Hypericum perforatum

Hypericum perforatum
Scientific classification
Kingdom: Plantae
Clade: Tracheophytes
Clade: Angiosperms
Clade: Eudicots
Clade: Rosids
Order: Malpighiales
Family: Hypericaceae
Genus: Hypericum
Section: Hypericum sect. Hypericum
Species:
H. perforatum
Binomial name
Hypericum perforatum
L.

Hypericum perforatum, known as perforate St John's-wort,[1] is a flowering plant in the family Hypericaceae and the type species of the genus Hypericum.

Possibly a hybrid between H. maculatum and H. attenuatum, the species can be found across temperate areas of Eurasia and has been introduced as an invasive weed to much of North and South America, as well as South Africa and Australia. While the species is harmful to livestock and can interfere with prescription drugs, it has been used in folk medicine over centuries, and remains commercially cultivated in the 21st century. Hyperforin, a phytochemical constituent of the species, is under basic research for its possible biological properties.

Description

Translucent dots of glandular tissue on the leaves

Perforate St John's wort is a herbaceous perennial plant with extensive, creeping rhizomes. Its reddish stems are erect and branched in the upper section, and can grow up to 1 m (3 ft 3 in) high. The stems are woody near their base and may appear jointed from leaf scars.[2] The branches are typically clustered about a depressed base. It has opposite and stalkless leaves that are narrow and oblong in shape and 1–2 cm (0.39–0.79 in) long.[3] Leaves borne on the branches subtend the shortened branchlets. The leaves are yellow-green in color, with scattered translucent dots of glandular tissue.[4] 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 (0.98 in) across, have five petals and sepals, and are colored bright yellow with conspicuous black dots.[5] The flowers appear in broad helicoid cymes at the ends of the upper branches, between late spring and early to mid-summer. The cymes are leafy and bear many flowers. The pointed sepals have black glandular dots. The many stamens are united at the base into three bundles. The pollen grains are ellipsoidal.[6] The black and lustrous seeds are rough, netted with coarse grooves.[7]

When flower buds (not the flowers themselves) or seed pods are crushed, a reddish or purple liquid is produced.[8]

Taxonomy

Etymology

The specific epithet perforatum is Latin, referring to the perforated appearance of the plant's leaves.[7]

The common name "St John's wort" may 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" to differentiate it.

St John's wort is named as such because it commonly flowers, blossoms and is harvested at the time of the summer solstice in late June, around St John's Feast Day on 24 June. The herb would be hung on house and stall doors on St John's Feast day to ward off evil spirits and to safeguard against harm and sickness to people and live-stock. Alternatively, there may be a connection with the Knights Hospitaller. The genus name Hypericum is possibly 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.

Phylogeny

It is probable that Hypericum perforatum originated as a hybrid between two closely related species with subsequent doubling of chromosomes. One species is certainly a diploid a subspecies of Hypericum maculatum, either subspecies maculatum or immaculatum. Subspecies maculatum is similar in distribution and hybridizes easily with Hypericum perforatum, but subspecies immaculatum is more similar morphologically. The other parent is most likely Hypericum attenuatum as it possesses the features of Hypericum perforatum that Hypericum maculatum lacks. Though Hypericum maculatum is mostly western in its distribution across Eurasia and Hypericum attenuatum is mostly eastern, both species share distribution in Siberia, where hybridization likely took place. However, the subspecies immaculatum now only occurs in south-east Europe.[9]

Ecology

St John's wort reproduces both vegetatively and sexually. 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.[10] The seeds can persist for decades in the soil seed bank, germinating following disturbance.[11]

Distribution

Hypericum perforatum is native to temperate parts of Europe and Asia, but has spread to temperate regions worldwide as a cosmopolitan invasive weed.[12][13] It was introduced to North America from Europe.[14] The species 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.[12] Altitudes greater than 1500 m, rainfall less than 500 mm, and daily mean temperatures greater than 24 °C are considered limiting thresholds.[10]

Habitat

The flower occurs in prairies, pastures, and disturbed fields. It prefers sandy soils.[2]

Diseases

H. perforatum is affected by phytoplasma diseases, and when infected with Candidatus phytoplasma fraxini it undergoes several phytochemical changes and shows visible symptoms, including yellowing and witches' bloom symptoms. Naphthodianthrone, flavonoid, amentoflavone, and pseudohypericin levels are reduced; chlorogenic acid levels increased. Additionally, phytoplasma diseases greatly reduced the essential oil yield of the plant.[15]

Invasiveness

Although Hypericum perforatum is grown commercially in some regions of southeast 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.[12][11] 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.[16] Ingestion by livestock such as horses, sheep, and cattle can cause photosensitization, central nervous system depression, spontaneous abortion, or death.[16][17] Effective herbicides for control of Hypericum perforatum include 2,4-D, picloram, and glyphosate. In western North America the beetles Chrysolina quadrigemina, C. hyperici, and Agrilus hyperici have been introduced as biocontrol agents.[18]

Traditional medicine

Common St John's wort has been used in herbalism for centuries.[19][20] It was thought 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. Hypericum perforatum is a common species and is grown commercially for use in herbalism and traditional medicine.[20]

The red, oily extract of H. perforatum has been used in the treatment of wounds, including by the Knights Hospitaller, the Order of St John[19][21] Both hypericin and hyperforin are under study for their potential antibiotic properties.[22]

Side effects

St John's wort may cause allergic reactions and can interact in dangerous, sometimes life-threatening ways with a variety of prescribed medicines.[20][19] St John's wort is generally well tolerated, but it may cause gastrointestinal discomfort (such as nausea, abdominal pain, loss of appetite, and diarrhea), dizziness, confusion, fatigue, sedation, dry mouth, restlessness, and headache.[20][23][24][25][26]

The organ systems associated with adverse drug reactions to St John's wort and fluoxetine (an SSRI) have a similar incidence profile;[27] most of these reactions involve the central nervous system.[27] St John's wort also decreases levels of estrogens, such as estradiol, by accelerating its metabolism, and women on contraceptive pills are not advised to take it.[19] St John's wort may cause photosensitivity. This can lead to visual sensitivity to visible and ultraviolet light and to sunburns in situations that would not normally cause them.[23]

Interactions

St John's wort can interfere with the effects of many prescription drugs,[19][20] including the anti-psychotics risperidone and 9-hydroxyrisperidone (i.e. paliperidone, Xeplion or Invega),[28][29] cyclosporine, digoxin, HIV drugs, cancer medications including irinotecan, and warfarin.[19][20] Combining both St John's wort and antidepressants could lead to increased serotonin levels causing serotonin syndrome.[30] It should not be taken with the heart medication ranolazine.[31] Combining estrogen-containing oral contraceptives with St John's wort can lead to decreased efficacy of the contraceptive and, potentially, unplanned pregnancies.[32] Consumption of St John's wort is discouraged for those with bipolar disorder, schizophrenia or dementia, and for people using dietary supplements, headache medicine, anticoagulants, and birth control pills.[19][20]

Pharmacodynamics

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.[33] 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.[34]

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.[29]

Examples of drugs whose effectiveness may be reduced by St. John's wort
Class Drugs
Antiretrovirals Non-nucleoside reverse transcriptase inhibitors, protease inhibitors
Benzodiazepines Alprazolam, midazolam
Hormonal contraception Combined oral contraceptives
Immunosuppressants Calcineurin inhibitors, cyclosporine, tacrolimus
Antiarrhythmics Amiodarone, flecainide, mexiletine
Beta-blockers Metoprolol, carvedilol
Calcium channel blockers Verapamil, diltiazem, amlodipine, pregabalin
Statins (cholesterol-reducing medications) Lovastatin, simvastatin, atorvastatin
Others Digoxin, methadone, omeprazole, phenobarbital, theophylline, warfarin, levodopa, buprenorphine, irinotecan, risperidone, paliperidone
Reference: Rossi, 2005; Micromedex

Livestock poisoning

In large doses, St John's wort is poisonous to grazing livestock.[16] Behavioral 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 grazers 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 appetites. 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.

Diagnosis

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 milk production, or the transmission of a toxin in the milk. It may result in an undesirable flavor.[35]

Photosensitisation

Most clinical signs in animals are caused by photosensitisation.[36] Plants may induce either primary or secondary photosensitisation:

  • 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 tissue lesions, 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.

Chemistry

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.[37]

Chemical constituents

Chemical structure of hypericin

The plant contains the following:[38][39]

  • 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.[6][40][41][42] It also contains essential oils composed mainly of sesquiterpenes.[6]

Selected chemical constituents of Hypericum perforatum

Research

Antidepressant

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.[43] 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. In Germany, St. John's wort may be prescribed for mild to moderate depression, especially in children and adolescents.[44] 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.[45] A 2016 review noted that use of St. John's wort for mild and moderate depression was better than placebo for improving depression symptoms, and comparable to antidepressant medication.[46] A 2017 meta-analysis found that St. John’s wort had comparable efficacy and safety to SSRIs for mild-to-moderate depression and a lower discontinuation rate.[47]

While some studies and research reviews have supported the efficacy of St John's wort as a treatment for depression in humans, in the United States, it is not recommended as a replacement for more studied treatments, and it is advised that symptoms of depression warrant proper medical consultation.[19]

In the United States, St John's wort is considered a dietary supplement by the FDA, and is not regulated by the same standards as a prescription drug.[48][49] According to the United States National Center for Complementary and Integrative Health, "St. John's wort isn't consistently effective for depression"; however, they also note that it appears to be more effective than placebo and as effective as prescription SSRIs.[19] Supplement strength varies by manufacturer and possibly by batch.[50] With antidepressants, one "may have to try a few before finding what works best," notes the United States National Library of Medicine.[51] On average, lead levels in women taking St. John's wort are elevated about 20%.[52]

Phytochemicals and dietary supplement

St John's wort, similarly to other herbs, contains different phytochemical constituents.[38][53][54] Although St. John's wort is sold as a dietary supplement, there are no standardized manufacturing procedures, and some marketed products may be contaminated with metals, fillers or other impurities.[20]

Comparison of selected chemical constituents of Hypericum perforatum[38][55]
CompoundConc.[38]
[39][56]		log PPSApKaFormulaMWCYP1A2
[Note 1]		CYP2C9
[Note 2]		CYP2D6
[Note 3]		CYP3A4
[Note 4]		PGP
[Note 5]		t1/2[56] (h)Tmax[56] (h)Cmax[56] (mM)CSS[56] (mM)Notes/Biological activity[Note 6]
Phloroglucinols (2–5%)
Adhyperforin0.2–1.910–1371.48.51C36H54O4550.81 ? ? ? ? ? ? ? ? ? ?
Hyperforin2–4.59.7–1371.48.51C35H52O4536.78++/-–++3.5–162.5–4.415-23553.7–
Naphthodianthrones (0.03-3%)
Hypericin0.003-37.5–101566.9±0.2C30H16O8504.440–
(3.4 μM)		– (8.5 μM)–
(8.7 μM)		 ?2.5–6.56–480.66-46 ? ?
Pseudohypericin0.2–0.236.7±1.81767.16C30H16O9520.44 ? ? ? ? ?24.8–25.431.4–160.6–10.8–
Flavonoids (2–12%)
Amentoflavone
0.01–0.053.1–5.11742.39C30H18O10538.46 ?–
(35 nM)		– (24.3 μM)–
(4.8 μM)		 ? ? ? ? ? ?
Apigenin0.1–0.52.1±0.56876.63C15H10O5270.24 ? ? ? ? ? ? ? ? ? ?
Catechin2–41.8±0.851108.92C15H14O6290.27 ? ? ? ? ? ? ? ? ? ?
Epigallocatechin ?−0.5–1.51318.67C15H14O6290.27 ? ? ? ? ?1.7±0.4a1.3–1.6a ? ? ?
Hyperoside0.5-21.5±1.71746.17C21H20O12464.38 ? ? ? ? ? ? ? ? ?
Kaempferol ?2.1±0.61076.44C15H10O6286.24 ? ? ?+/- ? ? ? ? ? ?
Luteolin ?2.4±0.651076.3C15H10O6286.24– ? ? ? ? ? ? ? ? ?
Quercetin2–42.2±1.51276.44C15H10O7302.24–
(7.5 μM)
b		– (47 μM)
b		– (24 μM)
b		– (22 μM)
b		–20–72c8c ? ? ?
Rutin0.3–1.61.2±2.12666.43C27H30O16610.52 ? ? ? ? ? ? ? ? ? ?
Phenolic acids (~0.1%)
Caffeic acid0.11.4±0.477.83.64C9H8O4180.16 ? ? ?– ? ? ? ? ? ?
Chlorogenic acid<0.1%-0.36±0.431653.33C16H18O9354.310000 ? ? ? ? ? ?
Acronyms and symbols
Acronym/SymbolMeaning
MWMolecular weight in g•mol−1.
PGPP-glycoprotein
t1/2Elimination half-life in hours
TmaxTime to peak plasma concentration in hours
CmaxPeak plasma concentration in mM
CSSSteady state plasma concentration in mM
Partition coefficient.
PSAPolar surface area of the molecule in question in square angstroms (Å2). Obtained from PubChem
Conc.These values pertain to the approximation concentration (in %) of the constituents in the fresh plant material
–Indicates inhibition of the enzyme in question.
+Indicates an inductive effect on the enzyme in question.
0No effect on the enzyme in question.
5-HT5-hydroxytryptamine – synonym for serotonin.
DADopamine
NENorepinephrine
GABAγ-aminobutyric acid
GluGlutamate
GlyGlycine
ChCholine
a ?
b ?
c ?

Notes:

  1. ↑ In brackets is the IC50/EC50 value depending on whether it is an inhibitory or inductive action being exhibited, respectively.
  2. ↑ As with last note
  3. ↑ As with last note
  4. ↑ As with last note
  5. ↑ As with last note
  6. ↑ Values given in brackets are IC50/EC50 depending on whether it's an inhibitory or inductive action the compound displays towards the biologic target in question. If it pertains to bacterial growth inhibition the value is MIC50

See also

Notes

    References

    1. ↑ BSBI List 2007 (xls). Botanical Society of Britain and Ireland. Archived from the original (xls) on 26 June 2015. Retrieved 16 February 2014.
    2. 1 2 James L. Stubbendieck; Stephan L. Hatch; L. M. Landholt (2003). North American Wildland Plants: A Field Guide (illustrated ed.). University of Nebraska Press. p. 323. ISBN 978-0-8032-9306-9.
    3. ↑ Rose, F (2006). The wild flower key. Frederick Warne. p. 176. ISBN 978-0-7232-5175-0.
    4. ↑ 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. doi:10.1093/aob/mcl169. PMC 2806163. PMID 16891333.
    5. ↑ Stace, C. A. (2010). New Flora of the British Isles (Third ed.). Cambridge, U.K.: Cambridge University Press. p. 339. ISBN 978-0-521-70772-5.
    6. 1 2 3 Mehta, Sweety (18 December 2012). "Pharmacognosy of St. John's Wort". Pharmaxchange.info. Retrieved 16 February 2014.
    7. 1 2 Merrit Lyndon Fernald (1970). R. C. Rollins (ed.). Gray's Manual of Botany (Eighth (Centennial) – Illustrated ed.). D. Van Nostrand Company. p. 1010. ISBN 978-0-442-22250-5.
    8. ↑ "St John's wort Hypericum perforatum". Project Noah. 2013. Archived from the original on 8 August 2016. Retrieved 8 August 2016.
    9. ↑ Edzard Ernst, ed. (2003). Hypericum: The genus Hypericum. CRC Press. p. 19. ISBN 978-1-4200-2330-5.
    10. 1 2 Ramawat, Kishan Gopal. Bioactive Molecules and Medicinal Plants. Springer Science & Business Media, 2008. p. 152. ISBN 978-3-540-74603-4
    11. 1 2 "SPECIES: Hypericum perforatum" (PDF). Fire Effects Information System.
    12. 1 2 3 Ian Popay (22 June 2015). "Hypericum perforatum (St John's wort)". CABI. Retrieved 2 December 2018.
    13. ↑ "Hypericum perforatum L." Retrieved 19 August 2015.
    14. ↑ Charles Vancouver Piper; Rolla Kent Beattie (1915). Flora of the Northwest Coast. Press of the New era printing Company. p. 240.
    15. ↑ Marcone, C.; Bellardi, M.G.; Bertaccini, A. (2016). "Phytoplasma diseases of medicinal and aromatic plants". Journal of Plant Pathology. 98 (3): 379–404. doi:10.4454/JPP.V98I3.060. JSTOR 44280481.
    16. 1 2 3 "St John's wort – Hypericum perforatum". North West Weeds. Archived from the original on 31 March 2016. Retrieved 19 October 2015.
    17. ↑ Watt, John Mitchell; Breyer-Brandwijk, Maria Gerdina: The Medicinal and Poisonous Plants of Southern and Eastern Africa 2nd ed Pub. E & S Livingstone 1962
    18. ↑ Harper, John L. (2010). Population Biology of Plants. Blackburn Press. ISBN 978-1-932846-24-9.
    19. 1 2 3 4 5 6 7 8 9 "St. John's Wort". National Center for Complementary and Integrative Health, US National Institutes of Health. September 2016. Retrieved 1 February 2018.
    20. 1 2 3 4 5 6 7 8 "St. John's wort". Drugs.com. 6 February 2020. Retrieved 4 April 2020.
    21. ↑ 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. doi:10.1016/j.jep.2009.10.011. PMID 19833187.
    22. ↑ Schempp, Christoph M; Pelz, Klaus; Wittmer, Annette; Schöpf, Erwin; Simon, Jan C (June 1999). "Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria". The Lancet. 353 (9170): 2129. doi:10.1016/S0140-6736(99)00214-7. PMID 10382704. S2CID 26975932.
    23. 1 2 Ernst, E.; Rand, J. I.; Barnes, J.; Stevinson, C. (11 November 1998). "Adverse effects profile of the herbal antidepressant St. John's wort ( Hypericum perforatum L.)". European Journal of Clinical Pharmacology. 54 (8): 589–594. doi:10.1007/s002280050519. PMID 9860144. S2CID 25726974.
    24. ↑ Barnes, J.; Anderson, L.A.; Phillipson, J.D. (2002). Herbal Medicines: A guide for healthcare professionals (2nd ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85369-289-8.
    25. ↑ Parker, Vivien; Wong, Al bert HC; Boon, Heather S; Seeman, Mary V (February 2001). "Adverse Reactions to St John's Wort". The Canadian Journal of Psychiatry. 46 (1): 77–79. doi:10.1177/070674370104600112. PMID 11221494.
    26. ↑ Greeson, Jeffrey M.; Sanford, Britt; Monti, Daniel A. (February 2001). "St. John's wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature". Psychopharmacology. 153 (4): 402–414. doi:10.1007/s002130000625. PMID 11243487. S2CID 22986104.
    27. 1 2 Hoban, Claire L.; Byard, Roger W.; Musgrave, Ian F. (July 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 (7): 747–51. doi:10.1111/1440-1681.12424. PMID 25988866. S2CID 22189214. 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%).
    28. ↑ Wang, Jun-Sheng; Ruan, Ying; Taylor, Robin M.; Donovan, Jennifer L.; Markowitz, John S.; DeVane, C. Lindsay (December 2004). "The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein". The International Journal of Neuropsychopharmacology. 7 (4): 415–419. doi:10.1017/S1461145704004390. PMID 15683552.
    29. 1 2 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. doi:10.1002/mnfr.200700081. PMC 2562898. PMID 18214850.
    30. ↑ Borrelli, Francesca; Izzo, Angelo A. (27 October 2009). "Herb–Drug Interactions with St John's Wort (Hypericum perforatum): an Update on Clinical Observations". The AAPS Journal. 11 (4): 710–727. doi:10.1208/s12248-009-9146-8. PMC 2782080. PMID 19859815.
    31. ↑ MedlinePlus Encyclopedia: Ranolazine
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