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St John's wort
Hypericum perforatum, also known as Tipton's weed, rosin rose, goatweed, chase-devil, or Klamath weed, is a species of flowering plant in the genus Hypericum. With qualifiers, St John's wort is used to refer to any species of the genus Hypericum. Therefore, H. perforatum is sometimes called common St John's wort or perforate St John's wort to differentiate it. Hypericum is classified in the family Hypericaceae, having previously been classified as Guttiferae or Clusiaceae. Approximately 370 species of the genus Hypericum exist worldwide with a native geographical distribution including temperate and subtropical regions of Europe, Turkey, Ukraine, Russia, Middle East, India, and China. St John's wort is widely known as an herbal medicine for treating depression.
- 1 Botanical description
- 2 Ecology
- 3 Medicinal uses
- 3.1 Depression treatment use
- 3.2 Major depressive disorder
- 3.3 Dosage
- 3.4 Other medical uses
- 3.5 Chemical constituents
- 3.6 Adverse effects and drug interactions
- 3.7 Detection in body fluids
- 4 Livestock – forage poisoning
- 5 Other uses
- 6 See also
- 7 References
- 8 Further reading
- 9 External links
Hypericum perforatum is a yellow-flowering, stoloniferous or sarmentose, perennial herb indigenous to Europe. It has been introduced to many temperate areas of the world and grows wild in many meadows. The herb's common name 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 plant's traditional use in warding off evil by hanging plants over a religious icon in the house during St John's day. The species name perforatum refers to the presence of small oil glands in the leaves that look like windows, which can be seen when they are held against the light.
St John's wort is a perennial plant with extensive, creeping rhizomes. Its stems are erect, branched in the upper section, and can grow to 1 m high. It has opposing, stalkless, narrow, oblong leaves that are 12 mm long or slightly larger. The leaves are yellow-green in color, with transparent dots throughout the tissue and occasionally with a few black dots on the lower surface. Leaves exhibit obvious translucent dots when held up to the light, giving them a ‘perforated’ appearance, hence the plant's Latin name.
Its flowers measure up to 2.5 cm across, have five petals, and are colored bright yellow with conspicuous black dots. 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 glandular dots in the tissue. 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.
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 January (in Southern hemisphere) temperature greater than 24 degrees 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.
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 dominating extent of making productive land nonviable or becoming an invasive species in natural habitats and ecosystems. Ingestion by livestock can cause photosensitization, central nervous system depression, spontaneous abortion, and can lead to 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.
Depression treatment use
St John's wort is widely known as a herbal treatment for depression. In some countries, such as Germany, it is commonly prescribed for mild depression, especially in children and adolescents. It is proposed that the mechanism of action of St. John's wort is due to the inhibition of reuptake of certain neurotransmitters.
The available evidence suggests that the Hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; and c) have fewer side-effects than standard antidepressants.
There are two issues that complicate the interpretation of our findings:
1) While the influence of precision on study results in placebo-controlled trials is less pronounced in this updated version of our review compared to the previous version (Linde 2005a), results from more precise trials still show smaller effects over placebo than less precise trials.
2) Results from German-language countries are considerably more favourable for Hypericum than trials from other countries.
In one study, St John's wort was not found to be effective for patients suffering from dysthymia, a less severe and more chronic variety of depression. However, St John's wort has been shown to be effective in the treatment of mild to moderate depression in certain studies.
Standardized extracts are generally available over the counter, though in some countries (such as the Republic of Ireland) a prescription is required. Extracts are usually in tablet or capsule form, and also in teabags and tinctures.
Major depressive disorder
An analysis of twenty-nine clinical trials with more than five thousand patients was conducted by Cochrane Collaboration. The review concluded that extracts of St John's wort were superior to placebo in patients with major depression. St John's wort had similar efficacy to standard antidepressants. The rate of side-effects was half that of newer SSRI antidepressants and one-fifth that of older tricyclic antidepressants.
The National Center for Complementary and Alternative Medicine (NCCAM) and other NIH-affiliated organizations hold that St John's wort has minimal or no effects beyond placebo in the treatment of major depression. This conclusion is based primarily on one trial of 340 volunteers, with negative outcome conducted by NCCAM. The authors of the study themselves, as well as several others, pointed out the low assay sensitivity of this study, and how only limited conclusions can be drawn from its results. The same study also indicated that sertraline (Zoloft) has no positive effects vs the same placebo.
Most studies on St John's wort for treating depression use doses of 300 mg of hydroalcoholic extract called WS 5570 (standardized contents of 3%–6% hyperforin and 0.12%–0.28% hypericin) one to three times daily to achieve a therapeutic effect. For hypericin, such a dosage equates to 1-2.5 mg/day, while for hyperforin this equates to 27–54 mg/day. No cases of overdose are known.. However, dosage of St. John's wort for treating depression is complicated by several factors.
Uncertainty surrounding active ingredient
Similarly to SSRIs the precise mechanism of St. John's Wort for treating depression is not well understood. The situation is complicated further in the case of St. John's wort due the plant potentially containing several active ingredients.
The major active antidepressive constituents in St John's wort are thought to be hyperforin and hypericin, although other biologically active constituents present, for example, flavonoids and tannins, may also be involved. Initially, it was believed that hypericin is the active ingredient in St. John's wort due to it being responsible for toxic effects on livestock grazing on St. John's wort, however, more recently it has been shown that hyperforin content correlates with theurapeutic effect in mild to moderate depression. It has been shown to inhibit the uptake of 5-HT, dopamine, and noradrenaline. Hyperforin also has affinity for GABA and glutamate transporters. On the other hand, a hyperforin-free extract of St John's wort (Ze 117 – Remotiv) may still have significant antidepressive effects.
Hypericin and hyperforin have very different pharmacological half lives, potentially having an impact on the optimal dosing frequency. Hypericin is reported to have an elimination half-life of 33.8h +/- 18.8h, while hyperforin has an elimination half-life of between 9 and 12 hours 
Lack of regulatory standardization in preparations
Different parts of the plant contain different proportions of the active ingredients, which can cause large variations in active ingredient concentration in preparations purchased by a consumer.
Often unclear labeling
As there are no regulatory labeling requirements, the product labeling can sometimes be confusing. Often the St. John's wort extract is not standardized to a specific active ingredient. e.g. "Each tablet contains 425 mg of extract (as dry extract) from St John’s Wort (Hypericum perforatum L.) (3.5-6:1) (equivalent to 1490-2550mg of St John’s Wort)." . It is not clear from such a label whether the extract is standardized to contain a known percentage hypericum or hyperforin, whether the figure which should be compared for dosing purposes is the extract figure or the St. John's Wort figure, as well as a large potential variation in extract concentration (3.5-6:1).
Other medical uses
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.
A randomized controlled trial of St John's wort found no significant difference between it and placebo in the management of ADHD symptoms over eight weeks. However, the St John's wort extract used in the study, originally confirmed to contain 0.3% hypericin, was allowed to degrade to levels of 0.13% hypericin and 0.14% hyperforin. Given that the level of hyperforin was not ascertained at the beginning of the study, and levels of both hyperforin and hypericin were well below that used in other studies, little can be determined based on this study alone. 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.
A research team from the Universidad Complutense de Madrid (UCM) published a study entitled "Hypericum perforatum. Possible option against Parkinson's disease", which suggests that St John's wort has antioxidant active ingredients that could help reduce the neuronal degeneration caused by the disease.
St John's wort alleviated age-related long-term memory impairment in rats.
As an oil extract of the fresh flowers, St. John's wort is considered an anti-inflammatory and is traditionally used in the Balkans, in Italy, in Switzerland and in other countries as a topical treatment for ailments such as bruises, cracks, stretch marks and hemorrhoids.
Herb and flowers contain various polyphenols: flavonoids (epigallocatechin, rutin, hyperoside, isoquercetin, quercitrin, quercetin, I3,II8-biapigenin, amentoflavone, astilbin, miquelianin), phenolic acids (chlorogenic acid, 3-O-coumaroylquinic acid), and various naphtodianthrones: (hypericin, pseudohypericin, protohypericin, protopseudohypericin), phloroglucinols (hyperforin, adhyperforin). The naphthodianthrones hypericin and pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be the active components. It also contains essential oils composed mainly of sesquiterpenes.
The exact mechanism by which St John's wort functions is unclear and subject to conjecture. The St John's wort mechanism is believed to involve inhibition of serotonin (5‑HT) reuptake, much like the conventional selective serotonin reuptake inhibitor (SSRI) antidepressants. The major active antidepressive constituents in St John's wort are thought to be hyperforin and hypericin, although other biologically active constituents present, for example, flavonoids and tannins, may also be involved.
Hyperforin acts as a reuptake inhibitor of monoamines. This should not be confused with monoamine oxidase inhibitors (MAOIs), a separate class of antidepressants. Instead of inhibiting monoamine oxidase, hyperforin inhibits the reuptake of serotonin and somewhat norepinephrine and dopamine -acting as a monoamine reuptake inhibitor (MRI) including decreasing GABA and including increasing glutamate. According to one study, hyperforin content correlates with therapeutic effect in mild to moderate depression. It has been shown to inhibit the uptake of 5-HT and to a lesser extent norepinephrine and dopamine. Hyperforin also has affinity for GABA and glutamate transporters. On the other hand, a hyperforin-free extract of St John's wort (Ze 117 – Remotiv) may still have significant antidepressive effects.
Hypericin was initially believed to act as a monoamine oxidase inhibitor, but this has been disproved and it is currently believed that hypericin and other constituents of St. John's Wort act as monoamine reuptake inhibitors. 
Adverse effects and drug interactions
St John's wort is generally well tolerated, with an adverse effect profile similar to placebo. The most common adverse effects reported are gastrointestinal symptoms, dizziness, confusion, tiredness and sedation. It 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 P450 system in the liver.
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. Related to this, recent studies concluded that the extract reacts with light, both visible and ultraviolet, to produce free radicals, molecules that can damage the cells of the body. These can react with vital proteins in the eye that, if damaged, precipitate out, causing cataracts. This finding is contradicted by the results of another recent study, which found that St John's wort inhibits free radical production in both cell-free and human vascular tissue, revealing antioxidant properties of the compound.
St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzyme CYP3A4, but also CYP2C19. This results in the increased metabolism of those drugs, resulting in decreased concentration and clinical effect. The principal constituents thought to be responsible are hyperforin and amentoflavone.
St John's wort also has been shown to cause drug interactions through the induction of the P-glycoprotein (P-gp) efflux transporter. Increased P-gp expression results in decreased absorption and increased clearance of those drugs, which leads to lower clinical concentrations and 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|
For a complete list, see CYP3A4 ligands and CYP2C9 ligands. For further updating on interactions and appropriate management, see Herbological.com – St John's Wort Interactions table (outdated since 2005).
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, meperidine (pethidine), Levorphanol|
|CNS stimulants||Phentermine, diethylpropion, amphetamines, sibutramine, cocaine|
|Psychedelic drugs||Methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), psilocybin / psilocin, Mescaline and virtually every serotonergic psychedelic.|
|Others||Selegiline, tryptophan, buspirone, lithium, linezolid, 5-HTP dextromethorphan,|
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.
Livestock – forage poisoning
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.
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