Hypericum perforatum: Traditional uses, clinical trials, and drug interactions

Document Type : Review Article

Authors

1 Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

10.22038/ijbms.2022.65112.14338

Abstract

Hypericum perforatum (Hypericaceae), known as Saint John’s wort (SJW), has been used in different systems of traditional medicine such as Chinese traditional medicine, Greek traditional medicine, and Islamic traditional medicine. The plant and its active constituents such as hyperforin and hypericin have a wide range of medicinal uses, particularly as anti-depressant, wound-healing, and antibacterial agents. In recent decades, many clinical trials have been performed to investigate the safety and efficacy of this medicinal plant. However, to the best on our knowledge, there is no comprehensive review article in this regard. In the current study, we aim to have a comprehensive review of the clinical trials of SJW to evaluate its efficacy and safety as well as its application in traditional medicine. Clinical studies investigating the safety, interactions, and efficacy of SJW were identified and summarized, including contributions from 2000 until December 2021. According to the results, these clinical studies were divided into three main categories based on the type of disease: psychiatric, endocrine, and skin problems. Important details of the studies, including the type and duration of the study, the type and percentage of the effective compounds or the extract used, the number of patients, and the obtained results were also discussed. In addition, co-administration and drug interaction of SJW with other drugs were summarized. SJW is a valuable medicinal plant, especially for psychiatric disorders. However, precautions should be taken while administrating the plant.

Keywords


1. Emami S, Aghazari F, Joharchi MR. Les Phanerogames endemiques de la flore d’Iran. L’Université de Téhéran des Sciences Médicales; 2011.
2. Emami S, Nadjafi F, Amine G, Amiri M, Khosravi  M, Nasseri M. Les espèces de plantes médicinales utilisées par les guérisseurs traditionnels dans la province de Khorasan, nord-est de l’Iran. Ethnopharmacologia 2012; 48: 48-59.
3. Velingkar VS, Gupta GL, Hegde NB. A current update on phytochemistry, pharmacology and herb–drug interactions of Hypericum perforatum. Phytochem Rev 2017; 16: 725-744.
4. Božin B, Kladar N, Grujić N, Anačkov G, Samojlik I, Gavarić N, et al. Impact of origin and biological source on chemical composition, anticholinesterase and antioxidant properties of some St. John’s wort species (Hypericum spp., Hypericaceae) from the Central Balkans. Molecules 2013; 18: 11733-11750.
5. Tokgöz HB, Altan F. Hypericum perforatum L.: A medicinal plant with potential as a curative agent against obesity-associated complications. Mol Biol Rep 2020; 47: 8679-8686.
6. Ng QX, Venkatanarayanan N, Ho CYX. Clinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysis. J Affect Disord 2017; 210: 211-221.
7. Zhang R, Ji Y, Zhang X, Kennelly EJ, Long C. Ethnopharmacology of Hypericum species in China: A comprehensive review on ethnobotany, phytochemistry and pharmacology. J Ethnopharmacol 2020; 254: 112686.
8. Clarke R. Are modern preparation methods compromising the efficacy of Chinese herbal medicines? An investigation using Guan Ye Lian Qiao (Hypericum perforatum L.). Journal of Chiese Medicine 2010: 35-38.
9. Gunther R. Dioscorides,‘De materia medica,’The Greek herbal of Dioscordes. New York: Hafner Publishing Co; 1968.
10. Solati K, Karimi M, Rafieian-Kopaei M, Abbasi N, Abbaszadeh S, Bahmani MJMrimc. Phytotherapy for wound healing: The most important herbal plants in wound healing based on Iranian ethnobotanical documents. Mini Rev Med Chem 2021; 21:500-519.
11. Ansâri Shirâzi AH. Ekhtiyârât Badiʿi. (Badiʿi’s Choises). Tehran: Pakhshe Razi Private Joint Stock Co; 1993.
12. Herawi AR. Al-Abniyah an Haqâyeq al-Adwiah (Basics of Realities on Drugs). Tehran: Tehran University Publications; 1992.
13. Ibn Sinâ HA. Al-Qânun fi aṭ-Ṭibbe (Canon of Medicine). Tehran Iran Almaʿee Publication; 2015.
14. Râzi MZ. Al-Hâwi fi aṭ-Ṭibbe (Comprehensive Book of Medicine). Hyderabad Osmania Oriental Publications Bureau, Osmania University; 1968.
15. Qarshi AA. Ash-Shâmel fi aṭ-Ṭibbe (The Comprehensive). Abu Dhabi Cultural Foundation Publications; 2005.
16. Ibn Beyṭâr AA. Al-Jâmʿee le Mofradât al- Adwyah wa al-Aghḏiah (Comprehensive Book in Simple Drugs and Foods). Beirut: Dâr al-Kotob al-Ilamiyah; 2001.
17. Aqili Alawi Khorâsâni Shirâzi MH. Makhzan al-Adwyah (Drug Treasure). Tehran: Sabz Arang Publisher; 2014.
18. Ghassâni AM. Ḥadiqat al-Azhâr fi Mâḥiyyat al-Uʿshb wa al-Uʿqqâr (Flower Garden in the Nature of Herbs and Drugs). Beirut: Dar al-Gharb al-Islami; 1990.
19. Anṭâki D. Taḏkirat Oli al-Albâb (Memorandum Book). Beirut: Dâr-al-Kotob al-Ilmiyah; 2000.
20. Stojanovic G, Dordevic A, Smelcerovic A. Do other Hypericum species have medical potential as St. John’s wort (Hypericum perforatum)? Curr Med Chem 2013; 20: 2273-2295.
21. Butterweck V, Böckers T, Korte B, Wittkowski W, Winterhoff H. Long-term effects of St. John’s wort and hypericin on monoamine levels in rat hypothalamus and hippocampus. Brain Res 2002; 930: 21-29.
22. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of Hypericum extract. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S57-59.
23. Oliveira AI, Pinho C, Sarmento B, Dias AC. Neuroprotective activity of Hypericum perforatum and its major components. Front Plant Sci 2016; 7: 1004.
24. Greeson JM, Sanford B, Monti DA. St. John’s wort (Hypericum perforatum): A review of the current pharmacological, toxicological, and clinical literature. Psychopharmacology (Berl) 2001; 153: 402-414.
25. Galeotti N, Vivoli E, Bilia AR, Vincieri FF, Ghelardini C. St. John’s wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase C γ and ɛ activity. Biochem Pharmacol 2010; 79: 1327-1336.
26. Tian JY, Tao RY, Zhang XL, Liu Q, He YB, Su YL, et al. Effect of Hypericum perforatum L. extract on insulin resistance and lipid metabolic disorder in high-fat-diet induced obese mice. Phytother Res 2015; 29: 86-92.
27. Moghaddam MHG, Roghani M, Maleki M. Effect of Hypericum perforatum aqueous extracts on serum lipids, aminotransferases, and lipid peroxidation in hyperlipidemic rats. Cardiovasc Res 2016; 5-11.
28. Reichling J, Weseler A, Saller R. A current review of the antimicrobial activity of Hypericum perforatum L. Pharmacopsychiatry 2001; 34 Suppl 1: S116-118.
29. Sytar O, Svediene J, Loziene K, Paskevicius A, Kosyan A, Taran N. Antifungal properties of hypericin, hypericin tetrasulphonic acid and fagopyrin on pathogenic fungi and spoilage yeasts. Pharm Biol 2016; 54: 3121-3125.
30. Montoya A, Daza A, Munoz D, Rios K, Taylor V, Cedeno D, et al. Development of a novel formulation with hypericin to treat cutaneous leishmaniasis based on photodynamic therapy in in vitro and in vivo studies. Antimicrob Agents Chemother 2015; 59: 5804-5813.
31. Chen H, Muhammad I, Zhang Y, Ren Y, Zhang R, Huang X, et al. Antiviral activity against infectious bronchitis virus and bioactive components of Hypericum perforatum L. Front Pharmacol 2019; 10: 1272.
32. Pu X-y, Liang J-p, Wang X-h, Xu T, Hua L-y, Shang R-f, et al. Anti-influenza A virus effect of Hypericum perforatum L. extract. Virologica Sinica 2009; 24: 19.
33. Maduray K, Davids L. The anticancer activity of hypericin in photodynamic therapy. J Bioanal Biomed 2011; 6: 004.
34. Theodossiou TA, Hothersall JS, De Witte PA, Pantos A, Agostinis P. The multifaceted photocytotoxic profile of hypericin. Mol Pharm 2009; 6: 1775-1789.
35. Kleemann B, Loos B, Scriba TJ, Lang D, Davids LM. St John’s wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death. PLoS One 2014; 9: e103762.
36. Liu Y-h, Liu G-h, Mei J-j, Wang J. The preventive effects of hyperoside on lung cancer in vitro by inducing apoptosis and inhibiting proliferation through Caspase-3 and P53 signaling pathway. Biomed Pharmacother 2016; 83: 381-391.
37. Wölfle U, Seelinger G, Schempp CM. Topical application of St. Johnʼs wort (Hypericum perforatum). Planta Med 2014; 80: 109-120.
38. Süntar IP, Akkol EK, Yılmazer D, Baykal T, Kırmızıbekmez H, Alper M, et al. Investigations on the in vivo wound healing potential of Hypericum perforatum L. J Ethnopharmacol 2010; 127: 468-477.
39. Belwal T, Devkota HP, Singh MK, Sharma R, Upadhayay S, Joshi C, et al. St. John’s wort (Hypericum perforatum). Nonvitamin and Nonmineral Nutritional Supplements: Elsevier; 2019. 
40. Kasper S, Anghelescu I-G, Szegedi A, Dienel A, Kieser M. Superior efficacy of St John’s wort extract WS® 5570 compared with placebo in patients with major depression: A randomized, double-blind, placebo-controlled, multi-center trial [ISRCTN77277298]. BMC Medicine 2006; 4: 1-13.
41. Melzer J, Brignoli R, Keck ME, Saller R. A Hypericum extract in the treatment of depressive symptoms in outpatients: an open study. Forsch Komplementmed 2010; 17: 7-14.
42. Sindrup SH, Madsen C, Bach FW, Gram LF, Jensen TS. St. John’s wort has no effect on pain in polyneuropathy. Pain 2001; 91: 361-365.
43. Kobak KA, Taylor LV, Warner G, Futterer R. St. John’s wort versus placebo in social phobia: Results from a placebo-controlled pilot study. J Clin Psychopharmacol 2005; 25: 51-58.
44. Kobak KA, Taylor LV, Bystritsky A, Kohlenberg CJ, Greist JH, Tucker P, et al. St John’s wort versus placebo in obsessive–compulsive disorder: results from a double-blind study. Int Clin Psychopharmacol 2005; 20: 299-304.
45. Taylor LH, Kobak KA. An open-label trial of St. John’s wort (Hypericum perforatum) in obsessive-compulsive disorder. J Clin Psychiatry 2000; 61: 575-578.
46. Niederhofer H. St. John’s wort may improve some symptoms of attention-deficit hyperactivity disorder. Nat Prod Res 2010; 24: 203-205.
47. Weber W, Vander Stoep A, McCarty RL, Weiss NS, Biederman J, McClellan J. Hypericum perforatum (St John’s wort) for attention-deficit/hyperactivity disorder in children and adolescents: A randomized controlled trial. JAMA 2008; 299: 2633-2641.
48. Brattström A. Long-term effects of St. John’s wort (Hypericum perforatum) treatment: A 1-year safety study in mild to moderate depression. Phytomedicine 2009; 16: 277-283.
49. Yao G, Li J, Wang J, Liu S, Li X, Cao X, et al. Improved resting-state functional dynamics in post-stroke depressive patients after Shugan Jieyu capsule treatment. Front Neurosci 2020; 14: 297-306.
50. Gong L, Yang X, Feng Y, Fei Z, Wang M, Qin B, et al. The efficacy of integrative anti-depressive therapy on motor recovery after ischemic stroke–A randomized clinical trial. Eur J Integr Med 2020; 35: 101102.
51. Mannel M, Kuhn U, Schmidt U, Ploch M, Murck H. St. John’s wort extract LI160 for the treatment of depression with atypical features–A double-blind, randomized, and placebo-controlled trial. J Psychiatr Res 2010; 44: 760-767.
52. Niederhofer H. St John’s wort treating patients with autistic disorder. Phytother Res 2009; 23: 1521-1523.
53. Di Pierro F, Risso P, Settembre R. Role in depression of a multi-fractionated versus a conventional Hypericum perforatum extract. Panminerva Med 2018; 60: 156-160.
54. Stevinson C, Dixon M, Ernst E. Hypericum for fatigue—A pilot study. Phytomedicine 1998; 5: 443-447.
55. Sharpley A, McGavin C, Whale R, Cowen P. Antidepressant-like effect of Hypericum perforatum (St John’s wort) on the sleep polysomnogram. Psychopharmacology (Berl) 1998; 139: 286-287.
56. Sarris J, Fava M, Schweitzer I, Mischoulon D. St John’s wort (Hypericum perforatum) versus sertraline and placebo in major depressive disorder: Continuation data from a 26-week RCT. Pharmacopsychiatry 2012; 45: 275-278.
57. Papakostas GI, Crawford CM, Scalia MJ, Fava M. Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. Neuropsychobiology 2007; 56: 132-137.
58. Seifritz E, Hatzinger M, Holsboer-Trachsler E. Efficacy of Hypericum extract WS® 5570 compared with paroxetine in patients with a moderate major depressive episode–A subgroup analysis. Int J Psychiatry Clin Pract 2016; 20: 126-132.
59. Trompetter I, Krick B, Weiss G. Herbal triplet in treatment of nervous agitation in children. Wien Med Wochenschr 2013; 163: 52-57.
60. Singer A, Schmidt M, Hauke W, Stade K. Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: A reanalysis of data from a controlled clinical trial. Phytomedicine 2011; 18: 739-742.
61. Kasper S, Volz H, Möller H, Dienel A, Kieser M. Continuation and long-term maintenance treatment with Hypericum extract WS® 5570 after recovery from an acute episode of moderate depression—A double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol 2008; 18: 803-813.
62. Yechiam E, Ben-Eliezer D, Ashby NJS, Bar-Shaked M. The acute effect of Hypericum perforatum on short-term memory in healthy adults. Psychopharmacology (Berl) 2019; 236: 613-623.
63. Müller T, Mannel M, Murck H, Rahlfs VW. Treatment of somatoform disorders with St. John’s wort: A randomized, double-blind and placebo-controlled trial. Psychosom Med 2004; 66: 538-547.
64. Eatemadnia A, Ansari S, Abedi P, Najar S. The effect of Hypericum perforatum on postmenopausal symptoms and depression: A randomized controlled trial. Complement Ther Med 2019; 45: 109-113.
65. Canning S, Waterman M, Orsi N, Ayres J, Simpson N, Dye L. The efficacy of Hypericum perforatum (St John’s wort) for the treatment of premenstrual syndrome. CNS Drugs 2010; 24: 207-225.
66. Ghazanfarpour M, Kaviani M, Asadi N, Ghaffarpasand F, Ziyadlou S, Tabatabaee HR, et al. Hypericum perforatum for the treatment of premenstrual syndrome. Int J Gynaecol Obstet 2011; 113: 84-85.
67. Abdali K, Khajehei M, Tabatabaee HR. Effect of St John’s wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: A randomized, double-blind, placebo-controlled study. Menopause 2010; 17: 326-331.
68. Arentz S, Smith CA, Abbott J, Fahey P, Cheema BS, Bensoussan A. combined lifestyle and herbal medicine in overweight women with polycystic ovary syndrome (PCOS): A randomized controlled trial. Phytother Res 2017; 31: 1330-1340.
69. Donovan JL, DeVane CL, Lewis JG, Wang JS, Ruan Y, Chavin KD, et al. Effects of St John’s wort (Hypericum perforatum L.) extract on plasma androgen concentrations in healthy men and women: A pilot study. Phytother Res 2005; 19: 901-906.
70. Schüle C, Baghai T, Sauer N, Laakmann G. Endocrinological effects of high-dose Hypericum perforatum extract WS 5570 in healthy subjects. Neuropsychobiology 2004; 49: 58-63.
71. van Die MD, Burger HG, Bone KM, Cohen MM, Teede HJ. Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: A randomized, controlled trial. Menopause 2009; 16: 156-163.
72. Fahami F, Asali Z, Aslani A, Fathizadeh N. A comparative study on the effects of Hypericum perforatum and passion flower on the menopausal symptoms of women referring to Isfahan city health care centers. Iran J Nurs Midwifery Res 2010; 15: 202-207.
73. Ryoo J-G, Chun S-I, Lee Y-J, Suh H-S. The Effects of St. John’s wort on premenstrual syndrome in single women: A randomized double-blind, placebo-controlled study. Clin Psychopharmacol Neurosci 2010; 8: 30-37.
74. Al-Akoum M, Maunsell E, Verreault R, Provencher L, Otis H, Dodin S. Effects of Hypericum perforatum (St. John’s wort) on hot flashes and quality of life in perimenopausal women: A randomized pilot trial. Menopause 2009; 16: 307-314.
75. Hajhashemi M, Ghanbari Z, Movahedi M, Rafieian M, Keivani A, Haghollahi F. The effect of Achillea millefolium and Hypericum perforatum ointments on episiotomy wound healing in primiparous women. J Matern Fetal Neonatal Med 2018; 31: 63-69.
76. Samadi S, Khadivzadeh T, Emami A, Moosavi NS, Tafaghodi M, Behnam HR. The effect of Hypericum perforatum on the wound healing and scar of cesarean. J Altern Complement Med 2010; 16: 113-117.
77. Clewell A, Barnes M, Endres JR, Ahmed M, Ghambeer DK. Efficacy and tolerability assessment of a topical formulation containing copper sulfate and Hypericum perforatum on patients with herpes skin lesions: A comparative, randomized controlled trial. J Drugs Dermatol 2012; 11: 209-215.
78. Najafizadeh P, Hashemian F, Mansouri P, Farshi S, Surmaghi MS, Chalangari R. The evaluation of the clinical effect of topical St Johns wort (Hypericum perforatum L.) in plaque type psoriasis vulgaris: A pilot study. Australas J Dermatol 2012; 53: 131-135.
79. Mansouri P, Mirafzal S, Najafizadeh P, Safaei-Naraghi Z, Salehi-Surmaghi MH, Hashemian F. The impact of topical Saint John’s wort (Hypericum perforatum) treatment on tissue tumor necrosis factor-alpha levels in plaque-type psoriasis: A pilot study. J Postgrad Med 2017; 63: 215-220.
80. Sardella A, Lodi G, Demarosi F, Tarozzi M, Canegallo L, Carrassi A. Hypericum perforatum extract in burning mouth syndrome: A randomized placebo-controlled study. J Oral Pathol Med 2008; 37: 395-401.
81. Kacerovská D, Pizinger K, Majer F, Šmíd F. Photodynamic therapy of nonmelanoma skin cancer with topical Hypericum perforatum extract—A pilot study. Photochem Photobiol 2008; 84: 779-785.
82. Obach RS. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp 2000; 294: 88-95.
83. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000; 97: 7500-7502.
84. Trana C, Toth G, Wijns W, Barbato E. St. John’s wort in patients non-responders to clopidogrel undergoing percutaneous coronary intervention: A single-center randomized open-label trial (St. John’s Trial). J Cardiovasc Transl Res 2013; 6: 411-414.
85. Mai I, Bauer S, Perloff ES, Johne A, Uehleke B, Frank B, et al. Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interaction. Clin Pharmacol Ther 2004; 76: 330-340.
86. Zahner C, Kruttschnitt E, Uricher J, Lissy M, Hirsch M, Nicolussi S, et al. No clinically relevant interactions of St. John’s wort extract Ze 117 low in Hyperforin with cytochrome P450 enzymes and P‐glycoprotein. Clin Pharmacol Ther 2019; 106: 432-440.
87. Mueller SC, Uehleke B, Woehling H, Petzsch M, Majcher-Peszynska J, Hehl EM, et al. Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxin. Clin Pharmacol Ther 2004; 75: 546-557.
88. Andren L, Andreasson Å, Eggertsen R. Interaction between a commercially available St. John’s wort product (Movina) and atorvastatin in patients with hypercholesterolemia. Eur J Clin Pharmacol 2007; 63: 913-916.
89. Markert C, Kastner IM, Hellwig R, Kalafut P, Schweizer Y, Hoffmann MM, et al. The Effect of induction of CYP 3A4 by St John’s wort on ambrisentan plasma pharmacokinetics in volunteers of known CYP 2C19 genotype. Basic Clin Pharmacol Toxicol 2015; 116: 423-428.
90. Loughren MJ, Kharasch ED, Kelton-Rehkopf MC, Syrjala KL, Shen DD. Influence of St. John’s wort on intravenous fentanyl pharmacokinetics, pharmacodynamics, and clinical effects: A randomized clinical trial. Anesthesiology 2020; 132: 491-503.
91. Mueller SC, Majcher-Peszynska J, Mundkowski RG, Uehleke B, Klammt S, Sievers H, et al. No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers. Eur J Clin Pharmacol 2009; 65: 81-87.
92. Bell EC, Ravis WR, Chan HM, Lin Y-J. Complementary and alternative medicine: Lack of pharmacokinetic interaction between St. John’s wort and prednisone. Ann Pharmacother 2007; 41: 1819-1824.
93. Lei H-P, Yu X-Y, Xie H-T, Li H-H, Fan L, Dai L-L, et al. Effect of St. John’s wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers. Xenobiotica 2010; 40: 275-281.
94. Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, et al. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John’s wort in renal transplant patients. Br J Clin Pharmacol 2003; 55: 203-211.
95. Goey AK, Meijerman I, Rosing H, Marchetti S, Mergui-Roelvink M, Keessen M, et al. The effect of St John’s wort on the pharmacokinetics of docetaxel. Clin Pharmacokinet 2014; 53: 103-110.
96. Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, et al. The interaction between St John’s wort and an oral contraceptive. Clin Pharmacol Ther 2003; 74: 525-535.
97. Nieminen TH, Hagelberg NM, Saari TI, Neuvonen M, Laine K, Neuvonen PJ, et al. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain 2010; 14: 854-859.
98. Hohmann N, Maus A, Carls A, Haefeli WE, Mikus G. St. John’s wort treatment in women bears risks beyond pharmacokinetic drug interactions. Arch Toxicol 2016; 90: 1013-1015.
99. Huppertz A, Werntz L, Meid AD, Foerster KI, Burhenne J, Czock D, et al. Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John’s wort should be avoided. Br J Clin Pharmacol 2018; 84: 2903-2913.
100. Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John’s wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 2004; 44: 89-94.
101. Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 2002; 94: 1247-1249.
102. Stage TB, Pedersen RS, Damkier P, Christensen MMH, Feddersen S, Larsen JT, et al. Intake of St. John’s wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone. Br J Clin Pharmacol 2015; 79: 298-306.
103. Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John’s wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 2005; 71: 402-408.
104. Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Neuvonen PJ, Olkkola KT. St John’s wort greatly decreases the plasma concentrations of oral S‐ketamine. Fundam Clin Pharmacol 2012; 26: 743-750.
105. Hojo Y, Echizenya M, Ohkubo T, Shimizu T. Drug interaction between St John’s wort and zolpidem in healthy subjects. J Clin Pharm Ther 2011; 36: 711-715.
106. Wang LS, Zhu B, Abd El-Aty AM, Zhou G, Li Z, Wu J, et al. The influence of St John’s wort on CYP2C19 activity with respect to genotype. J Clin Pharmacol 2004; 44: 577-581.
107. Lau WC, Welch TD, Shields T, Rubenfire M, Tantry US, Gurbel PA. The 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; 57: 86-93.
108. Szegedi A, Kohnen R, Dienel A, Kieser M. 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. BMJ 2005; 330: 503.
109. Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW, Zajecka J, et al. A Double-blind, randomized trial of St John’s wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol 2005; 25: 441-447.
110. Fuchs I, Hafner-Blumenstiel V, Markert C, Burhenne J, Weiss J, Haefeli WE, et al. Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity. Eur J Clin Pharmacol 2013; 69: 507-513.
111. Hafner V, Jager M, Matthee AK, Ding R, Burhenne J, Haefeli WE, et al. Effect of simultaneous induction and inhibition of CYP3A by St John’s wort and ritonavir on CYP3A activity. Clin Pharmacol Ther 2010; 87: 191-196.
112. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John’s wort. Lancet 2000; 355: 547-548.
113. Eagling VA, Wiltshire H, Whitcombe IW, Back DJ. CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica 2002; 32: 1-17.
114. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs 2003; 63: 769-802.
115. Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 2004; 76: 323-329.
116. Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000; 355: 548-549.
117. Karliova M, Treichel U, Malago M, Frilling A, Gerken G, Broelsch CE. Interaction of Hypericum perforatum (St. John’s wort) with cyclosporin A metabolism in a patient after liver transplantation. J Hepatol 2000; 33: 853-855.
118. Wittkowsky AK. Warfarin and other coumarin derivatives: Pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003; 3: 221-230.
119. Ehle M, Patel C, Giugliano RP. Digoxin: Clinical highlights: A review of digoxin and its use in contemporary medicine. Crit Pathw Cardiol 2011; 10: 93-98.
120. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, et al. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004; 57: 592-599.
121. Jackson A, D’Avolio A, Moyle G, Bonora S, Di Perri G, Else L, et al. Pharmacokinetics of the co-administration of boceprevir and St John’s wort to male and female healthy volunteers. J Antimicrob Chemother 2014; 69: 1911-1915.
122. Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W. Lack of effect of St John’s wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000; 68: 605-612.
123. Bell EC, Ravis WR, Lloyd KB, Stokes TJ. Effects of St. John’s wort supplementation on ibuprofen pharmacokinetics. Ann Pharmacother 2007; 41: 229-234.
124. Portoles A, Terleira A, Calvo A, Martinez I, Resplandy G. Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: An open-label, pharmacokinetic interaction clinical trial. J Clin Pharmacol 2006; 46: 1188-1194.
125. Fan L, Zhou G, Guo D, Liu Y-L, Chen W-Q, Liu Z-Q, et al. The pregnane X receptor agonist St John’s wort has no effects on the pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet 2011; 50: 605-611.
126. Gordon RY, Becker DJ, Rader DJ. Reduced efficacy of rosuvastatin by St. John’s wort. Am J Med 2009; 122: e1-2.
127. Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano S. Effect of St. John’s wort on the pharmacokinetics of theophylline in healthy volunteers. J Clin Pharmacol 2004; 44: 95-101.