United States, the Food and Drug Administration has not approved its use as an over-the-counter or prescription medicine for depression.
  • St. John’s wort is not a proven therapy for depression. Do not use St. John’s wort to replace conventional care or to postpone seeing your health care provider. Inadequately treated depression may become severe and, in some cases, may be associated with suicide. Consult a health care provider if you or someone you know may be depressed.
  • St. John’s wort may help some types of depression, similar to treatment with standard prescription antidepressants, but the evidence is not definitive.
  • Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants.
  • St. John’s wort can also limit the effectiveness of many prescription medicines.
  • Psychosis is a rare but possible side effect of taking St. John’s wort.
  • Tell all your health care providers about any complementary health approaches you use. Give them a full picture of what you do to manage your health. This will help ensure coordinated and safe care.

Depression

Depression is a medical condition that affects about 1 in 10 U.S. adults. Mood, thoughts, physical health, and behavior all may be affected. The symptoms and severity of depression can vary from person to person. Depression can be treated with conventional medicine, including antidepressants and certain types of psychotherapy 41.

Current research suggests that depression is caused by a combination of genetic, biological, environmental, and psychological factors 42.

Depression can happen at any age, but often begins in adulthood. Depression is now recognized as occurring in children and adolescents, although it sometimes presents with more prominent irritability than low mood. Many chronic mood and anxiety disorders in adults begin as high levels of anxiety in children.

Depression, especially in midlife or older adults, can co-occur with other serious medical illnesses, such as diabetes, cancer, heart disease, and Parkinson’s disease. These conditions are often worse when depression is present. Sometimes medications taken for these physical illnesses may cause side effects that contribute to depression. A doctor experienced in treating these complicated illnesses can help work out the best treatment strategy.

Risk factors include:

  • Personal or family history of depression
  • Major life changes, trauma, or stress
  • Certain physical illnesses and medications

Treatment: Things You Can Do

Depression, even the most severe cases, can be treated. The earlier that treatment can begin, the more effective it is. Here are other tips that may help you or a loved one during treatment for depression:

  • Try to be active and exercise.
  • Set realistic goals for yourself.
  • Try to spend time with other people and confide in a trusted friend or relative.
  • Try not to isolate yourself, and let others help you.
  • Expect your mood to improve gradually, not immediately.
  • Postpone important decisions, such as getting married or divorced, or changing jobs until you feel better. Discuss decisions with others who know you well and have a more objective view of your situation.
  • Continue to educate yourself about depression.

Treatment: Medications and Psychotherapy

Depression is usually treated with medications, psychotherapy, or a combination of the two. If these treatments do not reduce symptoms, electroconvulsive therapy (ECT) and other brain stimulation therapies may be options to explore.

  • Antidepressants are medicines that treat depression. They may help improve the way your brain uses certain chemicals that control mood or stress. You may need to try several different antidepressant medicines before finding the one that improves your symptoms and has manageable side effects.
  • Several types of psychotherapy (also called “talk therapy” or, in a less specific form, counseling) can help people with depression. Examples of evidence-based approaches specific to the treatment of depression include cognitive-behavioral therapy (CBT), interpersonal therapy (IPT), and problem-solving therapy.
  • Brain Stimulation Therapies: If medications do not reduce the symptoms of depression, electroconvulsive therapy (ECT) may be an option to explore. Other more recently introduced types of brain stimulation therapies used to treat medicine-resistant depression include repetitive transcranial magnetic stimulation (rTMS) and vagus nerve stimulation (VNS).

St. John’s Wort as Treatment for Depression

St. John’s wort is not a proven therapy for depression. Do not use St. John’s wort to replace conventional care or to postpone seeing your health care provider. Inadequately treated depression may become severe and, in some cases, may be associated with suicide. Consult a health care provider if you or someone you know may be depressed.

In the United States, the Food and Drug Administration (FDA) has not approved its use as an over-the-counter or prescription medicine for depression.

  • St. John’s wort is not a proven therapy for depression. Do not use St. John’s wort to replace conventional care or to postpone seeing your health care provider 41.
  • Inadequately treated depression may become severe and, in some cases, may be associated with suicide. Consult a health care provider if you or someone you know may be depressed 41.

Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. St. John’s wort can also limit the effectiveness of many prescription medicines.

The trial (analysis of results was completed in 2001) funded by the National Institute of Health, National Center for Complementary and Integrative Health 43 involving 340 men and women ages 18 and older with depression with average age of participants entering the study was approximately 42 years, took place from December 1998 to June 2000. 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.

The study 43 found no statistically significant difference between St. John’s wort and placebo on improvement in the Hamilton Depression Scale (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 44.

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.

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.

This review 45 concluded that St. John’s Wort was effective for the treatment of mild to moderate depression in comparison with placebo and equivalent to taking pharmaceutical antidepressants. However, the small sample sizes, variations between studies and failure to report levels of statistical significance mean that the results may not be reliable 45. In this review of six double-blind randomized controlled trials (n=977), St. John’s Wort was compared with pharmaceutical antidepressants such as imipramine (75 mg twice daily), fluoxetine (20 mg/day), sertraline (50 mg/day) or placebo. The dosing schedule of St. John’s Wort ranged from once to three times daily and total dosages ranged from 300 to 900 mg/day. The duration of treatment varied from 6 to 24 weeks. Diagnoses of depression in the included studies were made by reference to clinical history and by the use of evaluation tools such as the Hamilton Depression Rating Scale (HAM-D), the Clinical Global Impressions scale and the Depression scale. Outcomes in the included studies were only reported in terms of the HAM-D scale. The participants were aged from 18 to 70 years. Where gender ratios were reported, the percentage of females was higher than males. Participants taking St. John’s Wort showed a greater decrease in the HAM-D score when compared with placebo (1 randomized controlled trial, n=72), with a reduction from 19.7 (± 3.4) to 8.9 (± 4.3) for the St. John’s Wort group and from 20.1 (± 2.6) to 14.4 (± 6.8) for the placebo group. However, decreases in the HAM-D score were found to be similar between groups when comparing participants taking St. John’s Wort with those taking pharmaceutical antidepressants, including imipramine together with placebo (1 randomized controlled trial, n=324), fluoxetine (2 randomized controlled trials, n=310) and sertraline (2 randomized controlled trials, n=271).

A 2009 systematic review of 29 international studies in 5489 patients with depression 46, 47 that compared treatment with extracts of St. John’s wort for 4 to 12 weeks with placebo (an inactive substance that appears identical to the study substance) 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 including the United States, St. John’s wort extracts seemed less effective.

Two studies 48, 49, both sponsored by NCCIH and the National Institute of Mental Health, did not have positive results. Neither St. John’s wort nor a standard antidepressant medication decreased symptoms of minor depression better than a placebo in a 2011 study 50. The herb was no more effective than placebo in treating major depression of moderate severity in a large 2002 study.

Preliminary studies 51, 52 suggest that St. John’s wort may prevent nerve cells in the brain from reabsorbing certain chemical messengers, including dopamine and serotonin. Scientists have found that these naturally occurring chemicals are involved in regulating mood, but they are unsure exactly how they work.

St. John’s Wort as Treatment for Somatoform disorders

Somatoform disorders are mental symptoms such as pain and fear that lack a physical source or reason for their existence. Early evidence shows that St. John’s wort may help with somatoform disorders. Further research is needed to confirm these results 9.

St. John’s Wort as Treatment for Weight Loss

Early research shows that a combination product containing St. John’s wort was effective for weight loss. Further research of St. John’s wort alone is needed before a conclusion may be drawn 53.

St. John’s Wort as Treatment for Attention Deficit Hyperactivity Disorder (ADHD)

According to the National Institute of Mental Health at NIH, Attention Deficit Hyperactivity Disorder (ADHD) affects 3 to 5 percent of children in the United States and it is one of the most common mental disorders that develop in children 54. NIMH states that children with ADHD have impaired functioning in multiple settings, including home, school, and in relationships with peers. Children with chronic conditions like ADHD are reported to have higher rates of complementary and alternative medicine use and may turn to dietary and herbal supplements such as St. John’s wort. However, according to authors of a new NCCAM-funded study 55, St. John’s wort does not appear to have an impact on the symptoms of ADHD in children and adolescents. Another study 56 also showed no evidence to support its use in these patients and their use is discouraged because of the potential adverse effects these products could cause. A review 57 of available evidence regarding the use of complementary/alternative medicine like St. John’s Wort in adolescents with the attention deficit hyperactivity syndrome (ADHD) and mood disorders, does not show any favorable results beyond placebo.

Researchers at Bastyr University conducted an 8-week randomized, placebo-controlled, double-blind trial of St. John’s wort among a volunteer sample of 54 children aged 6 to17 years with ADHD. Participants were randomly assigned to receive 300 mg of Hypericum perforatum (St. John’s wort) standardized to 0.3 percent hypericin—an active ingredient in St. John’s wort—or placebo 3 times daily for 8 weeks. The participants were evaluated for changes in inattentiveness and hyperactivity from baseline at weeks 1, 2, 4, 6, and 8.

While symptom improvement was noted in both the treatment and the placebo groups, the data suggest that St. John’s wort had no additional benefit beyond that of placebo for treating symptoms of ADHD.

This study used a preparation of St. John’s wort with a standardized hypericin content. However the researchers note that studies involving St. John’s wort also standardized to hyperforin—another active ingredient in St. John’s wort—could be beneficial. Hyperforin is believed to inhibit reuptake of key brain chemicals—serotonin, dopamine, and norepinephrine. The authors note that hyperforin is highly unstable and can become inactive quickly. The researchers believe that if a St. John’s wort product with a higher and more stable hyperforin content became available, it would be worthy of further investigation in ADHD.

St Johns Wort Dosage

  • Adults (over 18 years old)

For anxiety, 900 milligrams of St. John’s wort has been taken by mouth twice daily for several weeks.

For cancer, 0.05-0.50 milligrams per kilogram of hypericin has been taken by mouth for up to three months.

For mild to moderate depression, 20-1,800 milligrams St. John’s wort has been taken by mouth once to three times for 4-52 weeks. Extracts of St. John’s wort used in studies included WS® 5570, WS 5572, WS 5573, ZE 117, STW 3-VI, STW3, PM235, LoHyp-57, LI 160, Psychotonin® forte extract,and Hyperforat® and were generally standardized to contain 0.3% hypericin and 2-5% hyperforin.

For severe depression, 900-1,800 milligrams of St. John’s wort (extracts LI 160 and WS® 5570) has been taken by mouth daily for 8-12 weeks.

For HIV, 0.5 milligrams per kilogram of hypericin has been taken by mouth, without evidence of benefit.

For irritable bowel syndrome, 450 milligrams of St. John’s wort has been taken twice daily for 12 weeks, without evidence benefit.

For nerve pain, three 900 microgram hypericin tablets were taken by mouth for two treatment periods of five weeks each.

For obsessive-compulsive disorder, 450-1,800 milligrams (standardized to 0.3% hypericin) were taken by mouth daily for 12 weeks.

For pain due to burning mouth syndrome, 300 milligram capsules of St. John’s wort (containing hypericin 0.31% and hyperforin 3.0%) have been taken by mouth three times daily for 12 weeks.

For menopausal symptoms, 300 milligrams St. John’s wort (Kira®) has been taken by mouth three times daily for 12 weeks and 0.4mg hypericin drops (Hyperforat®) has been taken by mouth daily for 12 weeks.

For premenstrual syndrome (PMS), 300-900 milligrams St. John’s wort (standardized to 3.38% hyperforin and 0.18% hypericin) or 1,360 micrograms of hypericin have been taken by mouth daily for two menstrual cycles.

For seasonal affective disorder (SAD), 900 milligrams and unspecified doses of St. John’s wort (LI 160 and Kira®) have been taken by mouth once to three times daily with or without light therapy for 4-8 weeks.

For smoking cessation, 300 milligrams St. John’s wort (LI-160 extract) has been taken by mouth once or twice daily for up to three months and a week.

For social phobia, 600-1,800 milligrams St. John’s wort has been taken by mouth daily for 12 weeks.

For somatoform disorders, 300 milligrams of St. John’s wort (LI 160 extract) has been taken by mouth twice daily for six weeks.

For atopic dermatitis, 1.5% hyperforin (verum) cream has been used on the skin twice daily for four weeks.

For psoriasis, St. John’s wort ointment has been used two times daily on the skin for four weeks.

For wound healing, 20% St. John’s wort in petroleum jelly has been used on the affected skin three times daily for 16 days.

  • Children (under 18 years old)

For ADHD, 300 milligrams of St. John’s wort (standardized to 0.3% hypericin) has been used in children three times daily for eight weeks, without evidence of benefit.

For depression, 150-1,800 milligrams St. John’s wort was taken by mouth once to three times daily for up to eight weeks.

St. John’s Wort Side Effects

The most common side effects of St. John’s wort include dry mouth, dizziness, gastrointestinal symptoms, increased sensitivity to sunlight, and fatigue 43. 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) 58 issued a Public Health Advisory on February 10, 2000, warning physicians of these potential adverse interactions and advising them to alert their patients.

  • St. John’s wort may cause anxiety, headache, muscle cramps, sweating, weakness, dry mouth, or skin irritation 59.
  • Use with caution when using St. John’s wort with drugs metabolized by cytochrome P450, as decreased drug effectiveness may occur.
  • St. John’s wort may increase the risk of photosensitivity. Use cautiously in people with sensitive skin or those taking photosensitizing drugs.
  • St. John’s wort may increase the risk of serotonin syndrome. Use cautiously in people taking agents that increase the risk of serotonin syndrome.St. John’s wort may result in altered menstrual flow, bleeding, unwanted pregnancies, and hormone level changes. Use cautiously in women taking contraceptives or other estrogen agents by mouth.
  • St. John’s wort may alter drug levels. Use cautiously in people taking agents for bacterial or fungal infections, agents for erectile dysfunction, antianxiety agents, antihistamines, fertility agents, P-glycoprotein agents, pain relievers, or theophylline.
  • St. John’s wort may cause mania or psychosis. Use cautiously in people with mental illnesses and those taking antipsychotics.
  • St. John’s wort may change how sugar is processed in the body. Use cautiously in people with diabetes or in those taking anti-diabetic agents.
  • St. John’s wort may cause high levels of thyroid-stimulating hormone (TSH). Use cautiously in people with thyroid disorders or those using thyroid hormones.
  • Use cautiously in people with cataracts, due to the potential association between an element St. John’s wort and cataracts.
  • St. John’s wort may cause heart burn, loss of appetite, diarrhea, nausea, vomiting, and constipation. Use cautiously in people with stomach and intestine problems.
  • St. John’s wort may cause liver damage. Use cautiously in people with liver problems or those taking agents that damage the liver.
  • St. John’s wort may alter blood pressure and cause increased or uneven heart rate. Use cautiously in people with high blood pressure or abnormal heart rhythms.
  • St. John’s wort may cause swelling. Use caution in people prone to swelling.
  • St. John’s wort may cause dizziness, tiredness, insomnia, problems with the nervous system, skin tingling or prickling, and nerve pain. Use cautiously in people taking agents that affect the nervous system.
  • St. John’s wort may lower the seizure threshold. Use cautiously in individuals with seizures, and drugs that may lower the seizure threshold.
  • St. John’s wort may lower cholesterol drug concentration and may increase cholesterol. Use cautiously in people with high cholesterol and those taking agents to lower levels of cholesterol.
  • St. John’s wort may stimulate release of certain hormones. Use cautiously with hormonal agents.
  • Avoid in people with a known allergy or sensitivity to St. John’s wort or to any of its parts.
  • St. John’s wort has decreased levels of drugs for HIV/AIDs. Avoid in people with HIV/AIDS who are taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors, as suggested by the U.S. Food & Drug Administration (FDA).
  • St. John’s wort has decreased levels of drugs that suppress the immune system. Avoid in individuals receiving transplants and taking agents that suppress the immune system (particularly cyclosporine).
  • Avoid in people with suicidal thoughts.
  • St. John’s wort resulted in difficulty inducing anesthesia and relaxation. Avoid before surgery.
  • St. John’s wort use with cancer agents may result in reduced effectiveness and treatment failure. Avoid in people using cancer agents.
  • St. John’s wort may result in result in reduced digoxin efficacy. Avoid using with cardiac glycosides such as digoxin.
  • St. John’s wort may decrease effectiveness of agents that thin blood. Avoid use in people with bleeding disorders or in those taking drugs that thin blood.

Avoid in pregnant and lactating women due to a lack of information.

References
  1. National Center for Complementary and Integrative Health, U.S. Department of Health & Human Services. St. John’s Wort and Depression: In Depth. https://nccih.nih.gov/health/stjohnswort/sjw-and-depression.htm
  2. Heinrich M., Vikuk V., Daniels R., Stintzing F.C., Kammerer D.R. Characterization of Hypericum perforatum L.(St. John’s wort) macerates prepared with different fatty oils upon processing and storage. Phytochem. Lett. 2017;20:470–480.
  3. Mills, S., Bone, K. (2000) Principles and Practice of Phytotherapy.Edinburgh : Churchill Livingstone.
  4. Rizzo, P., Altschmied, L., Ravindran, B. M., Rutten, T., & D’Auria, J. C. (2020). The Biochemical and Genetic Basis for the Biosynthesis of Bioactive Compounds in Hypericum Perforatum L., One of the Largest Medicinal Crops in Europe. Genes, 11(10), 1210. https://doi.org/10.3390/genes11101210
  5. Hofrichter, J., Krohn, M., Schumacher, T., Lange, C., Feistel, B., Walbroel, B., Heinze, H. J., Crockett, S., Sharbel, T. F., & Pahnke, J. (2013). Reduced Alzheimer’s disease pathology by St. John’s Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice. Current Alzheimer research, 10(10), 1057–1069. https://doi.org/10.2174/15672050113106660171
  6. Schempp CM, Pelz K, Wittmer A, Schöpf E, Simon JC. Antibacterial activity of hyperforin from St John’s wort, against multiresistant Staphylococcus aureus and gram-positive bacteria. Lancet. 1999 Jun 19;353(9170):2129. doi: 10.1016/S0140-6736(99)00214-7
  7. Hojo Y, Echizenya M, Ohkubo T, et al. Drug interaction between St John’s wort and zolpidem in healthy subjects. J.Clin.Pharm.Ther. 2011;36(6):711-715.
  8. Singer A, Schmidt M, Hauke W, et al. Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine. 6-15-2011;18(8-9):739-742.
  9. Bitran S, Farabaugh AH, Ameral VE, et al. Do early changes in the HAM-D-17 anxiety/somatization factor items affect the treatment outcome among depressed outpatients? Comparison of two controlled trials of St John’s wort (Hypericum perforatum) versus a SSRI. Int.Clin.Psychopharmacol. 2011;26(4):206-212.
  10. Sarris J, Panossian A, Schweitzer I, et al. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur. Neuropsychopharmacol. 2011;21(12):841-860.
  11. National Center for Complementary and Integrative Health. St. John’s Wort and Depression: In Depth. https://nccih.nih.gov/health/stjohnswort/sjw-and-depression.htm
  12. Scotti F., Löbel K., Booker A., Heinrich M. St. John’s Wort (Hypericum perforatum) Products – How Variable Is the Primary Material? Front. Plant Sci. 2019;9:1–12. doi: 10.3389/fpls.2018.01973
  13. Laakmann G., Schüle C., Baghai T., Kieser M. St. John’s Wort in mild to moderate depression: The relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31:54–59. doi: 10.1055/s-2007-979346
  14. Cervo L., Rozio M., Ekalle-Soppo C.B., Guiso G., Morazzoni P., Caccia S. Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extracts. Psychopharmacology. 2002;164:423–428. doi: 10.1007/s00213-002-1229-5
  15. Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int. J. Mol. Sci. 2017;18:2483. doi: 10.3390/ijms18112483
  16. Chatterjee S.S., Bhattacharya S.K., Wonnemann M., Singer A., Müller W.E. Hyperforin as a possible antidepressant component of Hypericum extracts. Life Sci. 1998;63:499–510. doi: 10.1016/S0024-3205(98)00299-9
  17. Müller W.E., Singer A., Wonnemann M. Hyperforin—Antidepressant activity by a novel mechanism of action. Pharmacopsychiatry. 2001;34:98–102. doi: 10.1055/s-2001-15512
  18. Schellenberg R., Sauer S., Dimpfel W. Pharmacodynamic effects of two different hypericum extracts in healthy volunteers measured by quantitative EEG. Pharmacopsychiatry. 1998;31:44–53. doi: 10.1055/s-2007-979345
  19. Dudek-Perić A.M., Gołąb J., Garg A.D., Agostinis P. Melanoma targeting with the loco-regional chemotherapeutic, Melphalan: From cell death to immunotherapeutic efficacy. Oncoimmunology. 2015;4:5–7. doi: 10.1080/2162402X.2015.1054600
  20. Garg A.D., Krysko D.V., Vandenabeele P., Agostinis P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol. Immunother. 2012;61:215–221. doi: 10.1007/s00262-011-1184-2
  21. Agostinis P., Vantieghem A., Merlevede W., De Witte P.A.M. Hypericin in cancer treatment: More light on the way. Int. J. Biochem. Cell Biol. 2002;34:221–241. doi: 10.1016/S1357-2725(01)00126-1
  22. Garg A.D., Nowis D., Golab J., Agostinis P. Photodynamic therapy: Illuminating the road from cell death towards anti-tumour immunity. Apoptosis. 2010;15:1050–1071. doi: 10.1007/s10495-010-0479-7
  23. Krysko O, Løve Aaes T, Bachert C, Vandenabeele P, Krysko DV. Many faces of DAMPs in cancer therapy. Cell Death Dis. 2013 May 16;4(5):e631. doi: 10.1038/cddis.2013.156
  24. Chen H., Muhammad I., Zhang Y., Ren Y., Zhang R., Huang X., Diao L., Liu H., Li X., Sun X., et al. Antiviral activity against infectious bronchitis virus and bioactive components of Hypericum perforatum L. Front. Pharmacol. 2019;10:1–22. doi: 10.3389/fphar.2019.01272
  25. Du X., Xiao R., Fu H., Yuan Z., Zhang W., Yin L., He C., Li C., Zhou J., Liu G., et al. Hypericin-loaded graphene oxide protects ducks against a novel duck reovirus. Mater. Sci. Eng. C. 2019;105:110052. doi: 10.1016/j.msec.2019.110052
  26. Mehjabin R., Xiong L., Huang R., Yang C., Chen G., He L., Liao L., Zhu Z., Wang Y. Full-length transcriptome sequencing and the discovery of new transcripts in the unfertilized eggs of Zebrafish (Danio rerio) G3 Genes Genomes Genet. 2019;9:1831–1838. doi: 10.1534/g3.119.200997
  27. Degar S., Prince A.M., Pascual D., Lavie G., Levin B., Mazur Y., Lavie D., Ehrlich L.S., Carter C., Meruelo D. Inactivation of the Human Immunodeficiency Virus by Hypericin: Evidence for Photochemical Alterations of p24 and a Block in Uncoating. AIDS Res. Hum. Retroviruses. 1992;8:1929–1936. doi: 10.1089/aid.1992.8.1929
  28. Lenard J., Rabsont A., Vanderoef R. Photodynamic inactivation of infectivity of human immunodeficiency virus and other enveloped viruses using hypericin and rose bengal: Inhibition of fusion and syncytia formation (vesicular stomatitis virus/influenza virus/Sendai virus/hemolysis) Proc. Natl. Acad. Sci. USA. 1993;90:158–162. doi: 10.1073/pnas.90.1.158
  29. Klemow M.K., Bartlow A., Crawford J., Kocher N., Shah J., Ritsick M. In: Herbal Medicine Biomolecular and Clinical Aspects. 2nd ed. Benzie I.F.F., Wachtel-Galor S., editors. Volume 9. CRC Press; Boca Raton, FL, USA: 2011.
  30. Zou Y., Lu Y., Wei D. Antioxidant activity of a flavonoid-rich extract of Hypericum perforatum L. in vitro. J. Agric. Food Chem. 2004;52:5032–5039. doi: 10.1021/jf049571r
  31. Silva B., Oliveira P.J., Dias A., Malva J.O. Quercetin, kaempferol and biapigenin from hypericum perforatum are neuroprotective against excitotoxic insults. Neurotox. Res. 2008;13:265–279. doi: 10.1007/BF03033510
  32. Bramanti E., Lenci F., Sgarbossa A. Effects of hypericin on the structure and aggregation properties of β-amyloid peptides. Eur. Biophys. J. 2010;39:1493–1501. doi: 10.1007/s00249-010-0607-x
  33. Chimon S., Shaibat M.A., Jones C.R., Calero D.C., Aizezi B., Ishii Y. Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer’s β-amyloid. Nat. Struct. Mol. Biol. 2007;14:1157–1164. doi: 10.1038/nsmb1345
  34. Oliveira, A. I., Pinho, C., Sarmento, B., & Dias, A. C. (2016). Neuroprotective Activity of Hypericum perforatum and Its Major Components. Frontiers in plant science, 7, 1004. https://doi.org/10.3389/fpls.2016.01004
  35. Patocka J. (2003). The chemistry, pharmacology, and toxicology of the biologically active constituents of the herb Hypericum perforatum L. J. Appl. Biomed. 1 61–70.
  36. Butterweck V, Schmidt M. St. John’s wort: role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr. 2007;157(13-14):356-61. doi: 10.1007/s10354-007-0440-8
  37. Wurglics M, Schubert-Zsilavecz M. Hypericum perforatum: a ‘modern’ herbal antidepressant: pharmacokinetics of active ingredients. Clin Pharmacokinet. 2006;45(5):449-68. doi: 10.2165/00003088-200645050-00002
  38. Hypericum Depression Trial Study Group Effects of Hypericum perforatum (St John’s Wort) in Major Depressive Disorder. J. Am. Med. Assoc. 2002;287:1807–1814. doi: 10.1001/jama.287.14.1807
  39. Linde K., Berner M.M., Kriston L. St John’s wort for major depression (Review) Wiley Cochrane Collab. 2008;4:1–55.
  40. Schempp C.M., Pelz K., Wittmer A., Schöpf E., Simon J.C. Antibacterial activity of hyperforin from St John’s wort, against multiresistant Staphylococcus aureus and gram-positive bacteria. Lancet. 1999;353:2129. doi: 10.1016/S0140-6736(99)00214-7
  41. National Center for Complementary and Integrative Health. St. John’s Wort and Depression. https://nccih.nih.gov/sites/nccam.nih.gov/files/SJW_and_Depression_11-30-2015.pdf
  42. National Institute of Mental Health. Depression. https://www.nimh.nih.gov/health/topics/depression/index.shtml
  43. National Center for Complementary and Integrative Health. Questions and Answers: A Trial of St. John’s Wort (Hypericum perforatum) for the Treatment of Major Depression. https://nccih.nih.gov/news/2002/stjohnswort/q-and-a.htm
  44. Shelton RC, Keller MB, Gelenberg AJ, et al. Effectiveness of St. John’s wort in major depression. JAMA, 2001; 285:1978-86.
  45. Clement K, Covertson CR, Johnson MJ, Dearing K. St. John’s wort and the treatment of mild to moderate depression: a systematic review. Holist Nurs Pract. 2006 Jul-Aug;20(4):197-203. doi: 10.1097/00004650-200607000-00008
  46. Linde K. St. John’s wort—an overview. Forschende Komplementärmedizin: Research in complementary medicine. 2009;16(3):146-155.
  47. Cochrane Review 8 October 2008. St. John’s wort for treating depression. http://www.cochrane.org/CD000448/DEPRESSN_st.-johns-wort-for-treating-depression.
  48. De Smet PA. Herbal remedies. New England Journal of Medicine. 2002;347(25):2046-2056.
  49. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287(14):1807-1814.
  50. Rapaport, M.H., Nierenberg, A.A., Howland, R., Dording, C., Schettler, P.J., and Mischoulon, D. The treatment of minor depression with St. John’s Wort or citalopram: Failure to show benefit over placebo. Journal of Psychiatric Research 45:931-941, 2011.
  51. Boyer EW, Shannon M. The serotonin syndrome. New England Journal of Medicine. 2005;352:1112-1120
  52. Clauson KA, Santamarina ML, Rutledge JC. Clinically relevant safety issues associated with St. John’s wort product labels. BMC Complementary and Alternative Medicine. 2008;8:42.
  53. Mayo Foundation for Medical Education and Research. MayoClinic. St. John’s wort (Hypericum perforatum). http://www.mayoclinic.org/drugs-supplements/st-johns-wort/background/hrb-20060053
  54. National Center for Complementary and Integrative Health. St. John’s Wort Shows No Impact on the Symptoms of ADHD. https://nccih.nih.gov/research/results/spotlight/061008.htm
  55. Weber W, Vander Stoep A, McCarty RL, et al. Hypericum perforatum (St. John’s Wort) for attention-deficit/hyperactivity disorder in children and adolescents. JAMA. 2008;299(22):2633–2641.
  56. Bloch MH, Mulqueen J. Nutritional Supplements for the Treatment of ADHD. Child Adolesc Psychiatric Clin N Am. 2014;23:883-97.
  57. Rev Chil Pediatr. 2017 Apr;88(2):294-299. doi: 10.4067/S0370-41062017000200018.Complementary/alternative medicine in adolescents with attention deficit hyperactivity disorder and mood disorders. https://www.ncbi.nlm.nih.gov/pubmed/28542667
  58. US Food and Drug Administration. Risk of Drug Interactions with St. John’s Wort and Indinavir and other Drugs. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm052238.htm
  59. Mayo Foundation for Medical Education and Research. MayoClinic. St. John’s wort (Hypericum perforatum). http://www.mayoclinic.org/drugs-supplements/st-johns-wort/safety/hrb-20060053
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