Hypericum perforatum

St John's wort (IPA pronunciation:, rhyming with hurt, or ) used alone refers to the species Hypericum perforatum, also known as Klamath weed or Goat 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.

The plant
Hypericum perforatum is a yellow-flowering, rhizomatous, perennial herb indigenous to Europe, which has been introduced to the Americas 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 picture in the house during St John's day. The species name perforatum refers to the small windows in the leaves, 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. 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 eco-systems. 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 recognised by leaf and flower type. Yellow, five petalled flowers approximately 20mm across occur between October to January (Late Spring/Early Summer - Southern Hemisphere). Leaves exhibit obvious translucent dots when held up to the light, giving them a ‘perforated’ appearance, hence the plant's Latin name. When flowers 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 1m high. It has opposing, stalkless, narrow, oblong leaves which are 12mm long or slightly larger. The leaves are yellowish-green in color, with transparent dots throughout the tissue and occasionally a few black dots on the lower surface. St. John's wort's flowers are five-petaled, bright yellow with conspicuous black dots, and measure up to 2.5 cm across. They appear in 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
Lifecycle and Climatic Requirements St. John’s Wort has a complex lifecycle containing a mature plant cycle, and 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 1500m, rainfall less than 500mm and a daily mean January temperature greater than 24 degrees are considered limiting thresholds. Depending upon 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 plant to grow vegetatively following defoliation by insects or grazing.

Clinical signs
At 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 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. As Hypericum photosensitisation does not produce jaundice, hepatogenous photosensitization may be discounted. 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.

Medicinal uses of the herb
The first recorded use of Hypericum for medicinal purposes dates back to ancient Greece, and 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. The aerial parts of the plant can be cut and dried for later use in the form of herbal tea, which has long been enjoyed both for its pleasant, though somewhat bitter, taste and for its medicinal properties.

In modern medicine, standardized Hypericum extract (obtained from H. perforatum) is commonly used as a treatment for depression and anxiety disorders. In homeopathy, Hypericum is used in the treatment of numerous medical problems, yet the rate of success has not been adequately documented, as is very often the case in homeopathy. Historically, the flowers and stems of St John's wort have also been used to produce red and yellow dyes.

St John's wort is today most widely known as a herbal treatment for depression. In some countries, such as Germany, Hypericum is prescribed for mild depression far more commonly than synthetic antidepressant medication. In most countries, standardized extracts are available over the counter – usually in tablet or capsule form, and also in teabags and tinctures.

Clinical evidence
Clinical studies of St John's wort preparations have mainly focused on the efficacy of the herb in clinical depression. Several studies and meta-analyses have found it to be effective in the treatment of mild to moderate depression, with fewer side effects than many conventional antidepressants. Other studies, including a major NIH study that focused on moderate to severe depression, have shown no improvements.

Evidence for efficacy
An early meta-study indicated that extracts of Hypericum may be more efficacious than placebo for the treatment of mild to moderately severe depressive disorders. This study, which covered the results from 23 smaller, earlier studies, is perhaps the most often cited by manufacturers and other supporters of St. John's wort.

This study was later updated to include further studies, for a total of 27, to form a Cochrane Review. The updated review found that Hypericum preparations were significantly superior to placebo (rate ratio 2.47; 95% confidence interval 1.69 to 3.61) and similarly effective as standard antidepressants (single preparations 1.01; 0.87 to 1.16, combinations 1.52; 0.78 to 2.94).

Another meta-analysis, with stricter inclusion criteria, found that Hypericum was more efficacious than placebo; and as efficacious as tricyclic antidepressants, with fewer adverse drug reactions. This meta-analysis showed that the response rate for St. John’s wort was significantly greater than that for placebo (73.2 versus 37.9%, respectively, relative risk 1.48 and 95% CI 1.03–1.92) and similar to that observed with tricyclic antidepressants (64 versus 66.4% for St. John’s wort and tricyclic antidepressants, respectively, relative risk 1.11 and 95% CI 0.92–1.29).

Other, more recent trials have also shown greater efficacy than placebo, and comparable efficacy to standard antidepressants with a superior adverse effect profile.

Additionally, a 2006 study involving 150 patients with minor depressive symptoms or dysthymia found that St. John's Wort has a clinically significant effect in patients with minor depression, but not those suffering from dysthymia. It was concluded that St. John's Wort can be effective in the treatment of people with minor depression with a Hamilton Depression Scale for Depression (HAM-D) score of up to 17.

Evidence against efficacy for Major Depressive Disorder
A major study funded by the NIH in the United States, found that Hypericum extract of St John's wort was ineffective in treating moderate to severe cases of major depression (Hypericum Depression Trial Study Group, 2002). This study involved 340 patients, diagnosed with Major Depressive Disorder based on DSM-IV criteria and assessed using Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impression (CGI) scores. The trial was a multi-centre randomised double-blind placebo-controlled trial, comparing one preparation of St John's wort (Li 160) to the antidepressant, sertraline and to placebo. Li 160 proved no more effective than placebo in alleviating moderately severe major depression. Sertraline was also no better than placebo in this study, based on the primary outcome measure (the HAM-D).

Pharmacology
The exact mechanism by which St. John's wort &mdash; and even conventional antidepressants &mdash; function 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. It may thus be useful to review that information before using, particularly the complications. The link to the Prozac Product/Prescribing Information is provided below.

The major active 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 has also been found to have excellent antibacterial properties; in ultrapurified form a concentration of 0.1mg/ml kills methicillin-resistant forms of Staphylococcus aureus (MRSA) (quotation from wissenschaft-online, in German).

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. Discrepancies in the dose-response relationship imply that constituents other than hyperforin are likely to also be involved. Also, a hyperforin free extract of St John's wort (Ze 117 - Remotiv) has been shown to have significant antidepressive effects. Therefore current thinking is that the whole extract should be considered the "active ingredient" and that one or two constituents cannot explain the activity of the product.

Dosage and formulations
The dosage and content of St John's wort preparations vary greatly between formulations, because of variability in the plant source and preparation processes. The doses of St. John’s wort extract used in clinical trials generally range from 350 to 1800 mg daily (equivalent to 0.4 to 2.7 mg hypericin depending on the preparation). Because of the variable nature of herbal medicines, the clinical trial results using one product cannot be extrapolated to other products containing the same herb (just as a prize winning wine is not the same as everything else made from grapes). Only a handful of products made from St John's wort have been used in clinical studies (for example, Li 160 and Ze 117).

The recommended dosage for various forms of St John's wort as recommended by the British Herbal Medicine Association Scientific Committee (1983) are as follows:
 * dried herb: 2-4 g or by infusion three times daily
 * liquid extract 2-4 mL (1:1 in 25% alcohol) three times daily
 * tincture 2-4mL (1:10 in 45% alcohol) three times daily

In markets where standardised extracts are not available, the content of marketed products can vary widely. Some brands of over-the-counter St. John's wort can have a totally different chemical profile than others. The same can even be true of two dosage units from different batches of the same brand. Even where extracts are standardised it is debatable whether using hypericin as the standard is useful, since other constituents including hyperforin are biologically active. Therefore the best way to ensure reliable results is to use the products which have been used in the clinical trials.

As with other antidepressants, Hypericum should be taken for at least four weeks before its effectiveness can be properly assessed.

Adverse effects
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.

Since the St. John's wort mechanism is probably inhibition of Serotonin (5-HT) reuptake, much like the conventional SSRI antidepressants, it may be useful to review that information before using, particularly the complications. The link to the PROZAC Product Information is provided below.

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.

Some research shows that St John's wort may adversely affect fertility in both men and women.

St. John's wort does interact with birth control pills and may reduce the effectiveness of oral contraceptives. ,

Use caution when discontinuing use. While you may not notice positive effects while using St John's Wort, suddenly discontinuing use can be quite unpleasant.

Pharmacokinetic interactions
St John's wort has been shown to cause multiple drug interactions mainly 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.

Pharmacodynamic interactions
St John's Wort may also contribute to serotonin syndrome in combination with other drugs which may elevate 5-HT (serotonin) levels in the central nervous system (CNS).