St. John's Wort (Hypericum perforatum)
1. Identity: Botanical and Chemical Overview
Botanical Identity
St. John's wort (SJW), known botanically as Hypericum perforatum, is a sprawling, leafy herb that grows in open, disturbed areas throughout much of the world's temperate regions. It derives from a flowering plant found in Europe and Asia. The genus name Hypericum belongs to the family Hypericaceae. The plant is a bushy perennial with yellow flowers, which blooms around St. John the Baptist's Day in June. Commercial products are derived from the dried flowering tops or aerial parts of the plant; these parts are harvested shortly before or during the flowering period.
Common Names and Etymology
St. John's wort is a plant with yellow flowers that has been widely used in various systems of traditional medicine, including Greek, Islamic, and Chinese medicine. The name St. John's wort apparently refers to John the Baptist, as the plant blooms around the time of the feast of St. John the Baptist in late June. St. John's Wort's Latin name, Hypericum perforatum, derives from Greek, meaning "over an apparition," referring to the belief that the herb was so offensive to evil spirits that the merest whiff of it caused spirits to depart.
Common Forms and Preparations
Hypericum preparations include the dried herb (chopped or powdered), alcoholic extract, oil, and tincture. An oil macerate (Oleum Hyperici) of its flowering aerial parts is widely used in traditional medicine across the Balkans as a topical wound and ulcer salve. In modern commercial contexts, the most common oral dosage forms are standardized tablets and capsules. Preparations vary greatly in chemical content and quality, and may be standardized regarding quantity of hyperforin (commonly 3% to 5%) or hypericin (commonly 0.3%) constituents.
2. Traditional and Historical Use
Ancient Greek and Roman Use
The use of this species as an herbal remedy to treat a variety of internal and external ailments dates back to the time of the ancient Greeks. Dioscorides, the foremost herbalist of the ancient Greeks, mentions four species of Hypericum—Uperikon, Askuron, Androsaimon, and Koris—which he recommends for sciatica, "when drunk with 2 heim of hydromel (honey-water)." References to the use of St. John's wort can be found in the last 2,000 years, dating back to the early Greeks.
Medieval and Christian European Traditions
The earliest use in Christian tradition may date back to the 6th century AD when, according to Gaelic tradition, the missionary St. Columba always carried a piece of St. John's wort because of his great regard for St. John. Some early Christian authors claimed that red spots, symbolic of the blood of St. John, appeared on leaves of Hypericum spp. on August 29, the anniversary of the saint's beheading, while others considered that the best day to pick the plant was on June 24, the day of St. John's feast. The herb became closely tied to midsummer celebrations and bonfires across Mediterranean Europe, and was woven into wreaths and protective bundles as part of seasonal ritual.
Medicinal Applications Across Cultures
Historically, St. John's wort has been used for a variety of conditions, including depression, stomach ulcers, and colds, and to aid wound healing. For centuries people have successfully used St. John's Wort for the treatment of ailments such as depression, anxiety, sleep disorders, viral infections, wounds, menstrual cramping, and kidney and lung ailments. In Europe, these preparations are commonly prescribed by medical doctors for burns, ulcers, and nervous disorders, especially mild depression.
Pharmaceutical companies, particularly in Europe, prepare standard formulations of this herb that are taken by millions of people. The plant's integration into medical practice in German-speaking countries was particularly strong; the German Commission E formally recognized SJW as a treatment for mild depressive disorders, anxiety, and nervous disturbances.
3. Key Constituents and Active Compounds
Major Chemical Classes
Chemical investigations into the constituents of H. perforatum have detected seven groups of medicinally active compounds. The most common classes include naphthodianthrones, phloroglucinols, and flavonoids (such as phenylpropanes, flavonol glycosides, and biflavones), as well as essential oils.
Additional phenolic compounds identified in H. perforatum flowers include the flavonol hyperoside, biflavonols such as amentoflavone and biapigenin, low levels of xanthone derivatives, common phenolic acids such as caftaric acid, chlorogenic acid, and ferulic acid, as well as tannins and catechin derivatives. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols, and naphthodianthrones.
Hypericin
Two major active constituents have been identified: hypericin (a naphthodianthrone) and hyperforin (a phloroglucinol). Many pharmacological activities appear to be attributable to hypericin and to the flavonoid constituents; hypericin is also reported to be responsible for the photosensitive reactions that have been documented for St. John's wort. Standardized commercial extracts are typically characterized by a minimum of 0.3% hypericin content.
Hyperforin
With regard to the antidepressant effects of St. John's wort, hyperforin, rather than hypericin as originally thought, has emerged as one of the major constituents responsible for antidepressant activity. Out of all individual substances of St. John's wort, only hyperforin and its structural analogue adhyperforin inhibit the re-uptake of the investigated neurotransmitters. However, hyperforin is unstable with light and heat, and thus should not be present in the light-aged oil macerate.
Other Contributors
Although the major constituent responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin, pseudohypericin, flavonoids, and oligomeric procyanidines may also play a direct or indirect role. Roughly 20% of extractable compounds are considered biologically active.
4. Mechanisms of Action
Monoamine Reuptake Inhibition
Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its actions is the moderate to high potency for inhibition of the reuptake of monoamines — serotonin, dopamine, and noradrenaline — and the amino-acid neurotransmitters GABA and glutamate.
Unlike standard reuptake inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na⁺ ion concentrations. This is mechanistically distinct from classical SSRIs: hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins but instead affects the sodium gradient, which then leads to an inhibition of uptake.
Receptor-Level Effects
In vivo, St. John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex, and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. At a receptor level, chronic treatment with hypericum downregulates β1-adrenoceptors and upregulates post-synaptic 5-HT1A and 5-HT2 receptors.
GABA and MAO Activity
The contributing mechanisms include inhibition of the reuptake of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in the synaptic cleft; binding to the GABA-A and GABA-B receptors, thereby inhibiting the binding of GABA ligands; increasing the density of 5-HT2 receptors in the frontal cortex of the brain; and inhibition of both monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) enzymes in the brain, thereby allowing more DA to be converted to NE. Initial biochemical studies reported that St. John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity, but that it inhibits the synaptosomal uptake of serotonin, dopamine, and noradrenaline with approximately equal affinity.
CYP Enzyme and PXR Activation
Preparations of SJW are potent activators of the pregnane X receptor (PXR) and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P-glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation.
5. Scientific Evidence by Area of Use
5.1 Mild to Moderate Depression
This is the most extensively studied application of St. John's wort, and it represents the area of strongest clinical evidence.
A Cochrane Review of SJW for depression documented available research studies published to 2008 and found a beneficial effect compared to both placebo and other antidepressant therapies across 29 double-blind randomized controlled trials (RCTs). The available evidence suggests that the hypericum extracts tested in the included trials: (a) are superior to placebo in patients with major depression; (b) are similarly effective as standard antidepressants; and (c) have fewer side effects than standard antidepressants.
An earlier Cochrane review of 14 randomized controlled trials (RCTs) with a total of 960 patients compared single preparations of St. John's wort with placebo. Patients in the included studies were recruited from practices of psychiatrists, general practitioners, internists, and one gynecologist; most of the patients were diagnosed with mild to moderate depression. All trials lasted four to six weeks and used various dosages of St. John's wort. The pooled response rate ratio was 2.5 (95% confidence interval [CI], 1.7 to 3.6), indicating a significant benefit.
In a separate meta-analysis, 27 clinical trials with a total of 3,808 patients were reviewed, comparing the use of St. John's wort and SSRIs. St. John's wort demonstrated comparable response (pooled RR 0.983, 95% CI 0.924–1.042) and remission (pooled RR 1.013, 95% CI 0.892–1.134) rates, and a significantly lower discontinuation/dropout rate compared to standard SSRIs (pooled OR 0.587, 95% CI 0.478–0.697).
Critically, larger, methodologically rigorous placebo-controlled trials have yielded more nuanced findings. A systematic review and meta-analysis of 37 double-blind RCTs comparing Hypericum monopreparation with either placebo or a standard antidepressant in adults with depressive disorders found that larger placebo-controlled trials restricted to patients with major depression showed only minor effects over placebo, while older and smaller trials not restricted to patients with major depression showed marked effects. Compared with standard antidepressants, Hypericum extracts had similar effects. Current evidence regarding Hypericum extracts is inconsistent and confusing.
One notable large RCT examined extract WS® 5570 in patients with mild or moderate major depressive episodes. In this double-blind, randomized, placebo-controlled, multi-center clinical trial, male and female adult outpatients with a mild or moderate major depressive episode (DSM-IV criteria) were enrolled, and 332 patients were randomized: 123 to WS® 5570 600 mg/day, 127 to WS® 5570 1200 mg/day, and 82 to placebo. The primary outcome measure was the change in total score on the Hamilton Rating Scale for Depression (HAM-D, 17-item version) between baseline and endpoint. An earlier trial by Lecrubier et al. demonstrated the efficacy of WS® 5570 at a dose of 300 mg three times daily for 6 weeks, showing it to be safe and more effective than placebo in patients with mild to moderate major depression. Additionally, WS® 5570 300 mg three times daily was demonstrated to be at least equally effective and better tolerated than paroxetine in patients with moderate to severe depression.
Evidence strength summary: Evidence from randomised controlled trials has confirmed the efficacy of St. John's wort extracts over placebo in the treatment of mild-to-moderately severe depression. Despite the seemingly overwhelming effects on neurotransmitters in the CNS, the clinical trial data suggest that the benefits are minimal and limited to those with mild to moderate depression.
5.2 Menopausal Symptoms
Small numbers of studies suggest that St. John's wort may be helpful for hot flashes associated with menopause and for somatic symptom disorder (a condition involving intense anxiety about physical symptoms). Benefit in reducing some climacteric symptoms in women with natural menopause has also been demonstrated. SJW has also been studied as a possible avenue for treating post-menopausal depression and some post-menopausal symptoms such as hot flashes.
Evidence strength: Limited; based on small numbers of studies. Evidence is insufficient to form definitive conclusions.
5.3 Anxiety Disorders
St. John's wort has been studied as a treatment for attention-deficit hyperactivity disorder (ADHD), irritable bowel syndrome, obsessive compulsive disorder, and premenstrual syndrome; as a possible aid to smoking cessation; and as an ingredient in topical preparations for wound healing. However, only a small amount of research has been done on the use of St. John's wort for each of these purposes, and the evidence hasn't clearly shown it to be helpful for any of them. NCCIH funded at least one clinical trial specifically investigating SJW in generalized social anxiety disorder.
Evidence strength: Preliminary and insufficient. No robust clinical evidence supports the use of SJW for anxiety disorders as a standalone indication.
5.4 Obsessive-Compulsive Disorder (OCD)
OCD is a disorder that is difficult to treat. Research is in the beginning stages of how St. John's wort may be useful in treating OCD; however, current clinical evidence is limited, and further research is necessary for efficacy.
Evidence strength: Insufficient; early-stage investigation only.
5.5 Attention-Deficit/Hyperactivity Disorder (ADHD)
Research shows that taking a St. John's wort extract for 8 weeks does not improve ADHD symptoms in children ages 6–17 years.
Evidence strength: A specific RCT (published in JAMA, 2008) found no benefit in children and adolescents. Evidence does not support use for ADHD.
5.6 Topical Wound Healing
An oil macerate (Oleum Hyperici) of the flowering aerial parts of H. perforatum is widely used in traditional medicine across the Balkans as a topical wound and ulcer salve. Other studies have shown that Oleum Hyperici reduces both wound size and healing time. The naphthodianthrone hypericin and phloroglucinol hyperforin are effective antibacterial compounds against various Gram-positive bacteria.
Applying an ointment containing St. John's wort three times daily for 16 days appears to improve wound healing and reduce scar formation after a Cesarean section (C-section).
Evidence strength: Promising but limited. Several small studies indicate topical benefit for wound healing and scar reduction, but large-scale RCTs are lacking.
5.7 Premenstrual Syndrome (PMS)
Premenstrual syndrome refers to a variety of symptoms that some women experience in the days before menstruation, including bloating, acne, breast swelling and tenderness, pain, irritability, and depression. Treatment of this syndrome often involves SSRIs. St. John's wort has been used as an alternative over-the-counter treatment that may lessen PMS symptoms. More research is necessary regarding the efficacy of treatment.
Evidence strength: Insufficient; the evidence has not clearly demonstrated benefit.
5.8 Seasonal Affective Disorder (SAD)
SAD is a form of depression that occurs during the winter months. There is fairly weak evidence supporting the use of St. John's wort supplements in the treatment of SAD.
Evidence strength: Weak. Only limited clinical trials exist and findings are not definitive.
5.9 Other Investigated Areas
Early research shows that taking hypericin, a chemical in St. John's wort, by mouth for up to 3 months might reduce tumor size and improve the survival rate in people with brain tumors. This represents early-phase, preliminary investigation and cannot be interpreted as established evidence for a clinical benefit.
Early research suggests that taking a specific St. John's wort product three times daily improves the severity of migraine pain but does not reduce how often migraines occur.
Documented pharmacological activities, including antidepressant, antiviral, and antibacterial effects, provide supporting evidence for several of the traditional uses stated for St. John's wort. However, most antiviral and anticancer data derive from preclinical (in vitro or animal) studies.
6. Body Systems and Health Areas
- Central Nervous System / Psychiatric: Depression (primary evidence base), anxiety, OCD, SAD, somatic symptom disorder
- Endocrine / Reproductive: Menopausal symptoms (hot flashes, mood changes), PMS
- Integumentary (Skin): Wound healing, scar reduction, burns, pressure sores, psoriasis (limited evidence)
- Antimicrobial: Antibacterial activity against Gram-positive organisms (primarily preclinical)
- Antiviral: Antiviral activity, particularly for hypericin (primarily preclinical)
- Gastrointestinal: Historically used for stomach ulcers; studied for irritable bowel syndrome (insufficient clinical evidence)
- Neurological: Migraine (early, very limited data only)
7. Dosage Forms and Dosages Reported in Studies
Oral Dosage Forms
Clinical trials evaluating the efficacy of St. John's wort in depression have commonly used 900 mg of extract daily in 3 divided doses for up to 12 weeks (range, 200 to 1,800 mg/day). In most studies, St. John's wort extract was standardized to 0.3% hypericin content and used at doses of 300 mg 3 times daily.
Some studies have used St. John's wort extract standardized to 0.2% hypericin at doses of 250 mg twice daily. St. John's wort extract standardized to 5% hyperforin has been used at doses of 300 mg 3 times daily.
For depression, some clinical trials in adults have used 300 milligrams of St. John's wort (of 0.3% hypericin extract) taken three times a day for up to 6 months. After the initial treatment, some people choose to go onto a lower maintenance dose of 300 milligrams to 600 milligrams of St. John's wort per day.
A total daily dose of 2–4 g of St. John's wort has been recommended by the Commission E Monographs. Most of the available clinical data have been carried out for 300 mg preparations of St. John's wort extract taken three times daily.
Topical Dosage Forms
Applying an ointment containing St. John's wort three times daily for 16 days appears to improve wound healing and reduce scar formation after a Cesarean section. Oil macerates (Oleum Hyperici) represent the traditional topical preparation applied to wounds, burns, and skin conditions.
Standardization
In systematic review, eight studies evaluated a hypericum extract that combined 0.3% hypericin and 1–4% hyperforin. The optimal dosage and dose regimen of St. John's wort extract have not been definitively established.
8. Safety Considerations and Drug Interactions
General Safety Profile
For most adults who are not taking any kind of medicine, St. John's wort appears to be safe when used for up to 12 weeks, and some studies indicate that it can be used safely for a year or more. Patients given hypericum extracts dropped out of trials due to adverse effects less frequently than those given older antidepressants (OR 0.24; 95% CI, 0.13 to 0.46) or SSRIs (OR 0.53, 95% CI, 0.34–0.83).
Common Adverse Effects
If taken orally in large doses or applied to the skin, St. John's wort might cause severe skin reactions after sun exposure. Other side effects can include diarrhea, dizziness, trouble sleeping, restlessness, and skin tingling. Adverse effects like allergic reactions, photosensitivity, nausea, headaches, diarrhea, skin irritation, and worsening psychotic symptoms in schizophrenia or bipolar disorder patients have also been documented.
Photosensitivity
Photosensitivity reactions affecting the skin are potentially serious adverse reactions associated with SJW. Recent data suggest that photosensitivity reactions are dose-related, with increased sensitivity associated with higher doses. Hypericin can cause phototoxic skin reactions if ingested or absorbed into the skin.
Serotonin Syndrome
Combining St. John's wort and certain antidepressants can lead to serotonin syndrome, with dangerous symptoms ranging from tremor and diarrhea to very dangerous confusion, muscle stiffness, drop in body temperature, and even death. Serotonin syndrome may first cause tachycardia, increased blood pressure, mydriasis, and sweating. Some may have a fever, and temperatures can rise above 106 degrees Fahrenheit.
St. John's wort affects the metabolism of several antidepressants, primarily through the CYP3A4, CYP2C9, and CYP2C19 enzymes. SSRIs such as citalopram, escitalopram, and sertraline, metabolized by CYP2C19, are more likely to interact with St. John's wort than those metabolized by CYP2D6, such as paroxetine, fluoxetine, and fluvoxamine.
CYP3A4 and P-glycoprotein Induction
Available data indicate that St. John's wort is a potent inducer of CYP 3A4 and P-glycoprotein (PgP), although it may inhibit or induce other CYPs, depending on the dose, route, and duration of administration. SJW has been determined to be an inducer of several CYP450 enzymes, including CYP3A4, CYP2C9, and CYP2C19. In addition, SJW appears to induce several transporter proteins, including P-gp and organic anion transporters.
In a clinical study, the administration of St. John's wort extract to 8 healthy male volunteers during 14 days resulted in an 18% decrease of digoxin exposure after a single digoxin dose (0.5 mg), and in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively.
Clinically Significant Drug Interactions
A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin, and oral contraceptives, resulting in a decrease in concentration or effect of the medicines. These drugs include HIV protease inhibitors, CYP3A4 HIV non-nucleoside reverse transcriptase inhibitors, ciclosporin, tacrolimus, irinotecan, imatinib mesylate, digoxin, oxycodone, and warfarin.
The induction of both CYP3A4 and P-glycoprotein by SJW constituents may act to reduce the plasma level of cyclosporin to subtherapeutic levels. This can lead to clinically significant consequences such as the rejection of a transplanted organ. Breakthrough bleeding among women taking both SJW and the oral contraceptive pill has been reported.
The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations.
Special Populations
It may be unsafe to use St. John's wort during pregnancy because it may increase the risk of birth defects. Breastfeeding infants of mothers who take St. John's wort can experience colic, drowsiness, and lethargy. A rare but possible side effect of taking St. John's wort is psychosis. Those with certain mental health disorders, such as bipolar disorder, are at risk of experiencing this rare side effect.
Regulatory Status
The herbal supplement has not been given FDA approval and is considered a dietary supplement in the United States, while in several European countries it is approved as a medicine for mild depression. The divergence in regulatory status reflects different evidentiary thresholds applied in different jurisdictions.
References
- Medical Attributes of St. John's Wort (Hypericum perforatum) – Herbal Medicine, NCBI Bookshelf
- St. John's Wort: Usefulness and Safety – NCCIH / NIH
- St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties – PubMed (Barnes et al., 2001)
- Mechanism of action of St John's wort in depression: what is known? – PubMed (Butterweck, 2003)
- St. John's wort for treating depression – Cochrane Review
- A systematic review of St. John's wort for major depressive disorder – PMC (Apaydin et al., 2016)
- Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis – Journal of Affective Disorders (Ng et al., 2017)
- St John's wort for depression: Meta-analysis of randomised controlled trials – ResearchGate (Linde et al., 2005)
- Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology – Nathan, 2001
- Current St. John's wort research from mode of action to clinical efficacy – ScienceDirect (Müller, 2003)
- The Chemical and Antibacterial Evaluation of St. John's Wort Oil Macerates Used in Kosovar Traditional Medicine – PMC
- St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4 – PubMed (Dürr et al., 2000)
- Clinical relevance of St. John's wort drug interactions revisited – PMC (Nicolussi et al., 2020)
- St John's wort (Hypericum perforatum): drug interactions and clinical outcomes – PMC
- Pharmacokinetic interactions of drugs with St John's wort – PubMed (Mills et al., 2004)
- St. John's Wort – StatPearls, NCBI Bookshelf
- Superior efficacy of St John's wort extract WS® 5570 compared to placebo: a randomized, double-blind, placebo-controlled multi-center trial – PMC
- Advantages and Disadvantages of Using St. John's Wort as a Treatment for Depression – PMC (Cureus, 2022)
- The Effects of St. John's Wort and its Interactions with SSRIs – PMC
- St. John's Wort and Depression – NCCIH Fact Sheet
- St. John's Wort for Depression – American Academy of Family Physicians (AAFP, 2005)
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