St John's Wort



St John's wort (traditionally, now sometimes the spelling pronunciation ) is the plant species Hypericum perforatum, also known as Tipton's Weed or Klamath weed, but, with qualifiers, is used to refer to any species of the genus Hypericum. Therefore, H. perforatum is sometimes called Common St John's wort to differentiate it. The species of Hypericum have been placed by some in the family Hypericaceae, but more recently have been included in the Clusiaceae. Approximately 370 species of the genus Hypericum exist worldwide with a native geographical distribution including temperate and subtropical regions of North America, Europe, Asia Minor, Russia, India, and China.

St. John's wort is widely known as a herbal treatment for depression.

The plant
Hypericum perforatum is a yellow-flowering, stoloniferous or sarmentose, perennial herb indigenous to Europe, which has been introduced to many temperate areas of the world and grows wild in many meadows. The 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 traditional use of the plant to ward 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.

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 useful vegetation to the extent of making productive land unviable or acts as an alien species in natural 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.

Identification
St John’s wort can be visually recognized by leaf and flower type. Yellow, five petaled flowers approximately 20 mm across occur between late Spring and early to mid Summer. Leaves exhibit obvious translucent dots when held up to the light, giving them a ‘perforated’ appearance, hence the plant's Latin name. When flower buds (not the flowers themselves) or seed pods are crushed, a reddish/purple liquid is produced.

Botanical description
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 which 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. 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. The sepals are pointed, with glandular dots in the tissue. There are many stamens, which are united at the base into three bundles.

Ecology
St John’s wort has a complex life cycle that includes a mature plant cycle with vegetative and sexual reproduction. 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 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.

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

Medical 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, adolescents, and where cost is a concern. A report in the Cochrane Review states, 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 which 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. Standardized extracts are generally available over the counter, though in some countries (such as Ireland) a prescription is required. Extracts are usually in tablet or capsule form, and also in teabags and tinctures. Herbalists are more likely to use a fluid extract than a tincture.

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 twice lower than for newer SSRI antidepressants and five times lower than for older tricyclic antidepressants. However, this review also noted that studies more favourably supporting the effects of St. John's wort as an antidepressant, were predominantly from German-speaking countries. The authors could not rule out the possibility that some smaller studies from those countries were flawed and reported overoptimistic results.

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 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.

St. John's wort has not been found to be effective for patients suffering from dysthymia, a less severe and more chronic variety of depression.

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 constituent chemical, hyperforin, may be useful for treatment of alcoholism, although dosage, safety and efficacy have not been studied. Hyperforin has also been found to have antibacterial properties against gram-negative bacteria, although dosage, safety and efficacy has not been studied.

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.

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 this plant with antidepressant properties has antioxidant active ingredients that could help reduce the neuronal degeneration caused by the disease.

Recent evidence suggests that daily treatment with St. Johns wort may improve the most common physical and behavioural symptoms associated with premenstrual syndrome.

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.

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 which, if damaged, precipitate out causing cataracts.

Pharmacokinetic interactions
St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzyme CYP3A4, but also CYP2C9. This results in the increased metabolism of those drugs, resulting in decreased concentration and clinical effect. The principal constituent thought to be responsible is hyperforin.

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.

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.

Pharmacodynamic interactions
St John's wort may also contribute to serotonin syndrome, a potentially life-threatening adverse drug reaction, in combination with other drugs which may elevate 5-HT (serotonin) levels in the central nervous system (CNS).

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.

Chemical composition
Herb and flowers contain different polyphenols : flavonoids (rutin, hyperoside, isoquercetin, quercitrin, quercetin, I3,II8-biapigenin, amentoflavone, astilbin, miquelianin), phenolic acids (chlorogenic acid, 3-O-coumaroylquinic acid), different 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 contains also essential oils (composed mainly of sesquiterpenes).

Pharmacology
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.

Some believe that hyperforin is the major constituent responsible for antidepressant activity, and it has been shown to inhibit the uptake of 5-HT, dopamine, noradrenaline, GABA and glutamate. On the other hand, a hyperforin-free extract of St John's wort (Ze 117 - Remotiv) may still have significant antidepressive effects.

Clinical signs
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, head shaking, 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, possibly 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.

Early 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 are caused by photosensitisation. Plants may induce either primary or secondary photosensitisation: primary photosensitisation directly from chemicals contained in ingested plants, or 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, at high and continuous dose rates changes in blood plasma indicative of some liver damage have been observed. 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.

History
The first recorded use of Hypericum for medicinal purposes dates back to ancient Greece, and it has been used ever since. Hypericum was also used by Native Americans internally as an abortifacient and externally as an anti-inflammatory, astringent, and antiseptic.

Its use as an herbal tea has long been enjoyed.

The flowers and stems of St John's wort have also been used to produce red and yellow dyes.