Hypericum perforatum L.

Last updated: 11 Apr 2017

Scientific Name

Hypericum perforatum L. 

Synonyms

Hypericum assurgens Peterm. ex Rouy, Hypericum deidesheimense Sch.Bip. ex Trevir., Hypericum lineolatum Jord., Hypericum marylandicum Biroli ex Colla, Hypericum officinale Gaterau [Illegitimate], Hypericum officinarum Crantz [Illegitimate], Hypericum perforatum var. albiflorum Choisy, Hypericum perforatum var. alpinum Parl., Hypericum perforatum var. anomalum Frid., Hypericum perforatum f. brevispathum A.Fröhl., Hypericum perforatum var. decompositum Nyár, Hypericum perforatum var. lineolatum (Jord.) Hayek, Hypericum perforatum f. lucidum A.Fröhl., Hypericum perforatum var. petiolatum var. petiolatum Peterm., Hypericum perforatum var. semihumifusum Nyár, Hypericum pseudoperforatum Bertol. [Unresolved], Hypericum vulgare Lam. [Illegitimate], Hypericum vulgare Bubani [Illegitimate]. [1]

Vernacular Name

English Common St. Johnswort, gammock, goatbeard, goatweed, herb-john, Klamath weed, penny-john, perforated St. John’s wort, St. John’s grass, rosin-rose, St. John’s wort, tipton weed, touch-and-heel [2]
India Basant, basanti, bassant, meerang, mongolu [2]
Arabic Bersemoun, dadhi, mesmoum [2]
South Africa Johanneskruid [2].

Geographical Distributions

Hypericum perforatum is originated from Gansu, Guizhou, Hebei, Henan, Hubei, Hunan, Jiangsu, Jiangxi, Shaanxi, Shandong, Shanxi, Sichuan, Xinjiang, Yunnan [North West India, Kazakhstan, Kyrgyzstan, Mongolia, Russia; North West Africa, South West to Central Asia, Atlantic islands, Europe (except extreme North); introduced into many parts of the world]. [3]

Botanical Description

H. perforatum is a member of Clusiaceae family. It is a perennial herb that can reach up to 20-60(-100) cm tall, erect from creeping and rooting base. [3]

The stems are numerous to few, much branched especially distally. Stems are 2-lined, with few black glands on lines. [3]

The leaves are sessile to subsessile; blade ± narrowly elliptic to ± narrowly oblong or linear, (0.7-)1-2.5(-3) cm × 3-7(-15) mm; thickly papery, abaxially paler; laminar glands pale, scattered and sometimes black, few, dots; intramarginal glands black, spaced, interspersed with small dense pale ones; main lateral veins ca. 2-paired, tertiary reticulation lax or scarcely visible; base subcordate-amplexicaul to rather narrowly cuneate, margin entire, plane or ± recurved, apex obtuse. [3]

The inflorescence is 3- to numerous-flowered, from 1-3 nodes; flowering branches curved-ascending from up to 15 or sometimes more nodes below, the whole nearly flat-topped to broadly pyramidal or cylindric; bracts and bracteoles to 4(-7) mm, narrowly lanceolate to linear, margin entire. [3]

The flowers are 1.5-2.5(-3) cm in diameter, stellate; buds narrowly ovoid, apex acute. Sepals free, erect in bud, recurved in fruit, narrowly oblong or lanceolate to linear, equal, 3-4(-5) × 1-1.2 mm; laminar glands pale and often a few black, in 2(-4) rows, streaks (basally) to dots; intramarginal glands black, few, or absent; margin entire, apex acute to acuminate with tip somewhat glandular; veins 3(-5). Petals golden yellow, oblong to oblong-elliptic, (0.8-)1.2-1.5 cm × 5-6 mm, 3-4 × as long as sepals, asymmetric; laminar glands black or pale, dots to lines, or often absent; intramarginal glands black or pale, distal, in sinuses when present; margin distally ± crenate. The stamens are 40-60, apparently 3-fascicled, longest 6-8 mm, and 0.5-0.7 × as long as petals. Ovary narrowly ovoid to ovoid-ellipsoid; styles 3, 4.5-6 mm, 1.5-2 × as long as ovary, broadly to rather narrowly spreading. [3]

The capsule is ovoid-conic to ovoid, 3-6.5 × 3-5 mm, 1-1.5 × as long as sepals; valves with abaxial vittae and lateral yellowish, elongate or short vesicles. [3]

The seeds are dark brown, ca. 1 mm; testa finely linear-foveolate. [3]

Cultivation

H. perforatum can be found at open woodlands, meadows, grasslands, and steppes, riverbanks, stony and grassy slopes, roadsides, in dry or well-drained habitats; 100-2800 m. [3]

Chemical Constituent

H. perforatum was found to contain hypericin and pseudohypericin. [4]

H. perforatum was found to contain hypericins (hypericin and pseudohypericin), hyperforin, and flavanoids (rutin, hyperoside, quercitrin, and quercetin). [5]

H. perforatum was found to contain naphtodianthrones (hypericin, pseudohypericin, protohypericin, protopseudohypericin), phloroglucinols (hyperforin, adhyperforin), flavonoids (quercetin, quercitrin, isoquercitrin, hyperoside, astilbin, miquelianin, I3,II8-biapigenin) and phenolic acids (chlorogenic acid, 3-O-coumaroylquinic acid). [6]

Plant Part Used

No documentation.

Traditional Use

No documentation.

Preclinical Data

Pharmacology

Antioxidant activity

Aerial parts of H. perforatum extracts were reported to exhibit antioxidant activity. Results indicated all the extracts promote the damage of proteins exhibiting a functional pro-oxidant role. [7]

Water extract of H. perforatum was reported to exhibit high antioxidant activity in DPPH test. [8]

H. perforatum extract (HPE) was found to exhibit antioxidant activity in animal study whereby multiple organ dysfunction induced by oxidative stress in mice was reduced by HPE due to its ability to reduce inducible nitric oxide synthase which subsequently prevent formation of nitric oxide. [9]

Ethanol extract of H. perforatum was found to reduce oxidative stress in reported study whereby the flavanoid constituent of the herb is able to inhibit peroxyl radicals induced by AAPH (inductor of lipid peroxidation). [10]

An animal study reported that H. perforatum have the potential to protect liver injury (ischemia reperfusion) in rats treated with the herb for a week due to its antioxidant effect. [11]

Antiacetylcholinesterase activity

Water extract of H. perforatum was found to exhibit inhibitory activity of acetylcholinesterase although not as potent as Hypericum androsaemum and Hyopericum undulatum. [8]

Antidepressant activity

H. perforatum extract was found to exhibit antidepressant activity, in vitro and ex vivo. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. [12][13]

H. perforatum extract was reported to amplify and improve the signal produced by serotonin once it binds to its receptor sites in the brain compare t0 placebo. [14]

H. perforatum contains the chemical melatonin (approximately 4.39 mcg/gm), which may also contribute to the antidepressant effects of the plant. [15]

A study on the relationship between nicotine withdrawal from smoking cessation with the antidepressant effect from H. perforatum reported significant results in the increase of serotonin content in H. perforatum treated mice having nicotine withdrawal. [16]

Anxiolytic activity

H. perforatum extract was found to exhibit anxiolytic activity in rats. Results indicated that H. perforatum increased sleeping duration and increased open arm entries indicating sedating and anxiolytic effect. [17]

Antiamnestic activity

The effects of administration of the antiamnestic dose of the H. perforatum extract and hyperforin were tested on prepulse inhibition of an acoustic startle response in rats. Disruption of prepulse inhibition resulted after treatment of rats with an antiamnestic dose of the extract (200 mg/kg for 3 days) and with hyperforin. Prepulse inhibition occur causing problems in managing memory process disturbances. [18]

Antiviral activity

Hypericin and pseudohypericin isolated from H. perforatum was found to exhibit antiviral activity. Results suggested that these compounds inhibit retroviruses by unconventional mechanisms and that the potential therapeutic value of hypericin and pseudohypericin should be explored in diseases such as AIDS. [19][20]

Hypericin isolated from H. perforatum was found to inhibit murine cytomegalovirus (MCMV), Sindbis virus, and human immunodeficiency virus type 1 (HIV-1), especially on exposure to fluorescent light. [21]

H. perforatum extract (HPE) was found to exhibit antiviral activity on piglets infected with porcine respiratory and reproductive syndrome virus (PRRSV). Results reported that HPE is effective in reducing the virus in the blood stream but not significant in playing a role in reducing the virus in the lungs. [22]

Ethanol extract of H. perforatum was found to exhibit in vitro anti-hepatitis B virus (HBV) effects. H. perforatum plays a role as an anti-hepatitis B agent as studies report that it is able inhibits viral antigens by affecting the transcription of hepatitis-B virus. [23]

Phototoxicity activity

Administration of H. perforatum extract which contained the same compound of hypericin will lesser skin photosensitization reactions compare with pure hypericin. [24]

Antimicrobial activity

Crude methanol extract of nine Hypericum species found to exhibit antimicrobial activity. Although H. perforatum is reported to have antimicrobial activity as well, it is the least potent among other plant extracts when tested on antimicrobial assay. [25]

Neuroprotective activity

A combination of bromocriptine (BRC) and H. perforatum extract (HPE) were found to exhibit neuroprotective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in male Swiss Albino mice, which were randomly divided into seven groups of six animals each. Results indicated that HPE was able to improve movement performance, reduce dopamine level and decrease corpus striatum antioxidant level. [26]

Anti-inflammatory activity

The freeze-dry extract of H. perforatum was found to exhibit anti-inflammatory activity on Wistar albino rats. Results indicated H. perforatum extract to suppress both the inflammatory effect and the leukocyte infiltration. [27]

A laboratory study reported that the anti-inflammatory effect of H. perforatum extract in RAW 264.7 mouse macrophages was due to two pathway mechanism identified as JAK-STAT pathway and eicosanoid pathway, which reduced prostaglandin-E2 production. [28]

When acute inflammation is induced with carrageenan in the lungs of mice, H. perforatum was found to reduce the tissue injury by playing a role in the neutrophils and proinflammatory cytokines as well as up-regulation of poly(ADP) ribose and activation of redox-sensitive transcription factor and other transcription factors like STAT-3. [29]

Wound healing activity

Wound healing effect of H. perforatum extract was evaluated by comparing with dexpanthenol and titrated of Centella asiatica (TECA) on cultured chicken embryonic fibroblasts. Findings obtained in the present study indicated that H. perforatum extract exhibited a wound-healing activity whose mechanism of action is similar to that of TECA. Wound-healing activity of H. perforatum extract seems to be mainly due to the increase in the stimulation of fibroblast collagen production and the activation of fibroblast cells in polygonal shape, which plays a role in wound repair by closing damaged area. [30]

Olive oil extract of the aerial parts of H. perforatum was found to exhibit wound healing activity in in vivo excision and incision wound models. The ability of wound-healing effect of H. perforatum was indicated by showing tissue regenerating, improved tensile strength and epithelisation. [31]

Anticancer activity

H. perforatum extract is reported to be effective in causing apoptosis towards bladder cancer cells when used in photodynamic therapy due to its ability as a photosensitizer. [32]

Anticholesterol activity

A laboratory animal study found that ingestion of H. perforatum by 20 rabbits as diet regime for 45 days followed by regular diet and H. perforatum for 30 reduced cholesterol levels, leading to a decrease in the progression of atherosclerosis. [33]

Antinociceptive activity

Chloroform (CHL) and methanol (MET) extract of H. perforatum were found to exhibit antinociceptive activity. The therapeutic ability of CHL and MET to reduce sensitivity to pain stimuli was reported when administered to mice with thermal-induced and chemical-induced pain. Hypericin and hyperforin are the main constituents responsible for increasing the pain threshold. [34]

Toxicity

No documentation.

Clinical Data

Clinical findings

Antidepressant activity

H. perforatum has gained a great deal of attention for its use in minor depression. Its popularity has stemmed from its extensive use as an agent of choice in the treatment of mild to moderate depression. There are a variety of clinical studies which are claimed to support the use of H. perforatum in treating mild to moderate depression. [35][36][37]

A study reported that when the efficacy of H. perforatum was compared with selective serotonin reuptake inhibitor (SSRI) for the treatment of major depressive disorder, both showed similar and positive results with H. perforatum having lower withdrawal adverse events. [38]

Based on the original data from two double-blind, randomized, placebo-controlled clinical trials and the acute phase of a long-term study that investigated the antidepressant efficacy of H. perforatum extract WS 5570, a present re-analysis study of a subset of patients suffering from an acute episode of mild depression was investigated. The analysis shows that H. perforatum extract WS 5570 has a meaningful beneficial effect during acute treatment of patients suffering from mild depression and leads to a substantial increase in the probability of remission. [39]

Results from two independent randomized controlled trials have indicated that H. perforatum is no more beneficial than placebo in individuals with major depression [40][41]. However, one of these trials used sertraline (50 to 100 mg/day) as an active control and found no significant superiority of sertraline over placebo in this patient population as well [40]. Though these two trials may indicate that St. John’s wort is not effective for major depression, they neither confirm nor deny the use of H. perforatum in mild to moderate depression.

H. perforatum extract has been used to treat depressive symptoms. In 25 controlled clinical trials where Hypericum extract was compared with placebo and established antidepressants, improvement was obtained in 61 percent of patients on low-dose treatment (< 1.2 mg Hypericum extract), and in 75 percent of patients treated with a higher dose (2.7 mg). The side effects were mild and occurred at lower frequency than did those of other antidepressants. The constituents of Hypericum extract that is responsible for the antidepressant effect has not been identified. [42]

A human trial reported improvement in symptoms of attention-deficit hyperactive disorder (ADHD) when using H. perforatum, as found when testing with Conners’ hyperactivity. [43]

Antiviral activity

Hypercin isolated from H. perforatum was found to exhibit antiviral activity that includes human immunodeficiency virus (HIV). Following attachment and entry of HIV into a host cell, the HIV genomic RNA is reverse transcribed to cDNA. This step may be inhibited by hypericin, a compound that induces alterations of the retroviral capsid. Incubation of HIV with hypericin rendered the virus noninfectious. [44]

A study has been conducted to compare the use of unconventional remedies in two groups of HIV-positive men (N = 63). Employing a multiple-choice questionnaire, the aim of this experiment was to assess the use of and attitudes toward unconventional remedies. Individuals enrolled in the clinical trial protocols for investigational drugs used unconventional remedies significantly less than the community health center participants, who were enrolled in an open clinical trial of hypericin, an unproven remedy. [45]

The effect of H. perforatum extract (0.25 or 0.5 mg/kg body weight) was investigated in 30 HIV-infected patients with CD4 counts less than 350 cells/mm3. Results indicated hypericin caused significant phototoxicity but had no antiretroviral activity in the limited number of patients studied. [46]

A study shown that H. perforatum reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-h indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure. [47]

Analgesic activity

The use of H. perforatum in pain management is reported to be effective in the treatment of dental pain when homeopathic H. perforatum was the preferred remedy for pain, including post extraction pain and swelling. [48]

Precautions

Although no real evidence has been presented to support it, there is theoretically a potential for an interaction of H. perforatum with tyramine-containing foods, so these foods should be avoided. [49]

Based on evidence that H. perforatum may cause changes in the need for certain medications do not use H. perforatum supplements if you are taking prescription and/or OTC medications without the advice of your doctor or pharmacist. [50]

Allergic reactions have occurred in a small percentage of individuals who use H. perforatum. [50]

H. perforatum should not be taken in suicidal depression, psychosis or severe depression. [50]

H. perforatum has affected the metabolism of certain medications via alteration of P-glycoprotein and cytochrome P-450 3A4 expression. Changes in cyclosporine levels have been confirmed. Based on human data, do not use H. perforatum in transplant patients. Complications as well as transplant rejection have occurred with the use of this herb. [51][52]

The mechanism of action was believed to be liver enzyme induction and subsequent alterations of drug levels by the herb. Also, several reports have suggested that concurrent use of H. perforatum and SSRIs may result in "serotonin syndrome," including sweating, tremor, confusion, flushing and agitation. [53]

Side effects

H. perforatum may cause photosensitivity in high doses such as those used by the AIDS population. [46]

Based on pharmacology, animal data and human data, H. perforatum may cause photosensitivity. [54]

217 out of 440 patients treated with H. perforatum for one year were reported to have adverse events, including gastrointestinal (abdominal pain or gastritis) and skin (rash or pruritus) being the most common. [55]

A study conducted on rats and human using electric field stimulation test reported that H. perforatum inhibits the contraction of vas deferens that indirectly delays ejaculation function, potentially due to the hyperforin constituent content. [56]

Pregnancy/Breast Feeding

Do not use H. perforatum during pregnancy. [50][57][58]

Age limitation

Do not use in children under 2 years of age unless recommended by a physician. [50]

Adverse reaction

No documentation.

Interaction & Depletion

Interaction with drug

Animal studies and human case reports have reported that H. perforatum may increase the effects of these medications and possibly change the dose needed for treatment. These drugs include fluoxetine, fluvoxamine, paroxetine, sertraline, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, trimipramine, maprotiline, mirtazapine, trazodone, bupropion, venlafaxine, nefazodone, citalopram, protriptyline, phenelzine, tranylcypromine, and isocarboxazid. Use with caution. [35][36][37][40][41][59][60]

Studies have reported that H. perforatum may alter the metabolism or breakdown of certain medications in the body which may change the effects of these medications and possibly the dose needed for treatment. It is recommended not to use H. perforatum with these medications until further research is performed. These drugs include indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir. [47]

Studies have reported that H. perforatum may alter the metabolism or breakdown of certain medications in the body which may change the effects of these medications and possibly the dose needed for treatment. These drugs include azathioprine, basiliximab, cyclosporine, daclizumab, glatiramer, muromonab-cd3, mycophenolate mofetil, tacrolimus (FK506), sirolimus, methotrexate, prednisone, hydrocortisone, methylprednisolone, prednisolone, betamethasone, budesonide, triamcinolone, dexamethasone, and cortisone, [51] digoxin [61], theophylline, [62] and alprazolam [63]. Use with caution. 

Human case reports found that St. John's wort caused breakthrough bleeding and may have hormonal activity which may alter the effects of these medications and possibly the dose needed for treatment. These drugs include norethindrone, ethynodiol diacetate, norgestrel, norgestimate, ethinyl estradiol, drospirenone, desogestrel, levonorgestrel, conjugated estrogens, estradiol, estrone, esterified estrogens, estropipate, ethinyl estradiol, progesterone, medroxyprogesterone, hydroxyprogesterone, and norethindrone. Use with caution. [64][65]

Studies report that 5-HTP may act in the body like H. perforatum, which may alter the effects of this supplement and possibly the dose needed for treatment. Use with caution. [66]

Interaction with other Herbs

No documentation.

Contraindications

No documentation.

Dosage

Dosage Range

900 mg (standardized extract) daily, in divided doses. (Some individuals may experience benefit with as little as 300-600 mg daily.) Higher doses are used in viral infections, and should only be performed under the supervision of a doctor. [67]

Topically: Apply oil extract as needed to affected area(s). [68]

Liquid extract: (1:1) in 25% ethanol – 2-4 mL, 3 times a day. [68]

Tincture: (1:10) in 45% ethanol – 2-4 mL, 3 times a day. [68]

Most Common Dosage

No documentation.

Standardisation

No documentation.

Poisonous Management

No documentation.

Line drawing

No documentation.

References

  1. The Plant List. Ver1.1. Hypericum perforatum L. [homepage on the Inetrnet]. c2013 [updated 2012 Mar 23; cited 2017 Apr 11]. Available from: http://www.theplantlist.org/tpl1.1/record/kew-2858676.
  2. Quattrocchi U. CRC world dictionary of medicinal and poisonous plants: Common names, scientific names, eponyms, synonyms, and etymology. Volume III E-L. Boca Raton, Florida: CRC Press, 2012; p. 536.
  3. Flora of China. Hypericum perforatum Linnaeus. [homepage on the Internet]. No date [cited 2017 Apr 11]. Available from; http://www.efloras.org/florataxon.aspx?flora_id=2&taxon_id=200014237.
  4. Wagner H, Bladt S. Pharmaceutical quality of hypericum extracts. J Geriatr Psychiatry Neurol. 1994;1:S65-S68.
  5. Verma V, Smelcerovic A, Zuehlke S, et al. Phenolic constituents and genetic profile of Hypericum perforatum L. from India. Biochem Syst Ecol. 2008;36(3):201-206.
  6. Tatsis EC, Boeren S, Exarchou V, Trooganis AN, Vervoort J, Gerothanassis IP. Identification of the major constituwents of Hypericum perforatum by LC/SPE/NMR and/or LC/MS. Phytochemistry. 2007;68(3):383-393.
  7. Gioti EM, Fiamegos YC, Skalkos DC, Stalikas CD. Antioxidant activity and bioactive components of the aerials parts of Hypericum perforatum L. from Epirus, Greece. Food Chem. 2009;117(3):398-404.
  8. Hernandez MF, Falé PLV, Araújo MEM, Serralheiro MLM. Acetylcholinesterase inhibition and antioxidant activity of the water extracts of several Hypericum species. Food Chem. 2010;120(4):1076-1082.
  9. Mazzon E, Muià C, Crisafulli C, et al. Protective effect of Hypericum perforatum in zymosan-induced multiple organ dysfunction syndrome: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. Nitric Oxide. 2007;16(1):118-130. 
  10. Silva BA, Malva JO, Dias ACP. St. John’s Wort (Hypericum perforatum) extracts and isolated phenolic compounds are effective antioxidants in several in vitro models of oxidative stress. Food Chem. 2008;110(3):611-619.
  11. Aydin A, Sakrak O, Yilmaz TU, Kerem M. The effects of Hypericum perforatum on hepatic ischemia—reperfusion injury in rats. Bratisl Lek Listy. 2014;115(4):209-215.
  12. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol. 1994;1:S57-S59.
  13. Suzuki O, Katsumata Y, Bladt S, Wagner H. Inhibition of monoamine oxidase by hypericin. Planta Med. 1984;50(3):272-274.
  14. Müller WE, Rossol R. Effects of hypericum extract on the expression of serotonin receptors. J geriatr Psychiatry Neurol. 1994;1:S663-S664.
  15. Murch SJ, Simmons CB, Saxena PK. Melatonin in feverfew and other medicinal plants. Lancet. 1997;350(9091):1598-1599.
  16. Mannucci C, Pieratti A, Firenzuoli F, Caputi AP, Calapai G. Serotonin mediates beneficial effects of Hypericum perforatum on nicotine withdrawal signs. Phytomedicine. 2007;14(10):645-651.
  17. Rezaie A, Dorostkar KR, Pashazadeh M, Nejad SM. Study of sedative and anxiolytic effects of herbal extract Hypericum perferatum in comparison with diazepam in rats. Int J Infect Dis. 2008.
  18. Tadros MG, Mohamed MR, Youssef AM, Sabry GM, Sabry NA, Khalifa AE. Proapoptotic and prepulse inhibition (PPIA) disrupting effects of Hypericum perforatum in rats. J Ethnopharmacol. 2009;122(3):561-566.
  19. Lavie G, Valentine F, Levin B, et al. Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin. Proc Natl Acad Sci U S A. 1989;86(15):5963-5967.
  20. Meruelo D, Lavie G, Lavie D. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin. Proc Natl Acad Sci U S A. 1988;85(14):5230-5234.
  21. Hudson JB, Lopez-Bazzocchi I, Towers GH. Antiviral activities of hypericin. Antiviral Res. 1991;15(2):101-112.
  22. Pu XY, Liang JP, Shang RF, et al. Influence of Hypericum perforatum extract on piglet infected with porcine respiratory and reproductive syndrome virus. Agric Sci China. 2009;8(6):730-739.
  23. Pang R, Tao J, Zhang S, et al. In vitro anti-hepatitis B virus effect of Hypericum perforatum L. J Huazhong Univ Sci Technolog Med Sci. 2010;30(1):98-102.
  24. Schmitt LA, Liu Y, Murphy PA, Petrich JW, Dixon PM, Birt DF. Reduction in hypericin-induced phototoxicity by Hypericum perforatum extracts and pure compounds. J Photochem Photobiol B. 2006;85(2):118-130.
  25. Radulovic N, Vesna SJ, Stojanović G, Šmelcerović A, Spiteller M, Asakawa Y. Screening of in vitro antimicrobial and antioxidant activity of nine Hypericum species from the Balkans. Food Chem. 2007;103(1):15-21.
  26. Mohanasundari M, Srinivasan MS, Sethupathy S, Sabesan M. Enhanced neuroprotective effect by combination of bromocriptine and Hypericum perforatum extract against MPTP-induced neurotoxicity in mice. J Neurol Sci. 2006;249(2):140-144.
  27. Shipochliev T, Dimitrov A, Aleksandrova E. [Anti-inflammatory action of a group of plant extracts]. Vet Med Nauki. 1981;18(6):87-94.
  28. Hammer KD, Yum MY, Dixon PM, Birt DF. Identification of JAk-STAT pathways as important for the anti-inflammatory activity of a Hypericum perforatum fraction and bioactive constituents in RAW 264.7 mouse macrophages. Phytochemistry. 2010;71(7):716-725.
  29. Menegazzi M, Di Paola R, Mazzon E, et al. Hypericum perforatum attenuates the development of carrageenan-induced lung injury in mice. Free Radic Biol Med. 2006;40(5):740-753.
  30. Öztürk N, Korkmaz S, Öztürk Y. Wound-healing activity of St. John Wort (Hypericum perforatum L. ) on chicken embryonic fibroblasts. J Ethnopharmacol. 2007;111(1):33-39.
  31. Süntar IP, Akkol EK, Yilmazer D, et al. Investigations on the in vivo wound healing potential of Hypericum perforatum L. J Ethnopharmacol. 2010;127(2):468-477.
  32. Stavropoulos NE, Kim A, Nseyo UU, et al. Hypericum perforatum L. extract - Novel photosensitizer against human bladder cancer cells. J Photochem Photobiol B. 2006;84(1):64-69.
  33. Kabiri N, Setorki M. Regression of hypercholesterolemic atherosclerosis in rabbits by hydroalcoholic extracts of Hypericum perforatum. Atheroscler Suppl. 2012; 6(3):2540-2549.
  34. Galeotti N, Vivoli E, Bilia AR, Bergonzi MC, Bartolini A, Ghelardini C. A prolonged protein kinase C-mediated, opiod-related antinociceptive effect of St John’s Wort in mice. J pain. 2010;11(2):149-159.
  35. Volz HP. Controlled clinical trials of Hypericum extracts in depressed patients--An overview. Pharmacopsychiatry. 1997;30(Suppl 2):72-76.
  36. Müller WE, Rolli M, Schäfer C, Hafner U. Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry. 1997;30(Supp 2):102-107.
  37. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St. John's Wort for depression--An overview and meta-analysis of randomised clinical trials. BMJ. 1996;313(7052):253-258.
  38. Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(1):118-127.
  39. Kasper S, Gastpar M, Müller WE, et al. Efficacy of St. John's wort extract WS 5570 in acute treatment of mild depression: A reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci. 2008;258(1):59-63.
  40. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John's Wort) in major depressive disorder: A randomized controlled trial. JAMA. 2002;287(14):1807-1814.
  41. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John's wort in major depression: A randomized controlled trial. JAMA. 2001;285(15):1978-86.
  42. Nordfors M, Hartvig P. St John's wort against depression in favour again. Lakrtidningen. 1997;94:2365-2367.
  43. Niederhofer H. St. John’s wort may improve some symptoms of attention-deficit hyperactivity disorder. Nat prod Res. 2010;24(3):203-205.
  44. Degar S, Prince AM, Pascual D, et al. Inactivation of the human immunodeficiency virus by hypericin: Evidence for photochemical alterations of p24 and a block in uncoating. AIDS Res Hum Retroviruses. 1992;8(11):1929-1936.
  45. Dwyer JT, Salvato-Schille AM, Coulston A, Casey VA, Cooper WC, Selles WD. The use of unconventional remedies among HIV-positive men living in California. J Assoc Nurses AIDS Care. 1995;6(1):17-28.
  46. Gulick RM, McAuliffe V, Holden-Wiltse J, et al. Phase I studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in HIV-infected adults. AIDS clinical trials group protocols 150 and 258. Ann Intern Med. 1999;130(6):510-514.
  47. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John's Wort. Lancet. 2000;355(9203):547-548.
  48. Raak CK, Büssing A, Gassmann G, Boehm K, Ostermann T. A systematic review of remedies and indications of the use of homeopathic Hypericum perforatum (St. John's Wort) in dental practice. Homeopathy. 2009; 1(4):204-210.
  49. Miller LG. Herbal medicines: Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158(20):2200-2211.
  50. Drug.com. Know more. Be sure. St. John’s wort. [homepage on the Internet]. c2000-2017 [cited 2017 Apr 11]. Available from: https://www.drugs.com/cdi/st-john-s-wort.html.
  51. Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute heart transplant rejection due to Saint John’s wort. Lancet. 2000;355(9203):548-549.
  52. Ernst E. St John’s Wort supplements endanger the success of organ transplantation. Arch Surg. 2002;137(3):316-319.
  53. Lantz MS, Buchalter E, Giambanco V. St. John’s wort and antidepressant drug interactions in the elderly. J geriatr Psychiatry Neurol. 1999;12(1):7-10.
  54. Brockmöller J, Reum T, Bauer S, Kerb R, Hübner WD, Roots I. Hypericin and pseudohypericin: Pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry. 1997;30(Suppl2):94-101.
  55. 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(4):277-283.
  56. Capasso R, Borrelli F, Montanaro V, Altieri V, Capasso F, Izzo AA. Effects of the antidepressant St. John’s wort (Hypericum perforatum) on rat and human vas deferens contractility. J Urol. 2005;173(6):2194-2197.
  57. Grush LR, Nierenberg A, Keefe B, Cohen LS. St John's wort during pregnancy. JAMA. 1998;280(18):1566.
  58. Ondrizek RR, Chan PJ, Patton WC, King A. An alternative medicine study of herbal effects on the penetration of zona-free hamster oocytes and the integrity of sperm deoxyribonucleic acid. Fertil Steril. 1999;71(3):517-522.
  59. Berbentseva NA, Mishenkova EL, Garagulia OD. [Action of tannins from Hypericum perforatum L. on the influenza virus]. Mikrobiol. 1972;34(6):768-772.
  60. Wagner H, Bladt S. Pharmaceutical quality of Hypericum extracts. J Geriatr Psychiatry Neurol. 1994;7(Suppl1):S65-S68.
  61. Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther. 1999;66(4):338-345.
  62. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother. 1999;33(4):502.
  63. Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St. John's Wort on drug metabolism by induction of cytochrome p450 3A4 enzyme. Obstet Gynecol Surv. 2004;59(5):358-359.
  64. Rey JM, Walter G. Hypericum perforatum (St John’s wort) in depression: Pest or blessing? Med J Aust. 1998;169(11-12):583-586.
  65. Jobst KA, Mclntyre M, George DS, Whitelegg M. Safety of St John’s wort (Hypericum perforatum). Lancet. 2000;355(9203):575.
  66. Kahn RS, Westenberg HG. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Discord. 1985;8(2):197-200.
  67. Mayo Clinic. Drugs and Supplements St. John’s wort (Hypericum perforatum). [homepage on the Internet]. c1998-2017 [cited 2017 Apr 11]. Available from: http://www.mayoclinic.org/drugs-supplements/st-johns-wort/dosing/hrb-20060053.
  68. PDR for herbal medicines, 2nd edition. Montvale, NJ: Medical Economics Company, 2000; p. 722.