Hypericum perforatum, known as perforate St John's-wort, common Saint John's wort and St John's wort,[note 1] is a flowering plant in the family Hypericaceae. The common name "St John's wort" may be used to refer to any species of the genus Hypericum. Therefore, Hypericum perforatum is sometimes called "common St John's wort" or "perforate St John's wort" in order to differentiate it. It is a medicinal herb with antidepressant activity and potent anti-inflammatory properties as an arachidonate 5-lipoxygenase inhibitor and COX-1 inhibitor.
- 1 Botanical description
- 2 Ecology
- 3 Medical uses
- 4 Side effects
- 5 Interactions
- 6 Mechanism of action
- 7 Livestock
- 8 Chemistry
- 9 Research
- 10 See also
- 11 Notes
- 12 References
- 13 Further reading
- 14 External links
The common name "St John's wort" comes from its traditional flowering and harvesting on St John's Day, 24 June. The genus name Hypericum is derived from the Greek words hyper (above) and eikon (picture), in reference to the tradition of hanging plants over religious icons in the home during St John's Day, to ward off evil.
Perforate St John's wort is a herbaceous perennial plant with extensive, creeping rhizomes. Its stems are erect, branched in the upper section, and can grow to 1 m high. It has opposite, stalkless, narrow, oblong leaves that are 1–2 cm long.:176 The leaves are yellow-green in color, with scattered translucent dots of glandular tissue. The dots are conspicuous when held up to the light, giving the leaves the 'perforated' appearance to which the plant's Latin name refers. The flowers measure up to 2.5 cm across, have five petals, and are colored bright yellow with conspicuous black dots.:339 The flowers appear in broad cymes at the ends of the upper branches, between late spring and early to mid summer. The sepals are pointed, with black glandular dots. There are many stamens, which are united at the base into three bundles. The pollen grains are ellipsoidal.
When flower buds (not the flowers themselves) or seed pods are crushed, a reddish/purple liquid is produced.
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St John's wort reproduces both vegetatively and sexually. It thrives in areas with either a winter- or summer-dominant rainfall pattern; however, distribution is restricted by temperatures too low for seed germination or seedling survival. Altitudes greater than 1500 m, rainfall less than 500 mm, and a daily mean temperature greater than 24 °C are considered limiting thresholds.[who?] Depending on environmental and climatic conditions, and rosette age, St John's wort will alter growth form and habit to promote survival. Summer rains are particularly effective in allowing the plant to grow vegetatively, following defoliation by insects or grazing.
Although Hypericum perforatum is grown commercially in some regions of south east Europe, it is listed as a noxious weed in more than twenty countries and has introduced populations in South and North America, India, New Zealand, Australia, and South Africa. In pastures, St John's wort acts as both a toxic and invasive weed. It replaces native plant communities and forage vegetation to the extent of making productive land nonviable or becoming an invasive species in natural habitats and ecosystems. Ingestion by livestock such as horses, sheep, and cattle can cause photosensitization, central nervous system depression, spontaneous abortion or death. Effective herbicides for control of Hypericum include 2,4-D, picloram, and glyphosate. In western North America three beetles Chrysolina quadrigemina, Chrysolina hyperici and Agrilus hyperici have been introduced as biocontrol agents.
Common St. John's-wort has long been used in herbalism. It was known to have medical properties in Classical Antiquity and was a standard component of theriacs, from the Mithridate of Aulus Cornelius Celsus' De Medicina (ca. 30 CE) to the Venice treacle of d'Amsterdammer Apotheek in 1686. Folk usages included oily extract ("St. John's oil") and Hypericum snaps.
Two main compounds of interest have been studied in more detail: hyperforin and hypericin. As psychiatric medication, it is usually taken as pills, or as tea. Standardised preparations are available, and research has mainly studied alcoholic extracts and isolated compounds. What research data exists supports a noticeable effect in many cases of light and medium depression, but no significant improvement of severe depression and OCD. Two authors of the study are employees at the alternative pharmaceutical company Dr. Willmar Schwabe Pharmaceuticals, which represents a significant conflicting interest.
The red, oily extract of H. perforatum may help heal wounds. Both hypericin and hyperforin are reported to have antibiotic properties. Justifying this view with the then-current doctrine of signatures, herbalist William Coles (1626–1662) wrote in the 17th century that:
"The little holes where of the leaves of Saint Johns wort are full, doe resemble all the pores of the skin and therefore it is profitable for all hurts and wounds that can happen thereunto."
Hypericum perforatum may also be capable of reducing the physical signs of opiate withdrawal.
Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs.
Major depressive disorder
Some studies have supported the efficacy of St John's wort as a treatment for depression in humans, but have not concluded it as a replacement for more studied treatments, and proper medical consultation. A 2015 meta-analysis review concluded that it has superior efficacy to placebo in treating depression; is as effective as standard antidepressant pharmaceuticals for treating depression; and has fewer adverse effects than other antidepressants. The authors concluded that it is difficult to assign a place for St. John's wort in the treatment of depression owing to limitations in the available evidence base, including large variations in efficacy seen in trials performed in German-speaking relative to other countries. It is proposed that the mechanism of action of St. John's wort is due to the inhibition of reuptake of certain neurotransmitters.
A 2008 Cochrane review of 29 clinical trials concluded that it was superior to placebo in patients with major depression, as effective as standard antidepressants and had fewer side-effects. According to the National Center for Complementary and Integrative Health (NCCIH) of the National Institutes of Health, it "may help some types of depression, though the evidence is not definitive"; can limit the efficacy of prescription medicines; and psychosis can occur as a rare side effect. The NCCIH notes that combining St John's wort with certain prescription antidepressants can lead to a "potentially life-threatening increase of serotonin", a brain chemical targeted by antidepressants. A 2016 review came to the same conclusions as the 2008 Cochrane review, but noted that the quality of evidence in regards to both effectiveness and incidence of adverse effects was reduced relative to that for conventional antidepressants.
St John's wort is generally well tolerated, with an adverse effect profile similar to placebo. Commonly reported adverse effects include gastrointestinal symptoms (nausea, abdominal pain, loss of appetite, and diarrhea), dizziness, confusion, fatigue, sedation, dry mouth, restlessness, and headache. The organ systems associated with adverse drug reactions to St John's wort and fluoxetine (an SSRI) have a similar incidence profile; most of these reactions involve the central nervous system. St John's wort also decreases the levels of estrogens, such as estradiol, by speeding up its metabolism, and should not be taken by women on contraceptive pills as it upregulates the CYP3A4 cytochrome of the P450 system in the liver.
St. John's wort has interactions with medications such as SSRI antidepressants, warfarin, and birth control. Combining both St John's wort and SSRI antidepressants could lead to increased serotonin levels causing serotonin syndrome. It should not be taken with the heart medication, ranolazine. Combining estrogen containing oral contraceptives with St John's wort can lead to decreased efficacy of the contraceptive and eventually unplanned pregnancies. St. John's wort has been known to decrease the blood concentrations of immunosuppressants (cyclosporine & tacrolimus), sedatives (midazolam & alprazolam), anticoagulants (phenprocoumon), chemotherapy drugs (irinotecan) and other medications. These are just a few of the drug interactions that St John's wort possesses. It is also known to decrease the efficacy of HIV medications, cholesterol medications, as well as transplant medications.
St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzymes CYP3A4 and CYP1A2. This drug-metabolizing enzyme induction results in the increased metabolism of certain drugs, leading to decreased plasma concentration and potential clinical effect. The principal constituents thought to be responsible are hyperforin and amentoflavone. There is strong evidence that the mechanism of action of these interactions is activation of the pregnane X receptor.
St John's wort has also been shown to cause drug interactions through the induction of the P-glycoprotein efflux transporter. Increased P-glycoprotein expression results in decreased absorption and increased clearance of certain drugs, leading to lower plasma concentrations and impaired clinical efficacy.
|Antiretrovirals||Non-nucleoside reverse transcriptase inhibitors, protease inhibitors|
|Hormonal contraception||Combined oral contraceptives|
|Immunosuppressants||Calcineurin inhibitors, cyclosporine, tacrolimus|
|Antiarrhythmics||Amiodarone, flecainide, mexiletine|
|Calcium channel blockers||Verapamil, diltiazem, amlodipine|
|Statins (cholesterol-reducing medications)||Lovastatin, simvastatin, atorvastatin|
|Others||Digoxin, methadone, omeprazole, phenobarbital, theophylline, warfarin, levodopa, buprenorphine, irinotecan|
|Reference: Rossi, 2005; Micromedex|
In combination with other drugs that may elevate 5-HT (serotonin) levels in the central nervous system (CNS), St John's wort may contribute to serotonin syndrome, a potentially life-threatening adverse drug reaction.
|Antidepressants||MAOIs, TCAs, SSRIs, SNRIs, mirtazapine|
|Opioids||Tramadol, pethidine (meperidine), levorphanol|
|CNS stimulants||Phentermine, diethylpropion, amphetamines, sibutramine, cocaine|
|Psychedelic drugs||Methylenedioxymethamphetamine (MDMA), LSD, dimethyltryptamine (DMT), MDA, 6-APB|
|Others||Selegiline, tryptophan, buspirone, lithium, linezolid, 5-HTP, dextromethorphan|
Mechanism of action
St. John's wort, similarly to other herbs, contains a whole host of different chemical constituents that may be pertinent to its therapeutic effects. Hyperforin and adhyperforin, two phloroglucinol constituents of St John's wort, are TRPC6 receptor agonists and, consequently, they induce noncompetitive reuptake inhibition of monoamines (specifically, dopamine, norepinephrine, and serotonin), GABA, and glutamate when they activate this ion channel. In humans, the active ingredient hyperforin is also an inhibitor of PTGS1, arachidonate 5-lipoxygenase, SLCO1B1 and an inducer of cMOAT. Hyperforin is also a anti-inflammatory compound with anti-angiogenic, antibiotic, and neurotrophic properties. Hyperforin also has an antagonistic effect on NMDA receptors, a type of glutamate receptor. Moreover, St John's wort is known to downregulate the β1 adrenoceptor and upregulate postsynaptic 5-HT1A and 5-HT2A receptors, both of which are a type of serotonin receptor. Other compounds may also play a role in St John's wort's antidepressant effects. Such compounds include: oligomeric procyanidines, flavonoids (quercetin), hypericin, and pseudohypericin.
In large doses, St John's wort is poisonous to grazing livestock (cattle, sheep, goats, horses). Behavioural signs of poisoning are general restlessness and skin irritation. Restlessness is often indicated by pawing of the ground, headshaking, head rubbing, and occasional hindlimb weakness with knuckling over, panting, confusion, and depression. Mania and hyperactivity may also result, including running in circles until exhausted. Observations of thick wort infestations by Australian graziers include the appearance of circular patches giving hillsides a 'crop circle' appearance, it is presumed, from this phenomenon. Animals typically seek shade and have reduced appetite. Hypersensitivity to water has been noted, and convulsions may occur following a knock to the head. Although general aversion to water is noted, some may seek water for relief.
Severe skin irritation is physically apparent, with reddening of non-pigmented and unprotected areas. This subsequently leads to itch and rubbing, followed by further inflammation, exudation, and scab formation. Lesions and inflammation that occur are said to resemble the conditions seen in foot and mouth disease. Sheep have been observed to have face swelling, dermatitis, and wool falling off due to rubbing. Lactating animals may cease or have reduced milk production; pregnant animals may abort. Lesions on udders are often apparent. Horses may show signs of anorexia, depression (with a comatose state), dilated pupils, and injected conjunctiva.
Increased respiration and heart rate is typically observed while one of the early signs of St John's wort poisoning is an abnormal increase in body temperature. Affected animals will lose weight, or fail to gain weight; young animals are more affected than old animals. In severe cases death may occur, as a direct result of starvation, or because of secondary disease or septicaemia of lesions. Some affected animals may accidentally drown. Poor performance of suckling lambs (pigmented and non-pigmented) has been noted, suggesting a reduction in the milk production, or the transmission of a toxin in the milk.
- primary photosensitisation directly from chemicals contained in ingested plants
- secondary photosensitisation from plant-associated damage to the liver.
Araya and Ford (1981) explored changes in liver function and concluded there was no evidence of Hypericum-related effect on the excretory capacity of the liver, or any interference was minimal and temporary. However, evidence of liver damage in blood plasma has been found at high and long rates of dosage.
Photosensitisation causes skin inflammation by a mechanism involving a pigment or photodynamic compound, which when activated by a certain wavelength of light leads to oxidation reactions in vivo. This leads to lesions of tissue, particularly noticeable on and around parts of skin exposed to light. Lightly covered or poorly pigmented areas are most conspicuous. Removal of affected animals from sunlight results in reduced symptoms of poisoning.
Detection in body fluids
Hypericin, pseudohypericin, and hyperforin may be quantitated in plasma as confirmation of usage and to estimate the dosage. These three active substituents have plasma elimination half-lives within a range of 15–60 hours in humans. None of the three has been detected in urine specimens.
- Flavonoids (e.g. epigallocatechin, rutin, hyperoside, isoquercetin, quercitrin, quercetin, amentoflavone, biapigenin, astilbin, myricetin, miquelianin, kaempferol, luteolin)
- Phenolic acids (e.g. chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, p-hydroxybenzoic acid, vanillic acid)
- Naphthodianthrones (e.g. hypericin, pseudohypericin, protohypericin, protopseudohypericin)
- Phloroglucinols (e.g. hyperforin, adhyperforin)
- Tannins (unspecified, proanthocyanidins reported)
- Volatile oils (e.g. 2-methyloctane, nonane, 2-methyldecane, undecane, α-pinene, β-pinene, α-terpineol, geraniol, myrcene, limonene, caryophyllene, humulene)
- Saturated fatty acids (e.g. isovaleric acid (3-methylbutanoic acid), myristic acid, palmitic acid, stearic acid)
- Alkanols (e.g. 1-tetracosanol, 1-hexacosanol)
- Vitamins & their analogues (e.g. carotenoids, choline, nicotinamide, nicotinic acid)
- Miscellaneous others (e.g. pectin, β-sitosterol, hexadecane, triacontane, kielcorin, norathyriol)
The naphthodianthrones hypericin and pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be among the numerous active constituents. It also contains essential oils composed mainly of sesquiterpenes.
St John's wort is being studied for effectiveness in the treatment of certain somatoform disorders. Results from the initial studies are mixed and still inconclusive; some research has found no effectiveness, other research has found a slight lightening of symptoms. Further study is needed and is being performed.
A major constituent chemical, hyperforin, may be useful for treatment of alcoholism, although dosage, safety and efficacy have not been studied. Hyperforin has also displayed antibacterial properties against Gram-positive bacteria, although dosage, safety and efficacy has not been studied. Herbal medicine has also employed lipophilic extracts from St John's wort as a topical remedy for wounds, abrasions, burns, and muscle pain. The positive effects that have been observed are generally attributed to hyperforin due to its possible antibacterial and anti-inflammatory effects. For this reason hyperforin may be useful in the treatment of infected wounds and inflammatory skin diseases. In response to hyperforin's incorporation into a new bath oil, a study to assess potential skin irritation was conducted which found good skin tolerance of St John's wort.
Hypericin and pseudohypericin have shown both antiviral and antibacterial activities. It is believed that these molecules bind non-specifically to viral and cellular membranes and can result in photo-oxidation of the pathogens to kill them.
Concentrations of bioactive substances can be altered by regulating the environment during plant growth like different levels of UV-B radiation, for instance.
Multiple studies have examined whether St John's wort improves some aspects of cognitive performance. Most studies have focused on the effect in rodents. A recent meta-analysis of 13 animal studies shows that administration of St John's wort improved performance in maze tasks in rodents (assessing long term or working memory). This meta-analysis also demonstrated that the cognitive enhancing effect, while stronger for rodents who had been subjected to stress impairments, was also considerable in healthy rodents. No study in humans has yet demonstrated such nootropic effects.
- Less common names and synonyms include Tipton's weed, rosin rose, goatweed, chase-devil, or Klamath weed.
- "BSBI List 2007". Botanical Society of Britain and Ireland. Archived from the original (xls) on 25 January 2015. Retrieved 17 October 2014.
- Mehta, Sweety (2012-12-18). "Pharmacognosy of St. John's Wort". Pharmaxchange.info. Retrieved 2014-02-16.
- "Enzymes". Hyperforin. Human Metabolome Database. 3.6. University of Alberta. 30 June 2013. Retrieved 12 December 2014.
Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions (PMID 17696442, 21751836, 12725578, 12018529 )
1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity
- Wölfle U, Seelinger G, Schempp CM (2014). "Topical application of St. John's wort (Hypericum perforatum)". Planta Med. 80 (2–3): 109–20. PMID 24214835. doi:10.1055/s-0033-1351019.
Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 µmol/L and 1.2 µmol/L, respectively , and of PGE2 production in vitro  and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) . Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo  and suppressed oxidative bursts in polymorphonuclear cells at 1.8 µmol/L in vitro . Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al.  to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.
- Gartlehner, G; Gaynes, BN; Amick, HR; Asher, G; Morgan, LC; Coker-Schwimmer, E; Forneris, C; Boland, E; Lux, LJ; Gaylord, S; Bann, C; Pierl, CB; Lohr, KN (December 2015). "Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder [Internet]." (PDF). AHRQ Comparative Effectiveness Reviews. PMID 26764438.
- "Hypericum perforatum L.". Retrieved 19 August 2015.
- Rose, F (2006). The wild flower key. Frederick Warne. ISBN 9780723251750.
- Zobayed SM, Afreen F, Goto E, Kozai T (2006). "Plant–Environment Interactions: Accumulation of Hypericin in Dark Glands of Hypericum perforatum". Annals of Botany. 98 (4): 793–804. PMC . PMID 16891333. doi:10.1093/aob/mcl169.
- Stace, C. A. (2010). New Flora of the British Isles (Third ed.). Cambridge, U.K.: Cambridge University Press. ISBN 9780521707725.
- "St John's wort Hypericum perforatum". Project Noah. 2013. Archived from the original on 8 August 2016. Retrieved 8 August 2016.
- "SPECIES: Hypericum perforatum" (PDF). Fire Effects Information System.
- "Archived copy". Archived from the original on 31 March 2016. Retrieved 2015-10-19.|Hypericum perforatum
- Watt, John Mitchell; Breyer-Brandwijk, Maria Gerdina: The Medicinal and Poisonous Plants of Southern and Eastern Africa 2nd ed Pub. E & S Livingstone 1962
- John L. Harper (2010). Population Biology of Plants. Blackburn Press. ISBN 978-1-932846-24-9.
- Fine Gardening retrieved November 23, 2015
- USDA.gov Retrieved November 23, 2015
- 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". BMJ. 330 (7490): 503. PMC . PMID 15708844. doi:10.1136/bmj.38356.655266.82.
- Samadi, S; Khadivzadeh, T; Emami, A; Moosavi, NS; Tafaghodi, M; Behnam, HR (2010). "The effect of Hypericum perforatum on the wound healing and scar of cesarean". Journal of alternative and complementary medicine. 16 (1): 113–7. PMID 20064022. doi:10.1089/acm.2009.0317.
- Süntar, Ipek Peşin; Akkol, Esra Küpeli; Yılmazer, Demet; Baykal, Turhan; Kırmızıbekmez, Hasan; Alper, Murat; Yeşilada, Erdem (2010). "Investigations on the in vivo wound healing potential of Hypericum perforatum L". Journal of Ethnopharmacology. 127 (2): 468–77. PMID 19833187. doi:10.1016/j.jep.2009.10.011.
- Schempp, Christoph M; Pelz, Klaus; Wittmer, Annette; Schöpf, Erwin; Simon, Jan C (1999). "Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria". The Lancet. 353 (9170): 2129. PMID 10382704. doi:10.1016/S0140-6736(99)00214-7.
- Coles, William (1657). Adam in Eden, or, Natures paradise. OCLC 217197164.[page needed]
- Subhan, F; Khan, N; Sewell, RD (2009). "Adulterant profile of illicit street heroin and reduction of its precipitated physical dependence withdrawal syndrome by extracts of St John's wort (Hypericum perforatum)". Phytotherapy Research. 23 (4): 564–71. PMID 19067385. doi:10.1002/ptr.2692.
- Caraci, F; Crupi, R; Drago, F; Spina, E (2011). "Metabolic drug interactions between antidepressants and anticancer drugs: Focus on selective serotonin reuptake inhibitors and hypericum extract". Current drug metabolism. 12 (6): 570–7. PMID 21395523. doi:10.2174/138920011795713706.
- "St. John's Wort and Depression: In Depth". Retrieved 2017-04-08.
- Nathan PJ (2001). "Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology". J. Psychopharmacol. 15 (1): 47–54. PMID 11277608. doi:10.1177/026988110101500109.
- Linde K, Kriston L, Rücker G, Jamila S, Schumann I, Meissner K, Sigterman K, Schneider A (February 2015). "Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: systematic review and network meta-analysis". Ann Fam Med. 13 (1): 69–79. PMC . PMID 25583895. doi:10.1370/afm.1687.
In network meta-analysis, tricyclic and tetracyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine), a low-dose serotonin antagonist and reuptake inhibitor (SARI; trazodone) and hypericum extracts were found to be significantly superior to placebo, with estimated odds ratios between 1.69 and 2.03. There were no statistically significant differences between these drug classes. Reversible inhibitors of monoaminoxidase A (rMAO-As) and hypericum extracts were associated with significantly fewer dropouts because of adverse effects compared with TCAs, SSRIs, the SNRI, a noradrenaline reuptake inhibitor (NRI), and noradrenergic and specific serotonergic antidepressant agents (NaSSAs). ... TCAs and SSRIs have the most solid evidence base. Further agents (hypericum, rMAO-As, SNRI, NRI, NaSSAs, SARI) showed some positive results, but limitations of the currently available evidence makes a clear recommendation on their place in clinical practice difficult.
- Linde K, Berner MM, Kriston L (2008). Linde K, ed. "St John's wort for major depression". Cochrane Database Syst Rev (4): CD000448. PMID 18843608. doi:10.1002/14651858.CD000448.pub3.
- "National Institute for Complementary and Integrative Health: St. John's Wort". Retrieved 2015-02-05.
- Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JN, Sorbero ME, Hempel S (2016). "A systematic review of St. John's wort for major depressive disorder". Syst Rev. 5 (1): 148. PMC . PMID 27589952. doi:10.1186/s13643-016-0325-2.
- Dörks, M; Langner, I; Dittmann, U; Timmer, A; Garbe, E (August 2013). "Antidepressant drug use and off-label prescribing in children and adolescents in Germany: results from a large population-based cohort study.". European Child & Adolescent Psychiatry. 22 (8): 511–8. PMID 23455627. doi:10.1007/s00787-013-0395-9.
- Fegert JM, Kölch M, Zito JM, Glaeske G, Janhsen K (February–April 2006). "Antidepressant use in children and adolescents in Germany". J Child Adolesc Psychopharmacol. 16 (1–2): 197–206. PMID 16553540. doi:10.1089/cap.2006.16.197.
- Ernst E, Rand JI, Barnes J, Stevinson C (1998). "Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.)". Eur. J. Clin. Pharmacol. 54 (8): 589–94. PMID 9860144. doi:10.1007/s002280050519.
- Barnes, J; Anderson, LA; Phillipson, JD (2002). Herbal Medicines: A guide for healthcare professionals (2nd ed.). London, UK: Pharmaceutical Press. ISBN 9780853692898.
- Parker V, Wong AH, Boon HS, Seeman MV (2001). "Adverse reactions to St John's Wort". Can J Psychiatry. 46 (1): 77–9. PMID 11221494.
- Greeson, JM; Sanford, B; Monti, DA (Feb 2001). "St. John's wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature.". Psychopharmacology. 153 (4): 402–14. PMID 11243487. doi:10.1007/s002130000625.
- Hoban, Claire L.; Byard, Roger W.; Musgrave, Ian F. (Jul 2015). "A comparison of patterns of spontaneous adverse drug reaction reporting with St. John's Wort and fluoxetine during the period 2000-2013". Clinical and Experimental Pharmacology and Physiology. 42: 747–51. PMID 25988866. doi:10.1111/1440-1681.12424. Retrieved 7 June 2015.
The organ systems affected by ADRs to St John's Wort and fluoxetine have a similar profile, with the majority of cases affecting the central nervous system (45.2%, 61.7%).
- Barr Laboratories, Inc. (March 2008). "ESTRACE TABLETS, (estradiol tablets, USP)" (PDF). wcrx.com. Retrieved 27 January 2010.
- Singh, Simon and Edzard Ernst (2008). Trick or Treatment: The Undeniable Facts About Alternative Medicine. W. W. Norton & Company. p. 218. ISBN 978-0-393-33778-5.
- Borrelli, F; Izzo, AA (December 2009). "Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations.". The AAPS Journal. 11 (4): 710–27. PMC . PMID 19859815. doi:10.1208/s12248-009-9146-8.
- pmhdev. "Ranolazine (By mouth) - National Library of Medicine - PubMed Health". mmdn/DNX5549. Retrieved 2017-06-21.
- Russo, Emilio; Scicchitano, Francesca; Whalley, Benjamin J.; Mazzitello, Carmela; Ciriaco, Miriam; Esposito, Stefania; Patanè, Marinella; Upton, Roy; Pugliese, Michela; Chimirri, Serafina; Mammì, Maria; Palleria, Caterina; De Sarro, Giovambattista (May 2014). "Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.". Phytotherapy Research. 28 (5): 643–655. PMID 23897801. doi:10.1002/ptr.5050.
- Skalli, Souad; Zaid, Abdelhamid; Soulaymani, Rachida (December 2007). "Drug Interactions With Herbal Medicines". Ther Drug Monit. 29 (6): 3.
- Tirona, RG; Bailey, DG (June 2006). "Herbal product-drug interactions mediated by induction.". British Journal of Clinical Pharmacology. 61 (6): 677–81. PMC . PMID 16722828. doi:10.1111/j.1365-2125.2006.02684.x.
- "St. John's wort - University of Maryland Medical Center". University of Maryland Medical Center. umm.edu. 24 June 2013. Retrieved 3 January 2014.
- Wenk M, Todesco L, Krähenbühl S (2004). "Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females" (PDF). Br J Clin Pharmacol. 57 (4): 495–499. PMC . PMID 15025748. doi:10.1111/j.1365-2125.2003.02049.x.
- Kober M, Pohl K, Efferth T (2008). "Molecular mechanisms underlying St. John's wort drug interactions". Curr. Drug Metab. 9 (10): 1027–37. PMID 19075619. doi:10.2174/138920008786927767.
- Gurley BJ, Swain A, Williams DK, Barone G, Battu SK (2008). "Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics". Mol Nutr Food Res. 52 (7): 772–9. PMC . PMID 18214850. doi:10.1002/mnfr.200700081.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Barnes, J; Anderson, LA; Phillipson, JD (2007) . Herbal Medicines (PDF) (3rd ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85369-623-0.
- "Pharmacology". Hyperforin. Drugbank. University of Alberta. Retrieved 5 December 2013.
- "Hyperforin". PubChem Compound. National Center for Biotechnology Information. Retrieved 3 December 2013.
- "Targets". Hyperforin. DrugBank. University of Alberta. Retrieved 4 December 2013.
- Nahrstedt A, Butterweck V (1997). "Biologically active and other chemical constituents of the herb of Hypericum perforatum L". Pharmacopsychiatry. 30 Suppl 2 (Suppl 2): 129–34. PMID 9342774. doi:10.1055/s-2007-979533.
- Butterweck V (2003). "Mechanism of action of St John's wort in depression : what is known?" (PDF). CNS Drugs. 17 (8): 539–62. PMID 12775192. doi:10.2165/00023210-200317080-00001.
- Müller WE (2003). "Current St John's wort research from mode of action to clinical efficacy". Pharmacol. Res. 47 (2): 101–9. PMID 12543057. doi:10.1016/S1043-6618(02)00266-9.
- "St. John's wort". Natural Standard. Cambridge, MA. Retrieved 13 December 2013.
- Greeson JM, Sanford B, Monti DA (February 2001). "St. John's wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature" (PDF). Psychopharmacology. 153 (4): 402–414. PMID 11243487. doi:10.1007/s002130000625.
- Anzenbacher, Pavel; Zanger, Ulrich M., eds. (2012). Metabolism of Drugs and Other Xenobiotics. Weinheim, Germany: Wiley-VCH. ISBN 978-3-527-63090-5. doi:10.1002/9783527630905.
- Jensen AG, Hansen SH, Nielsen EO (2001). "Adhyperforin as a contributor to the effect of Hypericum perforatum L. in biochemical models of antidepressant activity". Life Sci. 68 (14): 1593–1605. PMID 11263672. doi:10.1016/S0024-3205(01)00946-8.
- Krusekopf S, Roots I (2005). "St. John's wort and its constituent hyperforin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways". Pharmacogenet. Genomics. 15 (11): 817–829. PMID 16220113. doi:10.1097/01.fpc.0000175597.60066.3d.
- Obach RS (2000). "Inhibition of human cytochrome P450 enzymes by constituents of St. John's Wort, an herbal preparation used in the treatment of depression" (PDF). J. Pharmacol. Exp. Ther. 294 (1): 88–95. PMID 10871299.
- Kubin A, Wierrani F, Burner U, Alth G, Grünberger W (2005). "Hypericin--the facts about a controversial agent" (PDF). Curr. Pharm. Des. 11 (2): 233–253. PMID 15638760. doi:10.2174/1381612053382287.
- Peebles KA, Baker RK, Kurz EU, Schneider BJ, Kroll DJ (2001). "Catalytic inhibition of human DNA topoisomerase IIalpha by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum)". Biochem. Pharmacol. 62 (8): 1059–1070. PMID 11597574. doi:10.1016/S0006-2952(01)00759-6.
- Kerb R, Brockmöller J, Staffeldt B, Ploch M, Roots I (1996). "Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin" (PDF). Antimicrob. Agents Chemother. 40 (9): 2087–2093. PMC . PMID 8878586.
- Meruelo D, Lavie G, Lavie D (1988). "Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin" (PDF). Proc. Natl. Acad. Sci. U.S.A. 85 (14): 5230–5234. PMC . PMID 2839837. doi:10.1073/pnas.85.14.5230.
- Lavie G, Valentine F, Levin B, Mazur Y, Gallo G, Lavie D, Weiner D, Meruelo D (1989). "Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin" (PDF). Proc. Natl. Acad. Sci. U.S.A. 86 (15): 5963–5967. PMC . PMID 2548193. doi:10.1073/pnas.86.15.5963.
- Takahashi I, Nakanishi S, Kobayashi E, Nakano H, Suzuki K, Tamaoki T (1989). "Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activity". Biochem. Biophys. Res. Commun. 165 (3): December 1989. PMID 2558652. doi:10.1016/0006-291X(89)92730-7.
- von Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harmatz JS, Goldman P, Greenblatt DJ (2004). "Inhibition of human cytochromes P450 by components of Ginkgo biloba". J. Pharm. Pharmacol. 56 (8): 1039–1044. PMID 15285849. doi:10.1211/0022357044021.
- Lee JS, Lee MS, Oh WK, Sul JY (2009). "Fatty acid synthase inhibition by amentoflavone induces apoptosis and antiproliferation in human breast cancer cells" (PDF). Biol. Pharm. Bull. 32 (8): 1427–1432. PMID 19652385. doi:10.1248/bpb.32.1427.
- Wilsky S, Sobotta K, Wiesener N, Pilas J, Althof N, Munder T, Wutzler P, Henke A (2012). "Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication". Arch. Virol. 157 (2): 259–269. PMID 22075919. doi:10.1007/s00705-011-1164-z.
- Lee JS, Sul JY, Park JB, Lee MS, Cha EY, Song IS, Kim JR, Chang ES (2013). "Fatty acid synthase inhibition by amentoflavone suppresses HER2/neu (erbB2) oncogene in SKBR3 human breast cancer cells". Phytother Res. 27 (5): 713–720. PMID 22767439. doi:10.1002/ptr.4778.
- Katavic PL, Lamb K, Navarro H, Prisinzano TE (2007). "Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships". J. Nat. Prod. 70 (8): 1278–82. PMC . PMID 17685652. doi:10.1021/np070194x.
- Hanrahan JR, Chebib M, Davucheron NL, Hall BJ, Johnston GA (2003). "Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors". Bioorg. Med. Chem. Lett. 13 (14): 2281–4. PMID 12824018. doi:10.1016/s0960-894x(03)00434-7.
- Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC (1995). "Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects". Planta Med. 61 (3): 213–216. PMID 7617761. doi:10.1055/s-2006-958058.
- Bao YY, Zhou SH, Fan J, Wang QY (2013). "Anticancer mechanism of apigenin and the implications of GLUT-1 expression in head and neck cancers". Future Oncol. 9 (9): 1353–1364. PMID 23980682. doi:10.2217/fon.13.84.
- Lefort ÉC, Blay J (2013). "Apigenin and its impact on gastrointestinal cancers". Mol Nutr Food Res. 57 (1): 962–968. PMID 23197449. doi:10.1002/mnfr.201200424.
- Crespy, V; Williamson, G. "A Review of the Health Effects of Green Tea Catechins in In Vivo Animal Models" (PDF). The Journal of Nutrition. 134 (12): 3431S–3440S.
- Chacko SM, Thambi PT, Kuttan R, Nishigaki I (2010). "Beneficial effects of green tea: a literature review" (PDF). Chin Med. 5 (1): 1–9. PMC . PMID 20370896. doi:10.1186/1749-8546-5-13.
- Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, Heilmann J, Sand PG (2010). "Tea catechins' affinity for human cannabinoid receptors". Phytomedicine. 17 (1): 19–22. PMID 19897346. doi:10.1016/j.phymed.2009.10.001.
- Song M, Hong M, Lee MY, Jee JG, Lee YM, Bae JS, Jeong TC, Lee S (2013). "Selective inhibition of the cytochrome P450 isoform by hyperoside and its potent inhibition of CYP2D6". Food Chem. Toxicol. 59: 549–553. PMID 23835282. doi:10.1016/j.fct.2013.06.055.
- Li S, Zhang Z, Cain A, Wang B, Long M, Taylor J (2005). "Antifungal activity of camptothecin, trifolin, and hyperoside isolated from Camptotheca acuminata". J. Agric. Food Chem. 53 (1): 32–37. PMID 15631505. doi:10.1021/jf0484780.
- Zeng KW, Wang XM, Ko H, Kwon HC, Cha JW, Yang HO (2011). "Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid β-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway". Eur. J. Pharmacol. 672 (1–3): 45–55. PMID 21978835. doi:10.1016/j.ejphar.2011.09.177.
- Kim SJ, Um JY, Lee JY (2011). "Anti-inflammatory activity of hyperoside through the suppression of nuclear factor-κB activation in mouse peritoneal macrophages". Am. J. Chin. Med. 39 (1): 171–181. PMID 21213407. doi:10.1142/S0192415X11008737.
- Haas JS, Stolz ED, Betti AH, Stein AC, Schripsema J, Poser GL, Rates SM (2011). "The anti-immobility effect of hyperoside on the forced swimming test in rats is mediated by the D2-like receptors activation" (PDF). Planta Med. 77 (4): 334–339. PMID 20945276. doi:10.1055/s-0030-1250386.
- Zheng M, Liu C, Pan F, Shi D, Zhang Y (2012). "Antidepressant-like effect of hyperoside isolated from Apocynum venetum leaves: possible cellular mechanisms". Phytomedicine. 19 (2): 145–149. PMID 21802268. doi:10.1016/j.phymed.2011.06.029.
- Pal D, Mitra AK (2006). "MDR- and CYP3A4-mediated drug-herbal interactions". Life Sci. 78 (18): 2131–2145. PMID 16442130. doi:10.1016/j.lfs.2005.12.010.
- Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E (2007). "Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages" (PDF). Mediators Inflamm. 2007: 45673. PMC . PMID 18274639. doi:10.1155/2007/45673.
- Berger A, Venturelli S, Kallnischkies M, Böcker A, Busch C, Weiland T, Noor S, Leischner C, Weiss TS, Lauer UM, Bischoff SC, Bitzer M (2013). "Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases". J. Nutr. Biochem. 24 (6): 977–985. PMID 23159065. doi:10.1016/j.jnutbio.2012.07.001.
- Calderón-Montaño JM, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M (2011). "A review on the dietary flavonoid kaempferol". Mini Rev Med Chem. 11 (4): 298–344. PMID 21428901. doi:10.2174/138955711795305335.
- Seelinger G, Merfort I, Schempp CM (2008). "Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin". Planta Med. 74 (14): 1667–1677. PMID 18937165. doi:10.1055/s-0028-1088314.
- Lin Y, Shi R, Wang X, Shen HM (2008). "Luteolin, a flavonoid with potential for cancer prevention and therapy" (PDF). Curr Cancer Drug Targets. 8 (7): 634–646. PMC . PMID 18991571. doi:10.2174/156800908786241050.
- Theoharides TC, Asadi S, Panagiotidou S (April–June 2012). "A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders". Int J Immunopathol Pharmacol. 25 (2): 317–323. PMID 22697063.
- Yu MC, Chen JH, Lai CY, Han CY, Ko WC (2010). "Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [3H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia". Eur. J. Pharmacol. 627 (1–3): 269–275. PMID 19853596. doi:10.1016/j.ejphar.2009.10.031.
- Chen C, Zhou J, Ji C (2010). "Quercetin: a potential drug to reverse multidrug resistance". Life Sci. 87 (11–12): 333–338. PMID 20637779. doi:10.1016/j.lfs.2010.07.004.
- Kelly, GS (June 2011). "Quercetin" (PDF). Alternative Medicine Review. 16 (2): 172–194. ISSN 1089-5159.
- Ko WC, Shih CM, Lai YH, Chen JH, Huang HL (2004). "Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships". Biochem. Pharmacol. 68 (10): 2087–2094. PMID 15476679. doi:10.1016/j.bcp.2004.06.030.
- Chua LS (2013). "A review on plant-based rutin extraction methods and its pharmacological activities". J Ethnopharmacol. 150 (3): 805–817. PMID 24184193. doi:10.1016/j.jep.2013.10.036.
- Jaikang, C; Niwatananun, K; Narongchai, P; Narongchai, S; Chaiyasut, C (August 2011). "Inhibitory effect of caffeic acid and its derivatives on human liver cytochrome P450 3A4 activity". Journal of Medicinal Plants Research. 5 (15): 3530–3536.
- Hou, J; Fu, J; Zhang, ZM; Zhu, HL. "Biological activities and chemical modifications of caffeic acid derivatives". Fudan University Journal of Medical Sciences. 38 (6): 546–552. doi:10.3969/j.issn.1672-8467.2011.06.017.
- Zhao Y, Wang J, Ballevre O, Luo H, Zhang W (2012). "Antihypertensive effects and mechanisms of chlorogenic acids". Hypertens. Res. 35 (4): 370–374. PMID 22072103. doi:10.1038/hr.2011.195.
- [dead link]
- Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S, Lambert G, Mohr S, Yang CS (2002). "Pharmacokinetics of tea catechins after ingestion of green tea and (−)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability" (PDF). Cancer Epidemiol. Biomarkers Prev. 11 (10 Pt 1): 1025–1032. PMID 12376503.
- Walle T, Walle UK, Halushka PV (2001). "Carbon dioxide is the major metabolite of quercetin in humans" (PDF). J. Nutr. 131 (10): 2648–2652. PMID 11584085.
- St John's wort effects on animals Archived 26 February 2015 at the Wayback Machine.
- R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1445–1446.
- Umek A, Kreft S, Kartnig T, Heydel B (1999). "Quantitative phytochemical analyses of six hypericum species growing in slovenia". Planta Med. 65 (4): 388–90. PMID 17260265. doi:10.1055/s-2006-960798.
- Tatsis EC, Boeren S, Exarchou V, Troganis AN, Vervoort J, Gerothanassis IP (2007). "Identification of the major constituents of Hypericum perforatum by LC/SPE/NMR and/or LC/MS". Phytochemistry. 68 (3): 383–93. PMID 17196625. doi:10.1016/j.phytochem.2006.11.026.
- Schwob I, Bessière JM, Viano J.Composition of the essential oils of Hypericum perforatum L. from southeastern France.C R Biol. 2002;325:781-5.
- Kumar V, Mdzinarishvili A, Kiewert C, Abbruscato T, Bickel U, van der Schyf CJ, Klein J (2006). "NMDA receptor-antagonistic properties of hyperforin, a constituent of St. John's Wort" (PDF). J. Pharmacol. Sci. 102 (1): 47–54. PMID 16936454. doi:10.1254/jphs.FP0060378.
- Reuter J, Huyke C, Scheuvens H, Ploch M, Neumann K, Jakob T, Schempp CM (2008). "Skin tolerance of a new bath oil containing St. John's wort extract". Skin Pharmacol Physiol. 21 (6): 306–311. PMID 18667843. doi:10.1159/000148223.
- Cecchini C, Cresci A, Coman MM, Ricciutelli M, Sagratini G, Vittori S, Lucarini D, Maggi F (2007). "Antimicrobial activity of seven hypericum entities from central Italy". Planta Med. 73 (6): 564–6. PMID 17516331. doi:10.1055/s-2007-967198.
- Germ M, Stibilj V, Kreft S, Gaberščik A, Kreft I (2010). "Flavonoid, tannin and hypericin concentrations in the leaves of St. John's wort (Hypericum perforatum L.) are affected by UV-B radiation levels". Food Chemistry. 122: 471–474. doi:10.1016/j.foodchem.2010.03.008.
- Ben Eliezer D, Yechiam E (2016). "Hypericum perforatum as a cognitive enhancer in rodents: A meta-analysis". Scientific Reports. 6 (36700). doi:10.1038/srep35700.
- British Herbal Medicine Association Scientific Committee (1983). British Herbal Pharmacopoeia. West Yorkshire: British Herbal Medicine Association. ISBN 0-903032-07-4.
- Müller, Walter (2005). St. John's Wort and its Active Principles in Depression and Anxiety. Basel: Birkhäuser. ISBN 978-3-7643-6160-0. doi:10.1007/b137619.
|Wikispecies has information related to: Hypericum perforatum|
|Wikimedia Commons has media related to Hypericum perforatum.|
- "St. John's wort: MedlinePlus Supplements". U.S. National Library of Medicine. Retrieved 7 October 2009.
- Species Profile — St. Johnswort (Hypericum perforatum), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for St John's wort.