Skip to main content Accessibility help

St John's wort for depression: Meta-analysis of randomised controlled trials

  • Klaus Linde (a1), Michael Berner (a2), Matthias Egger (a3) and Cynthia Mulrow (a4)



Extracts of Hypericum perforatum (St John's wort) are widely used to treat depression. Evidence for its efficacy has been criticised on methodological grounds.


To update evidence from randomised trials regarding the effectiveness of Hypericum extracts.


We performed a systematic review and meta-analysis of 37 double-blind randomised controlled trials that compared clinical effects of Hypericum monopreparation with either placebo or a standard antidepressant in adults with depressive disorders.


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. In patients who meet criteria for major depression, several recent placebo-controlled trials suggest that Hypericum has minimal beneficial effects while other trials suggest that Hypericum and standard antidepressants have similar beneficial effects.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      St John's wort for depression
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      St John's wort for depression
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      St John's wort for depression
      Available formats


Corresponding author

Dr med. Klaus Linde, Centre for Complementary Medicine Research, Department of Internal Medicine II, Technische Universität Munchen, Kaiserstrasse 9, 80801 München, Germany. Tel: +49 89 726697 15; fax: +49 89 393484; e-mail:


Hide All

This review has been performed as an update an existing Cochrane; an expanded version will be published in the Cochrane Library

Declaration of interest

M.B. has received a grant for research on Hypericum from Schwabe and fees for speaking at a meeting. K.L. has received travel expenses for speaking at a symposium sponsored by Schwabe.



Hide All
Agrawal, A., Dixit, S. P., Dubey, G. P., et al (1994) Clinical evaluation of anti-depressant properties of basant (Hypericum perforatum). Pharmacopsychoecologia, 7, 253256.
Albertini, H. (1986) Evaluation d'un traitement homtéopathique de la névralgie dentaire. In: Recherche en Homéopathie (eds J. Boiron, P. Belon & E. Hariveau), pp. 7577. Lyon: Foundation Française pour la Recherche en Homéopathie.
American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders (3rd edn) (DSM–III). Washington, DC: APA.
American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders (3rd edn, revised) (DSM–III–R). Washington, DC: APA.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM–IV). Washington, DC: APA.
Anonymous (2000) Johanniskraut vs. SSRI – neue Erkenntnisse zur Wirksamkeit und Verträglichkeit. Nervenheilkunde, 19, 9293.
Behnke, K., Jensen, G. S., Graubaum, H. J., et al (2002) Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Advances in Therapy, 19, 4352.
Bendre, V. V. & Dharmadhikari, S. D. (1980) Arnica montana and Hypericum in dental practice. Hahnemann Gleanings, 47, 7072.
Bergmann, R., Nüssner, H. & Demling, J. (1993) Behandlung leichter bis mittelschwerer depressionen. Therapiewoche Neurologie Psychiatrie, 7, 235240.
Brenner, R., Azbel, V., Madhusoodanan, S., et al (2000) Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clinical Therapeutics, 22, 411419.
Brockmöller, J., Reum, T., Bauer, S., et al (1997) Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry, 30 (suppl. 2): 94101.
Czekalla, J., Gastpar, M., Hübner, W. D., et al (1997) The effect of hypericum extract on cardiac conduction as seen in the electrocardiogram compared to that of imipramine. Pharmacopsychiatry, 30 (suppl. 2): 8688.
Dittmer, T. L. J. (1992) Die Behandlung von psychovegetativen Störungen mit Johanniskraut-Öl (Jukunda–Rot–Öl–Kapseln). Naturheilpraxis mit Natumedizin, 45, 118122.
Ditzler, K., Gessner, B., Schatton, W. F. H., et al (1994) Clinical trial on Neuropas versus placebo in patients with mild to moderate depressive symptoms: a placebo-controlled, randomised double-blind study. Complementary Therapies in Medicine, 2, 513.
Egger, M., Davey Smith, G., Schneider, M., et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629634.
Furukawa, T. A., McGuire, H. & Barbui, C. (2002) Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ, 325, 991999.
Gaster, B. & Holroyd, J. (2000) St John's wort for depression. A systematic review. Archives of Internal Medicine, 160, 152156.
Halama, P. (1991) Wirksamkeit des Hypericum-Extraktes L1 160 bei 50 Patienten einer psychiatrischen Fachpraxis. Nervenheilkunde, 10, 305307.
Hammerness, P., Basch, E., Ulbricht, C., et al (2003) St John's wort: a systematic review of adverse effects and drug interactions for the consultation psychiatrist. Psychosomatics, 44, 271282.
Hänsgen, K. D. & Vesper, J. (1996) Antidepressive Wirksamkeit eines hochdosierten Hypericum-Extraktes. Münchener Medizinische Wochenschift, 138, 2933.
Häring, B., Hauns, B., Hermann, C., et al (1996) A double-blind, placebo-controlled pilot study of LI 160 in combination with chemotherapy in patients with solid tumors. Phytomedicine, 3 (suppl. 1), SL88.
Harrer, G., Hübner, W. D. & Podzuweit, H. (1993) Wirksamkeit und Verträglichkeit des Hypericum-Präparates L1160 im Vergleich mit Maprotilin. Multizentrische Doppelblindstudie mit 102 depressiven Patienten. Nervenheilkunde, 12, 297301.
Harrer, G., Schmidt, U., Kuhn, U., et al (1999) Comparison of equivalence between the St John's wort extract LoHyp-57 and fluoxetine. Arzneimittel Forschung/Drug Research, 49, 289296.
Harrer, G., Schmidt, U. & Kuhn, U. (1991) ‘Alternative’ Depressionsbehandlung mit einem Hypericum-Extrakt. TW Neurologie, 5, 710716.
Herberg, K. W. (1991) Fahrtüchtig trotz Einnahme eines Sedativums? Randomisierte, doppelblinde Untersuchung versus Plazebo. Therapiewoche, 41, 10391042.
Higgins, S. P. T., Thompson, S. G., Deeks, J. J., et al (2003) Measuring inconsistency in meta-analyses. BMJ, 327, 557560.
Hiller, K. O. & Rahlfs, V. (1995) Therapeutische Aquivalenz eines hochdosierten Phytopharmakons mit Amitriptylin bei ängstlich-depressiven Verstimmungen – Reanalyse einer randomisierten Studie unter besonderer Beachtung biometrischer und klinischer Aspekte. Forschende Komplementärmedizin, 2, 123132.
Hoffmann, J. & Kühl, E. D. (1979) Therapie von depressiven Zuständen mit Hypericin. Zeitschrift für Allgemeinmedizin, 55, 776782.
Hottenrott, K., Sommer, H. M., Lehrl, S., et al (1997) Der Einfluss von Vitamin E und Johanniskraut-Trockenextrakt auf die Ausdauerleistungsfähigkeit von Wettkampfsportlern. Eine placebo-kontrollierte Doppelblindstudie mit Langstreckenläufern und Triathleten. Deutsche Zeitschrift für Sportmedizin, 48, 2227.
Hübner, W. D., Lande, S. & Podzuweit, H. (1993) Behandlung larvierter Depressionen mit Johanniskraut. Nervenheilkunde, 12, 278280.
Hypericum Depression Trial Study Group (2002) Effect of Hypericum perforatum (St John's wort) in major depressive disorder – a randomized controlled trial. JAMA, 287, 18071814.
Jadad, A. R., Moore, R. A., Carroll, D., et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials, 17, 112.
Johnson, D., Siebenhüner, G., Hofer, E., et al (1992) Einfluss von Johanniskraut auf die ZNS-Aktivität. Neurol Psychiatr, 6, 436444.
Johnson, D., Ksciuk, H., Woelk, H., et al (1993) Wirkungen mit Johanniskraut-Extrakt LI 160 im Vergleich mit Maprotilin auf Ruhe-EEG und evozierte Potentiale bei 24 Probanden. Nervenheilkunde, 12, 328330.
Josey, E. S. & Tacket, R. L. (1999) St John's wort: a new alternative for depression? International Journal of Clinical Pharmacology and Therapeutics, 37, 111119.
Kalb, R., Trautmann-Sponsel, R. D. & Kieser, M. (2001) Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. Pharmacopsychiatry, 34, 96103.
Khan, A., Warner, H. A. & Brown, W. A. (2000) Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Archives of General Psychiatry, 57, 311317.
Kirsch, I., Moore, T. J., Scoboria, A., et al (2002) The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention and Treatment, 5, 23 (
Knüppel, L. & Linde, K. (2004) Adverse effects of St John's wort – a systematic review. Journal of Clinical Psychiatry, 65, 14701479.
König, C. (1993) Hypericum perforatum L. (Gemeines Johanniskraut) als Therapeutikum bei depressiven Verstimmungszuständen – eine Alternative zu synthetischen Arzneimitteln? Thesis, University of Basel.
Kugler, J., Schmidt, A., Groll, S., et al (1990a) Zur Pharmakodynamik eines Hypericum-Extraktes. Untersuchungen bei Patienten mitdepressiven Zuständen im Vergleich zu Bromazepam und Placebo. Zeitschrift fürAllgemeinmedizin, 66, 1320.
Kugler, J., Weidenhammer, W., Schmidt, A., et al (1990b) Therapie depressiver Zustände. Zeitschrift für Allgemeinmedizin, 66, 2129.
Laakmann, G., Schüle, C., Baghai, T., et al (1998) St John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Phamacopsychiatry, 31, 5459.
Lecrubier, Y., Clerc, G., Didi, R., et al (2002) Efficacy of St John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. American Journal of Psychiatry, 59, 13611366.
Lehrl, S. & Woelk, H. (1993) Ergebnisse von Messungen der kognitiven Leistungsfähigkeit bei Patienten unter der Therapie mit Johanniskraut. Nervenheilkunde, 12, 281284.
Lenoir, S., Degenring, F. H. & Saller, R. (1999) A double-blind randomised trial to investigate three different concentrations of a standardised fresh plant extract obtained from the shoot tips of Hypericum perforatum L. Phytomedicine, 6, 141146.
Linde, K. & Mulrow, C. D. (1998) St John's wort for depression (Cochrane Review). Cochrane Library, issue 4. Oxford: Update Software.
Linde, K., Ramirez, G., Mulrow, C. D., et al (1996) St John's wort for depression – an overview and meta-analysis of randomised clinical trials. BMJ, 313, 253258.
Linde, K., Jonas, W. B., Melchart, D., et al (2001) The methodological quality of randomized controlled trials of homeopathy, herbal medicines and acupuncture. International Journal of Epidemiology, 30, 526531.
Maisenbacher, J., Schmidt, U. & Schenk, N. (1995) Therapie mit Hypericum bei Angstzuständen. Therapiewoche Neurologie Psychiatrie, 9, 6570.
Martinez, B., Kasper, S., Ruhrmann, B., et al (1993) Hypericum in der Behandlung von saisonal abhängigen Depressionen. Nervenheilkunde, 12, 302307.
Montgomery, S. A., Hübner, W. D. & Grigoleit, H. G. (2000) Efficacy and tolerability of St John's wort extract compared with placebo in patients with a mild to moderate depressive disorder. Phytomedicine, 7 (suppl. 2), 107.
Murck, H. (2002) Die atypische Depression und verwandte Erkrankungen – neurobiologische Grundlagen fur ihre Behandlung mit Johanniskraut-Extrakt. Wiener Medizinische Wochenschrift, 152, 398403.
Osterheider, M., Schmidtke, A. & Beckmann, H. (1992) Behandlung depressiver Syndrome mit Hypericum (Johanniskraut) – eine placebokontrollierte Doppelblindstudie. Fortschritte der Neurologie Psychiatrie, 60 (suppl. 2): 210211.
Panijel, J. (1985) Die Behandlung mittelschwerer Angstzustände. Therapiewoche, 41, 46594668.
Philipp, M., Kohnen, R. & Hiller, K. O. (1999) Hypericum extract versus imipramine or placeboin patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ, 319, 15341539.
Quandt, J., Schmidt, U. & Schenk, N. (1993) Ambulante Behandlung leichter und mittelschwerer depressiver Verstimmungen. Der Allgemeinarzt, 2, 97102.
Reh, C., Laux, P. & Schenk, N. (1992) Hypericum-Extrakt bei Depressionen – eine wirksame Alternative. Therapiewoche, 42, 15761581.
Schlich, D., Braukmann, F. & Schenk, N. (1987) Behandlung depressiver Zustände mit Hypericinium. Psycho, 13, 440447.
Schmidt, U. & Sommer, H. (1993) Johanniskraut-Extrakt zur ambulanten Therapie der Depression. Fortschritte der Medizin, 111, 339342.
Schmidt, U., Schenk, N., Schwarz, I., et al (1989) Zur Therapie depressiver Verstimmungen. Psycho, 15, 665671.
Schmidt, U., Harrer, G., Kuhn, U., et al (1993) Wechselwirkungen von Hypericin-Extrakt mit Alkohol. Nervenheilkunde, 12, 314319.
Schrader, E. (2000) Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled studyin mild–moderate depression. International Clinical Psychopharmacology, 15, 6168.
Schrader, E., Meier, B. & Brattström, A. (1998) Hypericum treatment of mild–moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo-controlled, multicentre study. Human Psychopharmacology, 13, 163169.
Schulz, H. & Jobert, M. (1993) Der Einfluss von Johanniskraut auf das Schlaf-EEG bei älteren Probandinnen. Nervenheilkunde, 12, 323327.
Shelton, R. C., Keller, M. B., Gelenberg, A., et al (2001) Effectiveness of St John's wort in major depression. A randomized controlled trial. JAMA, 285, 19781986.
Sindrup, S. H., Madsen, C., Bach, F. W., et al (2000) St John's wort has no effect on pain in polyneuropathy. Pain, 91, 361365.
Sommer, H. & Harrer, G. (1994) Placebo-controlled doub e-blind study examining the effectiveness of an hypericum preparation in 105 mildly depressed patients. Journal of Geriatric Psychiatry and Neurology, 7 (suppl. 1), S9S11.
Spielberger, E. (1985) Johanniskraut-Präparat lindert selbstmittelschwere Depressionen Ärztliche Praxis, 37, 25462547.
Staffeldt, B., Kerb, R., Brockmöller, J., et al (1993) Pharmakokinetik von Hypericin und Pseudohypericin nach oraler Einnahme des Johanniskraut-Extrakts LI 160 bei gesunden Probanden. Nervenheilkunde, 12, 331336.
Steger, W. (1985) Depressive Verstimmungen. Zeitschrift für Allgemeinmedizin, 61, 914918.
Sterne, J. A. C., Gavaghan, D. J. & Egger, M. (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. Journal of Clinical Epidemiology, 53, 11191129.
Sterne, J. A., Egger, M. & Davey Smith, G. (2001) Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ, 323, 101105.
Thompson, S. G. & Sharp, S. J. (1999) Explaining heterogeneity in meta-analysis: acomparison of methods. Statistics in Medicine, 18, 26932708.
Van Gurp, G., Meterissian, G. B., Haiek, L. N., et al (2002) St John's wort or sertraline? Randomized controlled trial in primary care. Canadian Family Physician, 48, 905912.
Volz, H. P. (1997) Controlled clinical trials of Hypericum extracts in depressed patients – an overview. Pharmacopsychiatry, 30 (suppl. 2): 7276.
Volz, H. P., Eberhardt, R. & Grill, G. (2000) Wirksamkeit und Verträglichkeit des Johanniskrautextraktes D-0496 bei leichten bis mittelschweren depressiven Episoden – plazebokontrollierte Doppelblindstudie über 6 Wochen. Nervenheilkunde, 19, 401405.
Volz, H. P., Murck, H., Kasper, S., et al (2002) St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Psychopharmacology, 164, 294300.
Vorbach, E. U., Hübner, W. D. & Arnoldt, K. H. (1994) Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. Journal of Geriatric Psychiatry and Neurology, 7 (suppl. 1), S19S23.
Vorbach, E. U., Arnoldt, K. H. & Hübner, W. D. (1997) Efficacy and tolerability of St John's wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD–10. Pharmacopsychiatry, 30 (suppl. 2): 8185.
Walsh, B. T., Seidman, S. N., Sysko, R., et al (2002) Placebo response in studies of major depression-variable, substantial, and growing. JAMA, 287, 18401847.
Warnecke, G. (1986) Beeinflussung klimakterischer Depressionen. Zeitschrift fürAllgemeinmedizin, 62, 11111113.
Werth, W. (1989) Psychotonin M versus imipramin in der Chirurgie. Der Kassenarzt, 15, 6468.
Wheatley, D. (1997) L1160, an extract of St John's wort, versus amitriptyline in mildly to moderately depressed outpatients – acontrolled 6-weekclinical trial. Pharmacopsychiatry, 30 (suppl. 2): 7780.
Williams, J. W., Mulrow, C. D., Chiquette, E., et al (2000) A systematic review on newer pharmacotherapies for depression in adults, evidence report summary. Annals of Internal Medicine, 132, 743756.
Winkel, R., Koritsch, H. D., Piayda, H., et al (2000) St John's wort extract LI 160 in depressive, alcohol addicted patients. Phytomedicine, 7 (suppl. 2), 19.
Witte, B., Harrer, G., Kaptan, T., et al (1995) Behandlung depressiver Verstimmungen mit einem hochkonzentrierten Hypericumpräparat – eine multizentrische plazebokontrollierte Doppelblindstudie. Fortschritte der Medizin, 113, 404408.
Woelk, H. (2000) Comparison of St John's wort and imipramine for treating depression: randomised controlled trial. BMJ, 321, 536539.
World Health Organization (1977) Manual of the International Classification of Diseases (ICD–9). Geneva: WHO.
World Health Organization (1993) The ICD–10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: WHO.
Wurglics, M., Schulte-Löbbert, S., Dingermann, T., et al (2003) Rationale und traditionelle Johanniskrautpräparate. Deutscher Apotheker Zeitung, 143, 14541457.
Zeller, K. (2000) Once daily administration of Hypericum extract (STW 3): a convenient treatment. In: Herbal Medicinal Products for the Treatment of Pain (eds H. Chrubasik & B. D. Roufogalis), pp. 164168. Lismore: Southern Cross University Press.

Related content

Powered by UNSILO

St John's wort for depression: Meta-analysis of randomised controlled trials

  • Klaus Linde (a1), Michael Berner (a2), Matthias Egger (a3) and Cynthia Mulrow (a4)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.

St John's wort for depression: Meta-analysis of randomised controlled trials

  • Klaus Linde (a1), Michael Berner (a2), Matthias Egger (a3) and Cynthia Mulrow (a4)
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *