Hypericum perforatum

Hypericum perforatum
Scientific classification
Kingdom: Plantae
(unranked): Angiosperms
(unranked): Eudicots
(unranked): Rosids
Order: Malpighiales
Family: Hypericaceae
Genus: Hypericum
Species: H. perforatum
Binomial name
Hypericum perforatum
L.

Hypericum perforatum, known as perforate St John's-wort,[1] common Saint John's wort and St John's wort (/ˈsɪndʒənzwɜːrt/ SIN-jənz-wurt),[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.[3][4][5]

Botanical description

Translucent dots of glandular tissue on the leaves

Hypericum perforatum is native to parts of Europe and Asia[6] but has spread to temperate regions worldwide as a cosmopolitan invasive weed.

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.[7]:176 The leaves are yellow-green in color, with scattered translucent dots of glandular tissue.[8] 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.[9]: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.[2]

When flower buds (not the flowers themselves) or seed pods are crushed, a reddish/purple liquid is produced.[10]

Ecology

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. 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.

The seeds can persist for decades in the soil seed bank, germinating following disturbance.[11]

Invasive species

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.[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[12] 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.[12][13] 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.[14]

Medical uses

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.[15]

Hypericum perforatum is the most potent species and it is today grown commercially for use in herbalism and medicine.[16]

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,[17] but no significant improvement of severe depression and OCD.

The red, oily extract of H. perforatum may help heal wounds.[18][19] Both hypericin and hyperforin are reported to have antibiotic properties.[20] Justifying this view with the then-current doctrine of signatures, herbalist William Coles (1626–1662)[21] 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.[22]

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.[23]

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.[24][5][25] 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.[26] It is proposed that the mechanism of action of St. John's wort is due to the inhibition of reuptake of certain neurotransmitters.[2]

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.[27] 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.[28] 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.[29]

In Germany, St. John's wort is sometimes prescribed for mild to moderate depression, especially in children and adolescents.[30][31]

Side effects

St John's wort is generally well tolerated, with an adverse effect profile similar to placebo.[32] Commonly reported adverse effects include gastrointestinal symptoms (nausea, abdominal pain, loss of appetite, and diarrhea), dizziness, confusion, fatigue, sedation, dry mouth, restlessness, and headache.[33][34][35] The organ systems associated with adverse drug reactions to St John's wort and fluoxetine (an SSRI) have a similar incidence profile;[36] most of these reactions involve the central nervous system.[36] 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.[37]

St John's wort may rarely cause photosensitivity. This can lead to visual sensitivity to light and to sunburns in situations that would not normally cause them.[32]

St John's wort is associated with aggravating psychosis in people who have schizophrenia.[38]

Interactions

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.[39] It should not be taken with the heart medication, Ranolazine.[40] Combining estrogen containing oral contraceptives with St John's wort can lead to decreased efficacy of the contraceptive and eventually unplanned pregnancies.[41] 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.[42] 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.[43]

Consumption of St. John's wort is discouraged for those with bipolar disorder. There is concern that people with bipolar depression taking St. John's wort may be at a higher risk for mania.[44]

Pharmacokinetic

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.[45] 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.[46]

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.[47]

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
Statins (cholesterol-reducing medications) Lovastatin, simvastatin, atorvastatin
Others Digoxin, methadone, omeprazole, phenobarbital, theophylline, warfarin, levodopa, buprenorphine, irinotecan
Reference: Rossi, 2005; Micromedex

For a complete list, see CYP3A4 ligands and CYP2C9 ligands.

Pharmacodynamic

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.[48]

Drugs that may contribute to serotonin syndrome with St John's wort
Class Drugs
Antidepressants MAOIs, TCAs, SSRIs, SNRIs, mirtazapine
Opioids Tramadol, pethidine (meperidine), Levorphanol
CNS stimulants Phentermine, diethylpropion, amphetamines, sibutramine, cocaine
5-HT1 agonists Triptans
Psychedelic drugs Methylenedioxymethamphetamine (MDMA), LSD, Dimethyltryptamine (DMT), MDA, 6-APB
Others Selegiline, tryptophan, buspirone, lithium, linezolid, 5-HTP, dextromethorphan
Reference:[48]

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.[49] 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.[25][50][51] In humans, the active ingredient hyperforin is also an inhibitor of PTGS1, arachidonate 5-lipoxygenase, SLCO1B1 and an inducer of cMOAT.[50][51][52] Hyperforin is also a anti-inflammatory compound with anti-angiogenic, antibiotic, and neurotrophic properties.[50][51][52] Hyperforin also has an antagonistic effect on NMDA receptors, a type of glutamate receptor.[51] 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.[25] 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.[25][53][54][55]

Livestock

Poisoning

In large doses, St John's wort is poisonous to grazing livestock (cattle, sheep, goats, horses).[12] 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.

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 the milk production, or the transmission of a toxin in the milk.

Photosensitisation

Most clinical signs in animals are caused by photosensitisation.[105] Plants may induce either primary or secondary photosensitisation:

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.

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.[106]

Chemical constituents

Chemical structure of hypericin

The plant contains the following:[49][57]

The naphthodianthrones hypericin and pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be among the numerous active constituents.[2][107][108][109] It also contains essential oils composed mainly of sesquiterpenes.[2]

Research

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.[110][111] Hyperforin has also displayed antibacterial properties against Gram-positive bacteria, although dosage, safety and efficacy has not been studied.[112] Herbal medicine has also employed lipophilic extracts from St John's wort as a topical remedy for wounds, abrasions, burns, and muscle pain.[111] The positive effects that have been observed are generally attributed to hyperforin due to its possible antibacterial and anti-inflammatory effects.[111] For this reason hyperforin may be useful in the treatment of infected wounds and inflammatory skin diseases.[111] 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.[111]

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.[2]

Concentrations of bioactive substances can be altered by regulating the environment during plant growth like different levels of UV-B radiation, for instance.[113]

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).[114] 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.

See also

Notes

  1. ↑ Less common names and synonyms include Tipton's weed, rosin rose, goatweed, chase-devil, or Klamath weed.[2]

References

  1. ↑ "BSBI List 2007". Botanical Society of Britain and Ireland. Archived from the original (xls) on 2015-01-25. Retrieved 2014-10-17.
  2. 1 2 3 4 5 6 Mehta, Sweety (2012-12-18). "Pharmacognosy of St. John's Wort". Pharmaxchange.info. Retrieved 2014-02-16.
  3. ↑ "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
  4. ↑ 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 [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 µmol/L in vitro [56]. 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. [57] 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.
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  11. 1 2 "SPECIES: Hypericum perforatum" (PDF). Fire Effects Information System.
  12. 1 2 3 "Archived copy". Archived from the original on 31 March 2016. Retrieved 2015-10-19.|Hypericum perforatum
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  19. ↑ 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.
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  21. ↑ Coles, William (1657). Adam in Eden, or, Natures paradise. OCLC 217197164.
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