Hypericum perforatum

Antidepressants. Other antidepressants of herbal origin

ATC code: N06AX25

Brand names: Kira, Perika, St. John's Wort

Updated 19 Aug 2026 · Methodology

Indications

Mild-to-moderate depression

Second line

St. John's wort is one of the best-studied herbal options in depression. HMPC in 2018 granted well-established-use status for mild to moderate depressive episodes. The Linde Cochrane review 2008 pooled 29 RCTs with 5489 patients: a standardised St. John's wort extract was more effective than placebo and as effective as SSRIs (fluoxetine, sertraline, citalopram) in mild to moderate depression. NG222 (2022) permits St. John's wort in mild episodes but explicitly warns about multiple interactions. The effect builds over 4–6 weeks at 300 mg of standardised extract three times daily. In severe depression St. John's wort is not indicated – no efficacy data. If St. John's wort was prescribed and you take other medications, do not start before reviewing every pill with a doctor: the interaction list is long and clinically dangerous.

Not used in patients on other serotonergic drugs, anticoagulants, immunosuppressants, antiretrovirals, COCs or hypoglycemic agents – risk of serotonin syndrome or loss of efficacy of the primary drug.

Sources

ICD-10: F32.0 · ICD-11: 6A70.0

Somatoform disorders (medically unexplained symptoms)

Individual decision

For somatoform disorders – bodily symptoms without a clear organic cause – St. John's wort has a limited but real evidence base: two randomized trials of the LI 160 extract showed benefit over placebo on physical complaints. The evidence is small and unconfirmed by large studies, so the assessment stays cautious. The decision is individual and must account for the herb speeding up the breakdown of many medicines and weakening them.

Sources

ICD-10: F45 · ICD-11: 6C20

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

Local burn and damaged-skin care

Not recommended

St. John's wort oil is used topically for minor wounds, burns, grazes and skin irritation. The accepts this use by tradition only, without evidence of efficacy; the few small trials of hyperforin creams in dermatitis are inconsistent. Systemic interactions are unlikely with topical use, but the herb raises skin sensitivity to sunlight – treated areas are better kept out of the sun.

Sources

ICD-10: T20-T32 · ICD-11: ND90-ND9Z

Menopausal symptoms

Not recommended

St. John's wort is offered for hot flushes, menopausal complaints and premenstrual syndrome. The data are weak and inconsistent: several small trials and one meta-analysis show modest improvement in hot flushes and mood, but there is no large high-quality confirmation, and menopause guidelines do not list it as a first choice. Safety matters too: the herb lowers the effectiveness of hormone therapy and oral contraceptives by speeding their breakdown. For menopausal symptoms and PMS it is more sensible to discuss options with proven benefit with a doctor.

Sources

ICD-10: N95.1 · ICD-11: GA30

Severe depression

Not recommended

St. John's wort is sold as a «universal natural antidepressant», including for severe depressive episodes, postpartum depression, depression with psychotic features and suicidal ideation. This is a dangerous indication creep. HMPC limits well-established use to mild and moderate depression. RCTs in severe episodes either showed no benefit or had methodological flaws. NG222 (2022) recommends SSRIs/SNRIs plus CBT or interpersonal therapy in severe depression, with atypical antidepressants, lithium and ECT when needed. Replacing standard care with St. John's wort in severe depression raises the risk of relapse, hospitalisation and suicide. If St. John's wort was offered for severe depression, postpartum depression or bipolar disorder in place of prescribed therapy, consider seeking a second opinion.

Sources

ICD-10: F32.2 · ICD-11: 6A70.3

Stress and anxiety

Not recommended

St. John's wort is widely sold as a natural calming remedy for nerves, stress, anxiety and sleep. For these conditions its benefit is not proven: there are no clinical trials in anxiety disorders or insomnia, only isolated case reports with no effect. The herb's proven niche is mild-to-moderate depression, not anxiety or sleep. It is also far from harmless: it speeds up the breakdown of many medicines and weakens them – oral contraceptives, warfarin, immunosuppressants, HIV drugs – and combined with SSRI antidepressants it can trigger serotonin syndrome and raises skin sensitivity to sunlight. Taking it for nerves or sleep, especially alongside other medicines, carries real risk with no proven benefit.

Sources

ICD-10: F41.9 · ICD-11: 6B0Z

How to read tiers A–F

AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit

Mechanism of action

Active components of the extract – hypericin, hyperforin and flavonoids. Hyperforin inhibits synaptic reuptake of serotonin, norepinephrine, dopamine and GABA and activates TRPC6 calcium channels. The effect is weaker than that of SSRIs. In addition, St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein, which underlies clinically significant interactions with dozens of drugs.

Safety

Contraindications

Severe depression with suicidal ideation
Bipolar affective disorder (risk of manic switch)
Concomitant SSRIs, SNRIs, TCAs, MAOIs, triptans – risk of serotonin syndrome
Concomitant warfarin, cyclosporine, tacrolimus, digoxin, antiretrovirals, COCs
Pregnancy, breastfeeding
Age under 18 (insufficient data)
Fair-skinned patients with photodermatoses
Hypersensitivity to plant components

Serious adverse effects

Serotonin syndrome when combined with serotonergic drugs
Manic or hypomanic switch in patients with bipolar disorder
Severe photosensitization (phototoxic dermatitis)
Loss of HIV control when combined with antiretrovirals
Graft rejection when combined with immunosuppressants

Common adverse effects

Dyspepsia, nausea
Dry mouth
Fatigue, less often anxiety
Headache
Photosensitization

Uncommon adverse effects

Rash, allergic dermatitis
Emotional lability
ALT/AST elevation

Pregnancy: can you take Hypericum perforatum?

AEMPS summary of product characteristics (section 4.6): animal studies have given conflicting results, and the potential risk in humans is unknown. In the absence of sufficient clinical data, St John's wort is not recommended during pregnancy.

Breastfeeding: can you take Hypericum perforatum?

Extract components transfer into breast milk. Cases of infant colic and drowsiness have been reported. Not used during breastfeeding. Alternatives – psychotherapy and, if needed, sertraline (low milk transfer).

Calculate RID

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Practical notes

Timing and administration

Taken 2–3 times daily, preferably with meals. Effect develops over 2–4 weeks of regular use. Standardized extracts specify hypericin and hyperforin content – products of different manufacturers are not interchangeable at the same tablet weight.

Monitoring

Before initiation and every 4 weeks, depression severity is assessed by scales (, HAM-D). If there is no improvement at 4–6 weeks, the strategy is reviewed. ALT/AST monitoring at least every 3 months; rare cases of transaminase elevation have been reported.

Special situations

St. John's wort is a potent CYP3A4 and P-glycoprotein inducer. It reduces concentrations of warfarin (bleeding risk on withdrawal of St. John's wort), cyclosporine and tacrolimus (graft rejection risk), digoxin, theophylline, antiretrovirals (loss of viral control in HIV), COCs (unplanned pregnancy risk), statins (loss of efficacy), glibenclamide ( rise). Before initiation, all medications and supplements the patient takes must be reviewed.

Photoprotection

Photosensitization is possible in fair-skinned patients. During use, intense sun exposure and tanning beds are avoided, and SPF 50 sunscreens are used.

Common myths

Myth: «St. John's wort is natural, therefore safe». Fact: herbal origin does not guarantee safety. St. John's wort has dozens of clinically significant drug interactions, some of which can be life-threatening (graft rejection, serotonin syndrome, loss of HIV control).

Myth: «St. John's wort works for any depression». Fact: only for mild-to-moderate; not used in severe forms.

Myth: «St. John's wort can be combined with antidepressants for synergy». Fact: combination with SSRIs, SNRIs, TCAs and MAOIs raises serotonin syndrome risk and is not used.

Drug–nutrient interactions

Iron

Tannins in St. John's wort herb bind iron in the gut lumen and reduce its absorption. With concurrent iron supplements and St. John's wort, a 2-hour interval is maintained between them.

Drug–drug interactions

8 pairs found. Sorted from critical to minor.

MajorCiclosporinImmunosuppressants. Calcineurin inhibitors

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Ciclosporin and lowers its blood level, weakening its effect.

Symptoms

Fall in ciclosporin blood levels, risk of acute transplant rejection (confirmed in case reports).

Management

Contraindicated in transplant patients. Monitor ciclosporin levels; if the herb was used, stop it and track drug concentration.

Sources

British Journal of Pharmacology: Clinical relevance of St. John's wort drug interactions revisited (2020)

Pair details →Ciclosporin →

MajorEfavirenzAntiretroviral, non-nucleoside reverse transcriptase inhibitor (NNRTI)

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Efavirenz and lowers its blood level, weakening its effect.

Symptoms

Fall in antiretroviral levels, loss of HIV virological control and risk of drug resistance.

Management

Contraindicated with antiretroviral therapy. Do not use St. John's wort during HIV treatment.

Sources

British Journal of Pharmacology: Clinical relevance of St. John's wort drug interactions revisited (2020)

Pair details →Efavirenz →

MajorEthinylestradiolEstrogens. Natural and semisynthetic estrogens, plain

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Ethinylestradiol and lowers its blood level, weakening its effect.

Symptoms

Faster breakdown of estrogen and progestin, breakthrough bleeding, reduced contraceptive protection and risk of unintended pregnancy.

Management

Do not combine with oral contraceptives. While taking St. John's wort use a barrier method or another reliable form of contraception.

Sources

British Journal of Pharmacology: Clinical relevance of St. John's wort drug interactions revisited (2020)

Pair details →Ethinylestradiol →

MajorEverolimusmTOR kinase inhibitor – immunosuppressant and antineoplastic

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Everolimus and lowers its blood level, weakening its effect.

Symptoms

Reduced everolimus levels, loss of immunosuppressant or antitumor effect, risk of transplant rejection.

Management

Avoid the combination. Monitor everolimus levels and stop the herb.

Sources

Pair details →Everolimus →

MajorSertralineSelective serotonin reuptake inhibitors (SSRIs)

Mechanism

St John's wort contains hypericin and hyperforin – serotonergic activators and strong inducers of CYP3A4 and P-glycoprotein. On sertraline (SSRI), serotonergic activity adds up; serotonin syndrome risk arises.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever above 38.5 °C.

Management

The combination is not prescribed. Warn the patient that St John's wort is not a neutral herbal supplement but an active serotonergic with dozens of drug interactions. CYP3A4 induction persists for 1–2 weeks after stopping the herb.

Sources

Pair details →Sertraline →

MajorWarfarinVitamin K antagonist anticoagulants

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Warfarin and lowers its blood level, weakening its effect.

Symptoms

Drop in international normalized ratio (INR), weaker anticoagulation, risk of thrombosis and thromboembolism.

Management

Do not combine. If St. John's wort was already taken, stop it and monitor INR; the warfarin dose may need lowering after the herb is stopped.

Sources

British Journal of Pharmacology: Clinical relevance of St. John's wort drug interactions revisited (2020)

Pair details →Warfarin →

ModerateDigoxinCardiac glycosides (digitalis)

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Digoxin and lowers its blood level, weakening its effect.

Symptoms

Lower digoxin levels through P-glycoprotein induction, weaker rhythm control and control of heart failure symptoms.

Management

Avoid the combination. If needed, monitor digoxin levels and clinical response.

Sources

British Journal of Pharmacology: Clinical relevance of St. John's wort drug interactions revisited (2020)

Pair details →Digoxin →

MinorParacetamolAnilides. Analgesics and antipyretics

Mechanism

St John's wort is a CYP3A4 inducer and a weak CYP2E1 inducer. It may theoretically increase formation of paracetamol's hepatotoxic metabolite NAPQI on long-term combination, but clinical cases are rare.

Symptoms

Fatigue, nausea, jaundice, elevated liver enzymes. Symptoms possible on long-term combination (over 1 month) and high paracetamol dose (over 3 g/day).

Management

For short paracetamol courses (3–7 days), no specific adjustment needed. On long-term combination (St John's wort as phytotherapy for depression), cap paracetamol at 2 g/day. St John's wort has many interactions via CYP3A4 induction (contraceptives, warfarin, SSRIs) — reconsider its use.

Sources

Indiana University: Flockhart Table of Drug Interactions (CYP isoforms) (2023)

Pair details →Paracetamol →

Label mentions6 mentions

Verbatim lines from the interaction sections, in the language of the label

From other drugs’ labels

CriticalAtazanavir
«CONTRAINDICATIONS: Herbal Products St. John’s wort ( Hypericum perforatum )»
FDA, section 4 · Open on DailyMed
CriticalCobicistat
«CONTRAINDICATIONS: Herbal Products: St. John's wort ( Hypericum perforatum )»
FDA, section 4 · Open on DailyMed
CriticalDarunavir
«CONTRAINDICATIONS: • Alpha 1-adrenoreceptor antagonist: alfuzosin • Anti-gout: colchicine, in patients with renal and/or hepatic impairment • Antimycobacterial: rifampin • Antipsychotics: lurasidone…»
FDA, section 4 · Open on DailyMed
CriticalRitonavir
«CONTRAINDICATIONS: Herbal Products: St. John's Wort (hypericum perforatum)»
FDA, section 4 · Open on DailyMed
Sirolimus
«Weak and Moderate Inducers or Inhibitors of CYP3A4 and P-gp: Drugs and other agents that could decrease sirolimus concentrations: Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort…»
FDA, section 7 · Open on DailyMed
Theophylline
«Drug Interactions:: St. John's Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John's…»
FDA, section 7 · Open on DailyMed

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Frequently asked

What is Hypericum perforatum used for?

Hypericum perforatum is evaluated for the following indications with varying evidence strength: Mild-to-moderate depression (evidence tier B), Somatoform disorders (medically unexplained symptoms) (evidence tier C), Menopausal symptoms (evidence tier D). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Hypericum perforatum?

Common side effects of Hypericum perforatum (≥ 1 in 100): Dyspepsia, nausea, Dry mouth, Fatigue, less often anxiety, Headache, Photosensitization. See the Safety section for uncommon and serious reactions.

Is Hypericum perforatum safe during pregnancy?

Is Hypericum perforatum compatible with breastfeeding?

Who should not take Hypericum perforatum?

Hypericum perforatum is contraindicated in: Severe depression with suicidal ideation; Bipolar affective disorder (risk of manic switch); Concomitant SSRIs, SNRIs, TCAs, MAOIs, triptans – risk of serotonin syndrome; Concomitant warfarin, cyclosporine, tacrolimus, digoxin, antiretrovirals, COCs; Pregnancy, breastfeeding. Full list in the Safety section.

St. John's wort is natural, therefore safe

herbal origin does not guarantee safety. St. John's wort has dozens of clinically significant drug interactions, some of which can be life-threatening (graft rejection, serotonin syndrome, loss of HIV control).

St. John's wort works for any depression

only for mild-to-moderate; not used in severe forms.

St. John's wort can be combined with antidepressants for synergy

combination with SSRIs, SNRIs, TCAs and MAOIs raises serotonin syndrome risk and is not used.

Official sources

Direct links to regulator labels. Open in a new tab.

AEMPS / CIMALabel dated 11/18/2025
FDA / DailyMedLabel dated 09/02/2021
GRLS

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