St. John's Wort

Last Updated: October 7, 2023

St. John’s wort, also known by its Linnean name of Hypericum perforatum (HP), is an anti-depressant herb that is commonly used for its neurological effects. While it appears effective, it is well known to adversely interact with a variety of pharmaceuticals.

St. John's Wort is most often used for

What is St. John’s wort?

Hypericum perforatum (HP), commonly known as St. John’s wort, is a plant belonging to the Hypericaceae family with yellow, star-shaped flowers, native to Europe. St. John's wort typically blooms and is harvested towards the end of June, when St. John's feast day is celebrated. Traditionally, the plant was hung from doors on St. John’s feast day to protect against malevolent spirits and to ensure the well-being of both humans and animals.

Hypericin and hyperforin are the two main active metabolites of HP. Additionally, HP contains various other active compounds like flavonoids, as well as several inactive substances.[2]

In traditional Chinese medicine (TCM) the extract of HP has been used as a herbal remedy to treat depression. It is also recommended for the same purpose in many European countries.

What are the main benefits of St. John’s wort?

HP appears to be an effective treatment for mild to moderate depression. Several studies have investigated its clinical effects by comparing the Hamilton Depression Rating Scale (HAMD) scores of people taking HP to those of people taking a placebo or commonly prescribed antidepressant drugs. Many of these studies have indicated that HP extracts have a similar clinical response and remission rate to serotonin reuptake inhibitors (SSRIs), while also having a lower rate of treatment discontinuation due to side effects.[1][3][4]

In comparison to tricyclic antidepressants (TCAs), HP appears to have fewer side effects and a lower dropout rate during treatment.[4]

Furthermore, one in vitro study using a specific HP extract (containing only 4 compounds) found that that extract of HP increased neuronal plasticity (the ability of neurons and neural elements to adapt to internal or external stimuli such as chronic stress exposure) and neurogenesis (the formation of new neurons). Additionally, the HP extract exhibited anti-inflammatory properties and protected neurons from cytotoxicity induced by glutamate and N-methyl-D-aspartate (NMDA), which is considered a potential factor in depression.[5]

What are the main drawbacks of St. John’s wort?

Studies have shown that HP can interfere with the expression of enzymes of the cytochrome-P (CYP) family[6] and of P-glycoprotein, both of which play a role in the metabolism of various medications. This can result in altered effects of certain drugs, potentially leading to reduced effectiveness or unexpected outcomes. Common medications whose effect may be decreased by HP include some oral contraceptive pills, warfarin (an anticoagulant drug), cyclosporin (often used as an immunosuppressant in organ transplants),[7] digoxin (mostly used for atrial fibrillation), proton pump inhibitors (used to reduce stomach acid production), and some statins (cholesterol-lowering drugs).[1][8]

Furthermore, combining HP with other antidepressants that increase serotonin levels (e.g., SSRIs, MAOIs) may raise the risk of serotonin syndrome (or serotonin toxicity), a potentially life-threatening condition characterized by an excessive accumulation of serotonin in the system. Symptoms of serotonin syndrome include tachycardia, increased blood pressure, dilated pupils, sweating, and elevated body temperatures.[2] More data is required to verify the level of interaction with such medications.

Although St. John’s wort has been associated with fewer side effects compared to some antidepressant medications, the most common side effects reported with its use include gastrointestinal issues (e.g., abdominal pain or discomfort, nausea, and vomiting), headache, fatigue, sedation, dry mouth, vertigo, dizziness, restlessness, and photosensitivity. More studies are required to further investigate both short-term and long-term side effects of HP and to establish its safety profile when used as an antidepressant.[9]

How does St. John’s wort work?

St. John’s wort appears to have multiple potential mechanisms of action, some of which have yet to be clarified.

HP (and more specifically one of its main active compounds, hyperforin) can inhibit the reuptake of serotonin, norepinephrine, and dopamine. Although the exact mechanism is still unclear, it seems that HP does not inhibit their reuptake by blocking the presynaptic transporters, as SSRIs do. One hypothesis is that hyperforin instead works by increasing the intracellular concentration of sodium,[10] resulting in an increased concentration of monoamines available to interact with their postsynaptic receptors. This increased neurotransmitter activity is associated with improved mood and relief of depression symptoms.[2]

Additionally, both in vivo and in vitro studies have found that HP also works by activating the pregnane-X-receptor (PXR) cytochromes, which play a role in regulating the expression of certain enzymes of the cytochrome P450 system (specifically the CYP3A4 enzyme) and the P-glycoprotein (responsible for transporting drugs and other substances out of cells). The activation of the CYP pathway and/or the P-glycoprotein by HP may contribute to the interactions between HP and other drugs metabolized through these pathways.[2]

What are other names for St. John's Wort?
Note that St. John's Wort is also known as:
  • St. John's Wort
  • Hypericum Perforatum
  • Klamath Weed
  • Tipton Weed
  • Johanniskraut
  • 圣约翰草 (Guan Ye Lian Qiao)
Dosage information

The most common dosage of St. John's wort extract found in studies is 300mg a day, up to three times a day.[1]

Examine Database: St. John's Wort
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Update History
2023-10-07 00:30:04

New meta-analyses added


We added a few meta-analyses to our database and update the clinical effects accordingly.

Written By

Reviewed By

  1. ^Ng QX, Venkatanarayanan N, Ho CYClinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis.J Affect Disord.(2017-Mar-01)
  2. ^Peterson B, Nguyen HSt John's WortStatPearls.(2023-05)
  3. ^Zhao X, Zhang H, Wu Y, Yu CThe efficacy and safety of St. John's wort extract in depression therapy compared to SSRIs in adults: A meta-analysis of randomized clinical trials.Adv Clin Exp Med.(2022-Oct-11)
  4. ^Knüppel L, Linde KAdverse effects of St. John's Wort: a systematic review.J Clin Psychiatry.(2004-Nov)
  5. ^Bonaterra GA, Schwendler A, Hüther J, Schwarzbach H, Schwarz A, Kolb C, Abdel-Aziz H, Kinscherf RNeurotrophic, Cytoprotective, and Anti-inflammatory Effects of St. John's Wort Extract on Differentiated Mouse Hippocampal HT-22 Neurons.Front Pharmacol.(2017)
  6. ^McDonnell AM, Dang CHBasic review of the cytochrome p450 system.J Adv Pract Oncol.(2013-Jul)
  7. ^Bauer S, Störmer E, Johne A, Krüger H, Budde K, Neumayer HH, Roots I, Mai IAlterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients.Br J Clin Pharmacol.(2003 Feb)
  8. ^Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D, Mulcahy F, Feely JSt Johns wort increases expression of P-glycoprotein: implications for drug interactions.Br J Clin Pharmacol.(2002-Jan)
  9. ^Whiskey E, Werneke U, Taylor DA systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review.Int Clin Psychopharmacol.(2001-Sep)
  10. ^Singer A, Wonnemann M, Müller WEHyperforin, a major antidepressant constituent of St. John's Wort, inhibits serotonin uptake by elevating free intracellular Na+1.J Pharmacol Exp Ther.(1999-Sep)
  11. ^Thiede HM, Walper AInhibition of MAO and COMT by hypericum extracts and hypericin.J Geriatr Psychiatry Neurol.(1994-Oct)
  12. ^Butterweck VMechanism of action of St John's wort in depression : what is known?CNS Drugs.(2003)
  13. ^Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom AEffects of St. John's wort on irinotecan metabolism.J Natl Cancer Inst.(2002 Aug 21)
  14. ^Zhou S, Chan E, Pan SQ, Huang M, Lee EJPharmacokinetic interactions of drugs with St John's wort.J Psychopharmacol.(2004 Jun)
  15. ^Russo E, Scicchitano F, Whalley BJ, Mazzitello C, Ciriaco M, Esposito S, Patanè M, Upton R, Pugliese M, Chimirri S, Mammì M, Palleria C, De Sarro GHypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.Phytother Res.(2014 May)
  16. ^Wang XD, Li JL, Lu Y, Chen X, Huang M, Chowbay B, Zhou SFRapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical herb-drug interaction study.J Chromatogr B Analyt Technol Biomed Life Sci.(2007 Jun 1)
  17. ^Tannergren C, Engman H, Knutson L, Hedeland M, Bondesson U, Lennernäs HSt John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism.Clin Pharmacol Ther.(2004 Apr)
  18. ^Chen XW, Serag ES, Sneed KB, Liang J, Chew H, Pan SY, Zhou SFClinical herbal interactions with conventional drugs: from molecules to maladies.Curr Med Chem.(2011)
  19. ^Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano SEffect of St. John's wort on the pharmacokinetics of theophylline in healthy volunteers.J Clin Pharmacol.(2004 Jan)
  20. ^Lau WC, Welch TD, Shields T, Rubenfire M, Tantry US, Gurbel PAThe effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity.J Cardiovasc Pharmacol.(2011-Jan)
  21. ^Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AHSt John's Wort: effect on CYP3A4 activity.Clin Pharmacol Ther.(2000-May)
  22. ^Hammerness et al.St. John’s Wort: A Systematic Review of Adverse Effects and Drug Interactions for the Consultation PsychiatristPsychosomatics.(2003-07-01)
  23. ^Spiess D, Winker M, Dolder Behna A, Gründemann C, Simões-Wüst APAdvanced Safety Assessment of Herbal Medicines for the Treatment of Non-Psychotic Mental Disorders in Pregnancy.Front Pharmacol.(2022)
  24. ^Moretti ME, Maxson A, Hanna F, Koren GEvaluating the safety of St. John's Wort in human pregnancy.Reprod Toxicol.(2009-Jul)
  25. ^St. John's Wort.Drugs and Lactation Database (LactMed®).(2006)
Examine Database References
  1. Depression Symptoms - Linde K, Berner MM, Kriston LSt John's wort for major depression.Cochrane Database Syst Rev.(2008-Oct-08)
  2. Depression Symptoms - Rahimi R, Nikfar S, Abdollahi MEfficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis.Prog Neuropsychopharmacol Biol Psychiatry.(2009-Feb-01)
  3. Depression Symptoms - Linde K, Berner M, Egger M, Mulrow CSt John's wort for depression: meta-analysis of randomised controlled trials.Br J Psychiatry.(2005-Feb)
  4. Depression Symptoms - Cui YH, Zheng YA meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults.Neuropsychiatr Dis Treat.(2016)
  5. Depression Symptoms - Whiskey E, Werneke U, Taylor DA systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review.Int Clin Psychopharmacol.(2001-Sep)
  6. Depression Symptoms - Ng QX, Venkatanarayanan N, Ho CYClinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis.J Affect Disord.(2017-Mar-01)