Monograph: St. John's Wort - Oral

Date: 2023-01-27

NHPID name

Hypericum perforatum ( Germplasm Resources Information Network Taxonomy )

Proper name(s)

Hypericum perforatum ( USDA 2008 )

Common name(s)

• Goatweed ( Unavailable )
• Hypericum ( Anghelescu et al. 2006 , Gastpar et al. 2006 , Szegedi et al. 2005 , Wichtl 2004 )
• St. John's wort ( McGuffin et al. 2000 )
• St. John's-wort ( Unavailable )

Source material

Herb top ( Bradley 2006 , Mills and Bone 2005 , Hoffmann 2003 , Blumenthal et al. 2000 , Felter and Lloyd 1983[1898] , Wren 1907 )

Route Of administration

Oral

Dosage form(s)

• The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.
• This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use(s) or purpose(s)

Statement(s) to the effect of:

• (Traditionally) used in Herbal Medicine to help relieve restlessness and/or nervousness (calmative).  (Mills and Bone 2005, Hoffmann 2003, Blumenthal et al. 2000, Felter and Lloyd 1983[1898], Grieve 1971[1931])
• (Used in Herbal Medicine to) help(s) promote healthy mood balance and relieve sleep disturbances associated with mood imbalance.
• (Used in Herbal Medicine to) help(s) promote healthy mood balance.  (Anghelescu et al. 2006, Gastpar et al. 2006, Kasper et al. 2006, Fava et al. 2005, Mills and Bone 2005, Szegedi et al. 2005, Uebelhack et al. 2004, ESCOP 2003, Hoffmann 2003, Lecrubier et al. 2002, Volz et al. 2002, Kalb et al. 2001)

Dose(s)

Adults:

See Appendix 1 for examples of appropriate dosage preparations and frequencies of use, according to cited references. The purpose of Appendix 1 is to provide guidance to industry.

Duration of use

• Use for at least 1 week to see beneficial effects.  (Papakostas et al. 2007, Kalb et al. 2001)
• Consult a health care practitioner/health care provider/health care professional/doctor/ physician for use beyond 18 weeks.  (Anghelescu et al. 2006, Gastpar et al. 2006, Kasper et al. 2006, Fava et al. 2005, Mills and Bone 2005, Szegedi et al. 2005, Uebelhack et al. 2004, ESCOP 2003, HDTSG 2002, Lecrubier et al. 2002, Volz et al. 2002, Kalb et al. 2001)

Risk information

Statement(s) to the effect of:

Caution(s) and Warning(s):

• Avoid prolonged exposure to sunlight, ultraviolet light (UV) or UV therapy.  (Brinker 2010, Barnes et al. 2007, Mills and Bone 2005, ESCOP 2003, Hoffmann 2003, McGuffin et al. 1997)
• Consult a health care practitioner/health care provider/health care professional/doctor/ physician if symptoms persist or worsen.
• Consult a health care practitioner/health care provider/health care professional/doctor/ physician prior to use if you are taking antianxiety or seizure medications, antihistamines, bronchodilators, muscle relaxants and/or opiates.  (Brinker 2010, Barnes et al. 2007, Mills and Bone 2005)

Contraindication(s): Do not use this product if you are taking anti-cancer, antidepressant [e.g. selective serotonin reuptake inhibitors (SSRI)], cardiovascular, contraceptive medications, blood thinners, anti-HIV agents and/or medications to suppress the immune system (immunosuppressive medications). Known Adverse Reaction(s):

• Some people may experience mild gastrointestinal disturbances, nausea, restlessness and/or headaches.  (Barnes et al. 2007, ESCOP 2003)
• Stop use if hypersensitivity/allergy occurs.  (Barnes et al. 2007, ESCOP 2003)

See Appendix 2 to find the references of the Caution and Contraindication statements about medication use.

Non-medicinal ingredients

Must be chosen from the current Natural health products ingredients database and must meet the limitations outlined in the database.

Specifications

• The finished product specifications must be established in accordance with the requirements described in the NHPD Quality of natural health products guide.
• The medicinal ingredient must comply with the requirements outlined in the Natural health products ingredient database (NHPID).
• The medicinal ingredient may comply with the specifications outlined in one of the following pharmacopoeial monographs: (i) 'St. John's wort' from European Pharmacopoeia (Ph. Eur.) and (ii) 'St. John's wort' or 'Powdered St. John's wort' or 'Powdered St. John's wort extract' in US Pharmacopoeia (USP)

References cited

• Ahmed SM, Banner NR, Dubrey SW. 2001. Low cyclosporin-A level due to Saint-John's-wort in heart transplant patients. Journal of Heart and Lung Transplantation 20(7):795.
• Alscher DM, Klotz U. 2003. Drug interaction of herbal tea containing St. John's wort with cyclosporine. Transplant International 16(7):543-544.
• Anghelescu IG, Kohnen R, Szegedi A, Klement S, Kieser M. 2006. Comparisons of Hypericum extract WS 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression: results from a randomized multicenter study. Pharmacopsychiatry 39(6):213-219.
• Barnes J, Anderson LA, Philipson JD. 2007. Herbal Medicines, 3rd edition. London (GB): Pharmaceutical Press.
• Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. 2000. Drug interaction between St. John's wort and cyclosporine. The Annals of Pharmacotherapy 34(9):1013-1016.
• Bauer S, Störmer E, Johne A, Krüger H, Budde K, Neumayer HH, Roots I, Mai I. 2003. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients. British Journal of Clinical Pharmacology 55(2):203-211.
• BHP 1983: British Herbal Pharmacopoeia. Cowling (GB): British Herbal Medical Association; 1983.
• Blumenthal M, Goldberg A, Brinckmann J, editors. Herbal Medicine: Expanded Commission E Monographs. Boston (MA): Integrative Medicine Communications; 2000.
• Bolley R, Zülke C, Kammerl M, Fischereder M, Krämer BK. 2002. Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St John's wort. Transplantation 73(6):1009.
• Bove M. 2001. An Encyclopedia of Natural Healing for Children and Infants, 2nd edition. Toronto (ON): McGraw-Hill.
• Bradley PR, editor. British Herbal Compendium: A Handbook of Scientific Information on Widely Used Plant Drugs, Volume 2. Bournemouth (UK): British Herbal Medicine Association; 2006.
• Brattström A. 2009. Long-term effects of St. John's wort (Hypericum perforatum) treatment: a 1-year safety study in mild to moderate depression.
• Brinker F. 2001. Herb Contraindications and Drug Interactions, 3rd edition. Sandy (OR): Eclectic Medical Publications.
• Brinker F. 2010. Online Updates and Additions to Herb Contraindications and Drug Interactions, 3rd edition. Sandy (OR): Eclectic Medical Publications. [Updated 2010 July 13; Accessed 2013 January 30]. Available from: http://www.eclecticherb.com/emp/updatesHCDI.html
• Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W. 2000. Lack of effect of St John's Wort on carbazepine pharmacokinetics in healthy volunteers. Clinical Pharmacology and Therapeutics 68(6):605-612.
• DAB 6: Deutsches Arzneibuch. 1941. Pharmacopoea Germanica. Berlin (DE): Decker.
• Dannawi M. 2002. Possible serotonin syndrome after combination of buspirone and St John's wort. Journal of Psychopharmacology 16(4):401.
• De Maat MM, Hoetelmans RM, Math t RA, van Gorp EC, Meenhorst PL, Mulder JW, Beijnen JH. 2001. Drug interaction between St John's wort and nevirapine. AIDS 15(3):420-421.
• Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. 2003. Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects. Clinical Pharmacology and Therapeutics 73(1):41-50.
• Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K. 2000. St. John's wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clinical Pharmacology and Therapeutics 68(6):598-604.
• Eich-Höchli D, Oppliger R, Golay KP, Baumann P, Eap CB. 2003. Methadone maintenance treatment and St John's wort: a case report. Pharmacopsychiatry 36(1):35-37.
• Ernst E. 1999. Second thoughts about the safety of St. John's wort. Lancet 354(9195):2014-2016.
• ESCOP 2003: ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products, 2nd edition. Exeter (UK): European Scientific Cooperative on Phytotherapy and Thieme; 2003.
• European Pharmacopoeia, 6th edition. Strasbourg (France): Directorate for the Quality of Medicines and HealthCare of the Council of Europe (EDQM).; 2008
• FAO 1985. Food and Agriculture Organization of the United Nations. Planning and engineering data 2: Fish canning [online]. Myrseth A, editor. Fisheries Circular - C784; 1985. Rome (I): Food and Agriculture Organization of the United Nations Document Repository. Available at: http://www.fao.org/DOCREP/003/R6918E/R6918E02.HTM [Accessed 09 May 2008].
• Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW, Zajecka J, Murck H, Rosenbaum JF. 2005. A double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder. Journal of Clinical Psychopharmacology 25(5):441-447.
• Felter HW, Lloyd JU. King's American Dispensatory, Volume 1, 18th edition. Sandy (OR): Eclectic Medical Publications; 1983 [Reprint of 1898 original].
• Friede M, von Zepelin H, Freudenstein J. 2001. Differential therapy of mild to moderate depressive episodes (ICD-10 F 32.0; F 32.1) with St. John's wort. Pharmacopsychiatry 34(Supplement 1):S38-S41
• Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. 2004. Effect of St John's wort on imatinib mesylate pharmacokinetics. Clinical Pharmacology and Therapeutics 76(4):323-329.
• Gastpar M, Singer A, Zeller K. 2006. Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry 39(2):66-75.
• Gorski JC, Hamman MA, Wang Z, Vasavada N, Huang S, Hall SD. 2002. The effect of St John's wort on the efficacy of oral contraception. Clinical Pharmacology and Therapeutics 71:P25.
• Grieve M. 1971. A Modern Herbal, Volume 1. New York (NY): Dover Publications [Reprint of 1931 Harcourt, Brace & Company publication].
• Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. 2002. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clinical Pharmacology and Therapeutics 72(3):276-287.
• Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, Hilligoss JK, Miller M, Gorski JC. 2003. The interaction between St. John's wort and an oral contraceptive. Clinical Pharmacology and Therapeutics 74(6):525-535.
• HC 2007: Health Canada. Natural Health Products Directorate Monthly Communiqué Volume 3, Issue 4, December 2007 [online]. Ottawa (ON): Natural Health Products Directorate, Health Canada. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/_communiques/communique_dec07_e.html [Accessed 09 May 2008].
• Hebert MF, Park JM, Chen YL, Akhatar S, Larson AM. 2004. Effects of St. John's wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology 44(1):89-94.
• Hoffmann D. 2003. Medical Herbalism: The Science and Practice of Herbal Medicine. Rochester (VT): Healing Arts Press.
• Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. The Journal of the American Medical Association 287(14):1807-1814.
• Isacchi B, Bergonzi MC, Carnevali F, van der Esch SA, Vincieri FF, Bilia AR. 2007. Analysis and stability of the constituents of St. John's wort oils prepared with different methods. Journal of Pharmaceutical and Biomedical Analysis September 7. doi:10.1016/j.jpba.2007.08.025.
• Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. 2004. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. British Journal of Clinical Pharmacology 57(5):592-599.
• Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich, M, Roots I. 1999. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clinical Pharmacology and Therapeutics 66(4):338-345.
• Kalb R, Trautmann-Sponsel RD, Kieser M. 2001. Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial. Pharmacopsychiatry 34(3):96-103.
• Karliova M, Treichel U, Malagò M, Frilling A, Gerken G, Broelsch CE. 2000. Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A metabolism in a patient after liver transplantation. Journal of Hepatology 33(5):853-855.
• Kasper S, Anghelescu IG, Szegedi A, Dienel A, Kieser M. 2006. Superior efficacy of St John's wort extract WS 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial [ISRCTN77277298]. BMC Medicine 4:14.
• Kawaguchi A, Ohmori M, Tsuruoka S, Nishiki K, Harada K, Miyamori I, Yano R, Nakamura T, Masada M, Fujimura A. 2004. Drug interaction between St John's Wort and quazepam. British Journal of Clinical Pharmacology 58(4):403-410.
• Lecrubier Y, Clerc G, Didi R, Kieser M. 2002. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. The American Journal of Psychiatry 159(8):1361-1366.
• Mai I, Krüger H, Budde K, Johne A, Brockmöller J, Neumayer HH, Roots I. 2000. Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perforatum) with the immunosuppressant cyclosporin. International Journal of Clinical Pharmacology and Therapeutics 38(10):500-502.
• Maisenbacher P, Kovar KA. 1992. Analysis and stability of Hyperici oleum. Planta Medica 58(4):351-354.
• Markowitz JS, Donovan JL, DeVane CL, Talor RM, Ruan Y, Wang J, Chavin KD. 2003. Effect of St. John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. The Journal of the American Medical Association. 290(11):1500-1504.
• Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. 2002. Effects of St John's wort on irinotecan metabolism. Journal of the National Cancer Institute 94(16):1247-1249.
• Maurer A, Johne A, Bauer S, Brockmoller F, Conath I, Roots M, Langheinrich M, Hubner WD. 1999. Interaction of St. John's wort extract with phenprocoumon [Abstract]. European Journal of Clinical Pharmacology 55:A22.
• McGuffin M, Hobbs C, Upton R, Goldberg A, editors. 1997. American Herbal Products Association's Botanical Safety Handbook. Boca Raton (FL): CRC Press.
• McGuffin M, Kartesz JT, Leung AY, Tucker AO, editors. 2000. Herbs of Commerce, 2nd edition. Austin(TX): American Herbal Products Association.
• Mills S, Bone K. 2005. The Essential Guide to Herbal Safety. St. Louis (MO): Elsevier Churchill Livingstone.
• Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano S. 2004. Effect of St. John's wort on the pharmacokinetics of theophylline in healthy volunteers. Journal of Clinical Pharmacology 44(1):95-101.
• Moschella C, Jaber BL. 2001. Interaction between cyclosporine and Hypericum perforatum (St. John's wort) after organ transplantation. American Journal of Kidney Diseases 38(5):1105-1107.
• Mueller SC, Uehleke B, Woehling H, Petzsch M, Majcher-Peszynska J, Hehl EM, Sievers H, Frank B, Riethling AK, Drewelow B. 2004. Effect of St. John's wort dose and preparations on the pharmacokinetics of digoxin. Clinical Pharmacology and Therpeutics 75(6):546-557.
• Murphy A, Kern SE, Stanczyk FZ, Westhoff CL. 2005. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 71(6):402-408.
• Nebel A, Schneider BJ, Baker RK, Kroll DJ. 1999. Potential metabolic interaction between St. John's wort and theophylline. The Annals of Pharmacotherapy 33(4):502.
• Papakostas GI, Crawford CM, Scalia MJ, Fava M. 2007. Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. A replication of findings with the use of a double-blind, placebo-controlled trial of Hypericum perforatum versus fluoxetine. Neuropsychobiology 56(2-3):132-137
• Parker V, Wong AH, Boon HS, Seeman MV. 2001. Adverse reactions to St John's wort. Canadian Journal of Psychiatry 46(1):77-79.
• Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J. 2003. Interaction of St. John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. British Journal of Clinical Pharmacology 56(6):683-690.
• Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. 2000. Indinavir concentrations and St John's wort. Lancet 355(9203):547-548.
• Randløv C, Mehlsen J, Thomsen CF, Hedman C, von Fircks H, Winther K. 2006. The efficacy of St. John's Wort in patients with minor depressive symptoms or dysthymia-a double-blind placebo-controlled study. Phytomedicine 13(4):215-221.
• Rey JM, Walter G. 1998. Hypericum perforatum (St John's wort) in depression: pest or blessing? The Medical Journal of Australia 169(11-12):583-586.
• Roby CA, Dryer DA, Burstein AH. 2001. St. John's wort: effect on CYP2D6 activity using dextromethorphan-dextrorphan ratios. Journal of Clinical Psychopharmacology 21(5):530-532.
• Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. 2000. Acute heart transplant rejection due to Saint John's wort. Lancet 355(9203):548-549.
• Schrader E, Meier B, Brattström A. 1998. Hypericum treatment of mild-moderate depression in a placebo-controlled study: a prospective, double blind, randomised, placebo-controlled, multicenter study. Human Psychopharmacology: Clinical and Experimental 13:163-169.
• Schwarz UI, Büschel B, Kirch W. 2003. Unwanted pregnancy on self- medication with St John's wort despite hormonal contraception. British Journal of Clinical Pharmacology 55(1):112-113.
• Smith P, Bullock JM, Booker BM, Haas CE, Berenson CS, Jusko WJ. 2004. The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy 24(11):1508-1514.
• Sosa S, Pace R, Bornancin A, Morazzoni P, Riva A, Tubaro A, Della Loggia R. 2007. Topical anti-inflammatory activity of extracts and compounds from Hypericum perforatum L. The Journal of Pharmacy and Pharmacology 59(5):703-709.
• Sparreboom A, Cox MC, Acharya MR, Figg WD. 2004. Herbal remedies in the United States: potential adverse interactions with anticancer agents. Journal of Clinical Oncology 22(12):2489-2503.
• Spinella M, Eaton LA. 2002. Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild traumatic brain injury. Brain Injury 16(4):359-367.
• Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A. 2001. Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin. Clinical Pharmacology and Therapeutics 70(6):518-524.
• Szegedi A, Kohnen R, Dienel A, Kieser M. 2005. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. British Medical Journal 330(7490):503.
• Tannergren C, Engman H, Knutson L, Hedeland M, Bondesson U, Lennernäs H. 2004. St. John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism. Clinical Pharmacology and Therapeutics 75(4):298-309.
• Turton-Weeks SM, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. 2001. St John's wort: a hidden risk for transplant patients. Progress in Transplantation 11(2):116-120.
• Uebelhack R, Gruenwald J, Graubaum HJ, Busch R. 2004. Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial. Advances in Therapy 21(4):265-275.
• USDA 2008: ARS, National Genetic Resources Program. Germplasm Resources Information Network (GRIN). National Germplasm Resources Laboratory, Beltsville (MD). [Accessed 2008-01-21]. Available at http://www.ars-grin.gov/cgi-bin/npgs/html/tax_search.pl
• USP 32 : United States Pharmacopeial Convention. 2009. United States Pharmacopeia and the National Formulary (USP 32 - NF 27). Rockville (MD): The United States Pharmacopeial Convention.
• Volz HP, Murck H, Kasper S, Möller HJ. 2002. St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Psychopharmacology 164(3):294-300.
• Wang ZQ, Gorski C, Hamman MA, Huang S, Lesko LJ, Hall SD. 2001. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clinical Pharmacology and Therapeutics 70(4):317-326.
• Wang ZQ, Hamman MA, Huang SM, Lesko LJ, Hall SD. 2002. Effect of St John's wort on the pharmacokinetics of fexofenadine. Clinical Pharmacology and Therapeutics 71(6):414-420.
• Wheatley D. 1999. Hypericum in Seasonal Affective Disorder (SAD). Current Medical Research and Opinion 15(1):33-37
• Wichtl M, editor. Herbal Drugs and Phytopharmaceuticals: A Handbook for Practice on a Scientific Basis, 3rd edition. Stuttgart (D): Medpharm GmbH Scientific Publishers; 2004.
• Wren RC. 1907. Potter's Cyclopedia of Botanical Drugs and Preparations. London (GB): Potter and Clark.
• Xie R, Tan L, Polasek EC, Hong C, Teillol-Foo M, Gordi T, Sharma A, Nickens DJ, Arakawa T, Knuth DW, Antal EJ. 2003. CYP3A and P-glycoprotein induction with St. John's wort in healthy volunteers of selected ethnic populations. Journal of Clinical Pharmacology 45(3):352-356.

References reviewed

• Arold G, Donath F, Maurer A, Diefenbach K, Bauer S, Henneicke-von Zepelin HH, Friede M, Roots I. 2005. No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract. Planta Medica 71(4):331-337.
• Bjerkenstedt L, Edman GV, Alken RG, Mannel M. 2005. Hypericum extract LI 160 and fluoxetine in mild to moderate depression: a randomized, placebo-controlled multi-center study in outpatients. European Archives of Psychiatry and Clinical Neuroscience 255(1):40-47.
• Brenner R, Azbel V, Madhusoodanan S, Pawlowska M. 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(4):411-419.
• Cosmetic Ingredient Review Expert Panel. 2001. Final report on the safety assessment of Hypericum Perforatum extract and Hypericum perforatum oil. International Journal of Toxicology 20 (Suppl 2):31-39.
• Crowe S, McKeating K. 2002. Delayed emergence and St. John's wort. Anesthesiology 96(4):1025-1027.
• Findling RL, McNamara NK, O'Riordan MA, Reed MD, Demeter CA, Branicky LA, Blumer JL. 2003. An open-label pilot study of St. John's wort in juvenile depression. Journal of the American Academy of Child and Adolescent Psychiatry 42(8):908-914.
• Gastpar M, Singer A, Zeller K. 2005. Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry 38(2):78-86.
• Irefin S, Sprung J. 2000. A possible cause of cardiovascular collapse during anesthesia: long-term use of St. John's Wort. Journal of Clinical Anesthesia 12(6):498-499.
• Johne A, Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, Scholler G, Langheinrich M, Roots I.. 2002. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St John's wort (Hypericum perforatum). Journal of Clinical Psychopharmacology 22(1):46-54.
• Kasper S, Anghelescu IG, Szegedi A, Dienel A, Kieser M. 2007. Placebo controlled continuation treatment with Hypericum extract WS 5570 after recovery from a mild or moderate depressive episode. Wiener Medizinische Wochenschrift 157(13-14):362-366.
• Khawaja IS, Marotta RF, Lippmann S. 1999. Herbal medicines as a factor in delirium. Psychiatric Services 50(7):969-970.
• Kobak KA, Taylor LV, Bystritsky A, Kohlenberg CJ, Greist JH, Tucker P, Warner G, Futterer R, Vapnik T. 2005. St John's wort versus placebo in obsessive-compulsive disorder: results from a double-blind study. International Clinical Psychopharmacology 20(6):299-304.
• Linde K, Mulrow CD, Berner M, Egger M. 2005. St John's wort for depression. Cochrane Database of Systematic Reviews Issue 2. Art. No.:CD000448. DOI: 10.1002/14651858. CD000448.pub2.
• Mannel M. 2004. Drug interactions with St. John's wort: Mechanisms and clinical implications. Drug Safety 27(11):773-797.
• Moreno RA, Teng CT, Almeida KM, Tavares Junior H. 2006. Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression: a randomized double-blind trial in a Brazilian sample. Revista Brasileira de Psiquiatria 28(1):29-32.
• Müller T, Mannel M, Murck H, Rahlfs VW. 2004. Treatment of somatoform disorders with St. John's wort: a randomized, double-blind and placebo-controlled trial. Psychosomatic Medicine 66(4):538-547.
• Philipp M, Kohnen R, Hiller KO. 1999. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. British Medical Journal 319(7224):1534-1538.
• Schempp CM, Hezel S, Simon JC. 2003. Topical treatment of atopic dermatitis with Hypericum cream. A randomised, placebo-controlled, double-blind half-side comparison study. Der Hautarzt; Zeitschrift für Dermatologie, Venerologie, und Verwandte Gebiete 54(3):248-253.
• Schempp CM, Ludtke R, Winghofer B, Simon JC. 2000. Effect of topical application of hypericum perforatum extract (St. John's wort) on skin sensitivity to solar simulated radiation. Photodermatology, Photoimmunology and Photomedicine 16(3):125-128.
• Schulz H, Jobert M. 1994. Effects of hypericum extract on the sleep EEG in older volunteers. Journal of Geriatric Psychiatry and Neurology 7(Suppl 1):S39-S43.
• Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U. 2001. Effectiveness of St John's wort in major depression: a randomized controlled trial. The Journal of the American Medical Association 285(15):1978-1986.
• Simeon J, Nixon MK, Milin R, Jovanovic R, Walker S. 2005. Open-label pilot study of St. John's wort in adolescent depression. Journal of Child and Adolescent Psychopharmacology 15(2):293-301.
• van Gurp G, Meterissian GB, Haiek LN, McCusker J, Bellavance F. 2002. St John's wort or sertraline? Randomized controlled trial in primary care. Canadian Family Physician 48:905-912.
• Vorbach EU, Arnoldt KH, Hübner WD. 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):81-85.
• Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM, Li T, Liu J, Yang TL, Wang D, Zhong XY, Zhou HH. 2004. St. John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clinical Pharmacology and Therapeutics 75(3):191-197.
• Weber W, Vander Stoep A, McCarty RL, Weiss NS, Biederman J, McClellan J. 2008. Hypericum perforatum (St John's wort) for attention-deficit/hyperactivity disorder in children and adolescents: a randomized controlled trial. The Journal of the American Medical Association 299(22):2633-2641.
• Wenk M, Todesco L, Krähenbühl S. 2004. Effect of St John's Wort on the activities of CYP1A2, CYP3A4, N-acetyltransferase 2, and xanthine oxidase in healthy males and females. British Journal of Clinical Pharmacology 57(4):495-499.
• Wiersema J, León B. 1999. World Economic Plants: A Standard Reference. Boca Raton (FL): CRC Press LLC.
• Woelk H. 2000. Comparison of St John's wort and imipramine for treating depression: randomised controlled trial. British Medical Journal 321(7260):536-539.
• Yue QY, Bergquist C, Gerdén B. 2000. Safety of St John's wort (Hypericum perforatum). Lancet 355(9203):576-577.

Appendix 1: Examples of appropriate dosage preparations, frequencies of use and directions for use

ORAL:

Dried aerial parts:

2-4 g, per day (Blumenthal et al. 2000; BHP 1983)

Infusion:

• 2-4 g dried flowering tops, per day (Wichtl 2004; ESCOP 2003)
• 1.8-3.6 g dried herb, 3 times per day (Hoffmann 2003)
• Directions for use: Pour 250 ml (1 cup) of boiling water over 1 to 2 teaspoons of dried herb (flower) and infuse for 5-15 minutes (Wichtl 2004; Hoffmann 2003). 1 tsp =1.8 g (Wichtl 2004)

Fluid extract:

2-4 g dried equivalent, 3 times per day (1:1, 25% alcohol, 2-4 ml)(BHP 1983)

Tincture:

• 0.6-0.9 g dried equivalent, per day (1:5, 60 % ethanol, 3-4.5 ml)(ESCOP 2003)
• 0.4-0.8 g dried equivalent, 3 times per day (1:5, 40 % ethanol, 2-4 ml) (Hoffmann 2003)
• 0.2-0.4 g dried equivalent, 3 times per day (1:10, 45% ethanol, 2-4 ml) (BHP 1983)

Dry hydroalcoholic extract/solild hydroalcoholic extract:

• 300-600 mg, 3 times per day (3-7:1) (Anghelescu et al. 2006)
• 900 mg, per day (Gastpar et al. 2006)
• 600 mg, per day (3-7:1, 80% methanol) (Kasper et al. 2006)
• 1,200 mg, per day (3-7:1, 80% methanol) (Kasper et al. 2006)
• 300 mg, 3 times per day standardized to 0.12%-0.28% hypericin (Fava et al. 2005)
• 300 mg, 3 times per day (3-7:1) standardized to 3%-6% hyperforin and 0.12%-0.28% hypericin (Szegedi et al. 2005)
• 600 mg, 3 times per day (3-7:1) standardized to 3%-6% hyperforin and 0.12%-0.28% hypericin (Szegedi et al. 2005)
• 900 mg, per day (Uebelhack et al. 2004)
• 300 mg, 3 times per day (4-7:1) standardized to 3%-6% hyperforin and 0.12%-0.28% hypericin. (Lecrubier et al. 2002)
• 300 mg, 2 times per day (Volz et al. 2002)
• 300 mg, 3 times per day (2.5-5.0:1) standardized to 5% hyperforin (Kalb et al. 2001)
• 300 mg, 3 times per day (5-7:1) (Blumenthal et al. 2000)

 

Appendix 2: Examples of classes of medications that can be affected by St. John's wort

• Anti-cancer agents (Brinker 2008; Sparreboom et al. (2004); Frye et al. 2004; Smith et al. 2004; Hoffmann 2003; Mathijssen et al. 2002; Wang et al. 2001; Roby et al. 2001.);
• Anticoagulants (blood thinners) (Brinker 2008; Mills and Bone 2005; Jiang et al. 2004; Wichtl 2004; Brinker 2001; Maurer et al. 1999);
• Anticonvulsants (seizure medications) (Barnes et al. 2007; Burstein et al. 2000);
• Antidepressants such as SSRIs (selective serotonin reuptake inhibitors) (Brinker 2008; Bradley 2006; Mills and Bone 2005; ESCOP 2003; Brinker 2001);
• Antihistamines (Mills and Bone 2005; Hoffman 2003; Dresser et al. 2003; Xie et al. 2003; Wang et al. 2002);
• Anti-HIV agents (Brinker 2008; Barnes et al. 2007; ESCOP 2003; Hoffmann 2003; De Maat et al. 2001; Piscitelli et al. 2000);
• Anxiolytics (anti-anxiety) (Kawaguchi et al. 2004; Markowitz et al. 2003; Dannawi 2002; Spinella and Eaton 2002; Wang et al. 2001; Parker et al. 2001);
• Bronchodilators (Mills and Bone 2005; Morimoto et al. 2004; Nebel et al. 1999);
• Cardiovascular medications (Brinker 2008; Barnes et al. 2007; Bradley 2006; Mills and Bone 2005; Tannergren et al. 2004; Mueller et al. 2004; Sugimoto et al. 2001; Durr et al. 2000; Johne et al. 1999);
• Immunosuppressants (Brinker 2008; Bradley 2006; Hebert et al. 2004; Alscher and Klotz 2003; Bauer et al. 2003; Dresser et al. 2003; Bolley 2002; Ahmed et al. 2001; Moschella and Jaber 2001; Turton-Weeks 2001; Barone et al. 2000; Karliova et al. 2000; Mai et al. 2000; Ruschitzka et al. 2000; Ernst 1999; Rey and Walter 1998);
• Muscle relaxants (Gurley et al. 2002);
• Opiates (Brinker 2008; Mills and Bone 2005; Eich-Höchli et al. 2003; Brinker 2001)