Family: Hypericaceae Genus: Hypericum

Botanical Name: Hypericum Perforatum

Common: St. John's Wort, John's Grass, Klamath Weed

Other Hypericum species:

H. pyramidatum (Giant St. John's Wort)
H. glandulosum
H. humifussum
H. tetrapterum (Square stalked)
H. roeperanum
H. brasiliense
H. calycinum
H. chinese L
H. maculatum
H. tomentosum
H. bithynicum
H. balearicum
H. olympicum
H. patulum
H. hirsutum
H. revolutum
H. drummondii

St. John''s Wort, also known as Hypericum Perforatum, has a long history of medicinal usage. It's effect as a "tonic" for the nerves has been recorded as far back as the Roman period in Europe. ^{1 / 2} The name Wort is thought to be derived from the Old English word for plant. The origins of the designator "St. John" might be attributable to it's medicinal usage by the Knights of St. John in Jerusalem to heal the wounds of Crusaders or that it blooms around the Christian Feast of St. John.

It is a perennial, hardy plant that grows 1-3 feet tall, is shrub like, and has a woody root, lower stalk and branching, two-edged stems. Its composite leaves are green ovate to oblong and with reddish translucent subsurface oil glands. The 5-petaled flowers, arranged in terminal cymes, are bright yellow with multiple stamens and bloom from June through August. The sepals and petals are black dotted, frequently more so along the edges. The fruit is an ovate, three valvular capsule. Crushing the flowers produces a deep purple dye.

It grows throughout the United States, Australia and Europe in woods, open fields, and on the sides of roads. It grows especially well in lime rich soils. Other species of Hypericum grow throughout the world and most have a reputation as healing herbs. ^{3 / 4}

St. John's Wort also has a reputation as an invasive weed which can be harmful to livestock when ingested (see Toxicology and also, Adverse Effects) As such, considerable time and effort have been expended in efforts to control it's growth. In 1946, within the United States, the agricultural community introduced the Klamath weed beetle (Chrysolina quadrigemina) to biologically control this "weed". ⁵ Through this biological approach to control, the herb today is at an estimated 1% of its original population. ⁶ Problems arising from its toxic effects on livestock and tenacious growth have also caused it to become a vexation in Australia where it was introduced as a healing herb in the `1880's. ⁷

As a healing herb, the plant is thought to have been traditionally used for anxiety, depression, burns, wounds, bruises, nerve injuries, rheumatism, gout, jaundice, neuralgia, inflammation and ulcers. Usage in England can be traced back as far as the 1600's. With the onset of European colonization of America, it was discovered that the Native people of America also prescribed this herb for medicinal purposes. They are said to have used St. John's Wort for the treatment of diarrhea, fevers, snakebite, wounds and some skin problems. It was a common folk remedy in the 1800's for infection and inflammation, however, as with many herbs, it lost it's appeal by the early 1900's and further with the onset of antibiotics and modern allopathic medicine.

Though its popularity in America waned , its usage continued in Germany where it was used internally to treat depression, anxiety, nervous unrest and externally for contusions, myalgia, and first degree burns. The German Commission E recognized Hypericum Perforatum (dried above ground parts) as an approved herb in 1984. ⁸ It should be noted that though there are other species of Hypericum they are not mentioned in the Commission E monographs and very little medical research has been conducted on them to date.

Today, Hypericum Perforatum is a very common antidepressant sold in Germany, and there is speculation that it is prescribed four times more often than fluoxetine hydrochloride. ⁵ In the US for 1997, this herb was recorded as generating more than $45 million in sales annually. ⁸ Recently in America and due to it's increasing popularity ¹², the United States Pharmacopoeia/ National Formulary published a monograph and compendial standard for St. John's Wort ( November 15 ^th, 1998 - Ninth Supplement to the USP 23­NF 18 ) as part of it's Botanical monograph series. (Note: the USP was established in 1820 to create standards for the use and quality of pharmaceuticals and combined with the National Formulary in 1980). ^9/10

With this increase in popularity there is also a growing concern about the reliability of the St. John's Wort products being sold. In 1998, the Los Angeles Times conducted a study on the potency of 10 brands currently sold in America. Three of these products were reported as containing less than half the potency listed on its label (one tested as low as 20% of the listed potency). Four other brands had less than 90 percent of the potency listed. Only three brands contained the amounts listed on their labels. ¹¹ As the efficacy of the herb is dose dependent a subpotent product can be expected to be relatively ineffective.

Selling a standardized product is voluntary on the manufacturers part. Since it is thought that the quantity and composition of the bioconstituents and/or herb present effect the reliability and efficacy of a product, this is something to be aware of. The problem of inconsistent or incorrectly labeled product potency still exists. The correct genus and species, adulterations, absence of specific constituents, incorrect labeling, and labeling that lacks information should all be cause for care when purchasing any herbal product. It is often advisable to look for the U.S.P. notation on a product showing that the manufacturer follows standards established by the U.S. Pharmacopoeia.

Hypericum Perforatum has been favorably compared to numerous antidepressant drugs s.c. as amitriptyline, maprotiline, and imipramine. These studies have revealed equivalent results yet with reduced incident and severity of side effects. ^13/14/15 To date, there have been 23 randomized trials conducted which included 1757 patients with mild or moderate depressive disorders. The data collected and reviewed from these studies showed Hypericum extracts to be "significantly superior to a placebo" and "similarly effective as standard antidepressants". ¹⁸

Although its modes of action are not clearly understood, it's efficacy in the treatment of mild to moderate depression has been demonstrated. Unfortunately, it's therapeutic value for severe depression is still unknown. ¹⁷ The American Psychiatric Association started paying serious attention to St. John's Wort following their Toronto meeting held in 1998. Currently, new studies are being designed and conducted on it's effects in major depression. One "three-year study will test St. John's Wort against a standard serotonin reuptake inhibitor (SSRI) antidepressant and placebo in hundreds of patients. More than 50 of the nation's top psychiatrists competed for the 12 positions in the National Institute of Mental Health-sponsored study that began in July ." ¹⁹

Studies have also been conducted on its efficacy in treating seasonal affective disorder. In vitro investigations of Hypericum show possible antiviral activity. Also being reviewed is its usage in the enhancement of wound healing, as well as anti-inflammatory and analgesic activity. ¹⁶ (See Pharmacology and Clinical Studies)

St John's Wort is considered a safe herb and incidents of adverse reactions are rare however it is not recommended for allergic or photosensitive individuals. ^8/20

(See Adverse Reactions and also Contraindications).

Medicinal parts:

Though all parts of the plant leaves, stems and flowers may be used, the fresh flowers and tops are thought to have the most potency and are the parts approved for use by the German Commission E. St. John''s Wort yields its properties in water, ether, or alcohol. ⁸ It has been reported that the fresh flowers contain the highest concentrations of the constituent, Hypericin.

Biochemical Constituents -

Hypericum Perforatum:

St. John''s Wort''s full therapeutic potential has yet to be determined. Hypericin (a glycoside) was initially thought by many to be the main active constituent responsible for Hypericum''s success in treating depression. Current research, however, has shown that this may not be the case. Many believe that its abilities are derived from a number of other active ingredients. (See Pharmacology and Clinical Studies) Usually though, Hypericin content is still used when referring to standardized extracts.

Hypericum Perforatum:

(=)-Epicatechin, Brenzcatechin, Cadinene, Carotene, Carotenoids, Caryophyllene, Cery-Alcohol, Cineole, CIS-Trollixanthin, Emodinanthranol, Epicatechin, Flavonoids, Gurjunene. Hyperforin, Hypericins, Hypericodihydroanthrone, Hyperin, Hyperoside, Imanin, Isohypericin, Isoquercitrin, Isovaleric-Acid-Ester, Limonene, Lutein, Luteoxanthin, Mannitol, Methyl-2-Octane, Myrcene, N-Decanal, N-Nonane, N-Octanol, Novoimanin, Phenol, Phlobaphene, Phloroglucinol, Phytosterols, Pinene, Protohypericin, Protopseudohypericin, Provitamin-A, Pseudohypericodihydroanthrone, Pyrogallol, Quercetin, Quercitrin, Resorcynol, Rutin, Saponin, Tannins, Trollichrome, Violaxanthin ²¹

Multiple Hypericum Species

"Suspension cultures were established from the shoots of sterile germinated seeds of various provenances of seven Hypericum (H.) species in a half strength modified Murashige and Skoog liquid medium. In most strains of H. perforatum (18 provenances) and all strains of H. maculatum (6 provenances) as well as in the cultures of H. tomentosum, H. bithynicum, H. glandulosum and H. balearicum, hypericin and pseudohypericin could be proven, however, in extremely varying amounts. In general, the pseudohypericin content was significantly higher than that of hypericin. The flavonoid patterns, comprising monomeric quercetin derivatives and dimeric apigenin derivatives, varied among strains over a wide range." ²⁷
 
 

Other Hypericum species:

Hypericum roeperanum

"Four new xanthones have been isolated from the roots of Hypericum roeperanum. Their structures have been established by a combination of spectroscopic and chemical methods as 1,6-dihydroxy-5-methoxy- 4'',5''-dihydro-4'',4'',5''-trimethylfurano- (2'',3'':3,4)-xanthone (5-O- methyl-2-deprenylrheediaxanthone B), 1,6-dihydroxy-5-methoxy-6'',6''- dimethylpyrano-(2'',3'':3,4)-xanthone (5-O-methylisojacareubin), 1,3,5,6-tetrahydroxy-2-(2'',2''-dimethyl-4''-isopropenyl)-cyclopen tanylxanthone (5-O-demethylpaxanthonin) and 1,3,5,6-tetrahydroxy-4- trans-sesquilavandulylxanthone (roeperanone). In addition, 2- hydroxyxanthone, 5-hydroxy-2-methoxyxanthone, 1,5-dihydroxy-2- methoxyxanthone, 2-deprenyl rheediaxanthone B, isojacareubin and calycinoxanthone D have been isolated and characterized. Some of the isolated xanthones exhibited antifungal activity against Candida albicans." ²²

Hypericum brasiliense

"A new gamma-pyrone (hyperbrasilone), three known xanthones (1,5-dihydroxyxanthone, 5-hydroxy-1-methoxyxanthone and 6-deoxyjacareubin) and betulinic acid have been isolated from a dichloromethane extract of stems and roots of Hypericum brasiliense. Their structures were established by spectroscopic methods (UV, EI-MS, 1H and 13C NMR) and that of the gamma-pyrone was confirmed by X-ray crystallography. Hyperbrasilone and the xanthones were all antifungal against Cladosporium cucumerinum, while the three xanthones showed differing degrees of inhibition of monoamine oxidase A and B." ²³

"Three known phloroglucinols (japonicine A, uliginosin A and isouliginosin B) and a new phloroglucinol (hyperbrasiol A) have been isolated from a petrol extract of the leaves and flowers of Hypericum brasiliense. Their structures were established by spectroscopic methods (UV, DCI-MS, 1H and 13CNMR, includingSINEPT, HMBC, HSQC, DQFCOSY experiments). The substitution pattern of hyperbrasilol A was confirmed by X-ray crystallography. All four phloroglucinols were antibacterial against Bacillus subtilis in a TLC bioautographic assay. The flavonoids, kaempferol, luteolin, quercetin, quercitrin, isoquercitrin, hyperoside and guaijaverin, were isolated from a methanol extract of the same organs." ²⁴

Hypericum calycinum

"The new phloroglucinol derivative 1 has been isolated from the light petroleum ether extract of the aerial parts of Hypericum calycinum. Its structure has been established by means of 1H- and 13C-NMR spectroscopy and by nOe, MHQC, and HMBC experiments on its monomethyl ether derivative 3. Compound 1 was fungicidal against Cladosporium cucumerinum in a TLC bioassay. In addition, this new phloroglucinol derivative was also found to exert an interesting antimalarial activity in an in vitro test system." ²⁵

Hypericum japonicum

"A new antibiotic compound, sarothralin G from Hypericum japonicum Thunb.(Sarothra japonica) has been isolated and its structure was elucidated on the basis of spectroscopic data. The compound contains phloroglucinol and filicinic acid moieties." ²⁶
 

If taking St. John's Wort for treatment of Depression a delay in response may be experienced from the time you begin treatment to first signs of effect. With many antidepressants this delay can be three to four weeks in length. This is unknown in the case of St. John's Wort.

Lengths of administration are usually based on the severity of the symptoms and the type of problem.

To date, of 25 controlled therapy studies, dosages were typically between 300 to 900 mg total extract (usually hypericum extract LI 160) daily with the therapy duration lasting 2 to 6 weeks. ⁵⁴

TABLE 1 - Usual Dosage for Depression, Anxiety, Nervousness– Internal Use

TABLE 2 - Usual Dosage for External Usage

TABLE 3 – Teas/Infusion

Note:
" Patients receiving WS 5572 (5% hyperforin) exhibited the largest HAMD reduction, WS 5572 (5% hyperforin) was superior to placebo in alleviating depressive symptoms according to HAMD reduction (Mann- Whitney U-test: p = 0.004), whereas the clinical effects of WS 5573 (0.5% hyperforin) and placebo were descriptively comparable." ⁸⁰

"Clinical studies on the use of this plant for depression have utilized liquid tinctures and standardized solid extracts (0.3% hypericin--300 mg three times a day). Severe depression may also respond to this botanical, although it appears a larger dose is needed (600 mg solid extract three times a day)". ⁸¹

"For the analysis and improvement of the production procedure, the content of hypericin and pseudohypericin was measured experimentally. The drug material was extracted with different solvents and the yield was analyzed for each kind of solvent, its concentration and extraction temperature. Optimal yields were obtained with 80%methanol at temperatures of 80 degrees C." ¹⁶

No Information provided.

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74. Smyshliaeva AV, Nguyen LH, Kudriashov IuB: The Modification of a Radiation Lesion in Animals with an Aqueous Extract of Hypericum Perforatum L. 2 (Modifikatsiia luchevogo porazheniia zhivotnykh vodnym ekstraktom Hypericumperforatum L. Soobshchenie 2 )., Biol Nauki, 1992, (4), 9-13 (Published in Russian)
75. Smyshliaeva AV, Kudriashov IuB: The Modification of a Radiation Lesion in Animals with an Aqueous Extract of Hypericum Perforatum L. 1 (Modifikatsiia luchevogo porazheniia zhivotnykh vodnym ekstraktom Hypericumperforatum L. Soobshchenie 1)., Biol Nauki, 1992, (4), 7-9 (Published in Russian)
76. Okpanyi SN, Lidzba H, Scholl BC, Miltenburger HG: Genotoxicity of a Standardized Hypericum Extract (Genotoxizitat eines standardisierten Hypericum-Extraktes)., Arzneimittelforschung, 1990, Aug, 40(8), 851-5 (Published in German)
77. Kako MD, al-Sultan II Saleem AN: Studies of Sheep Experimentally Poisoned with Hypericum Perforatum., Vet Hum Toxicol, 1993, Aug,35,(4),298-300
78. Wagner H, Bladt S: Pharmaceutical Quality of Hypericum Extracts., J Geriatr Psychiatry Neurol, 1994, Oct, 7 Suppl 1, S65-8
79. Lewis WH: Medical Botany - Plants Effecting Man's Health, John Wiley & Sons, 1977, ISBN 0-471-53320-3
80. Harrer G, Schulz V: Clinical Investigation of the Antidepressant Effectiveness of Hypericum., J Geriatr Psychiatry Neurol, 1994, Oct, 7 Suppl 1,S6-8
81. Laakmann G, Schule C, Baghai T, Kieser M: St. John''s Wort in Mild to Moderate Depression: The Relevance of Hyperforin for the Clinical Efficacy., Pharmacopsychiatry, 1998, Jun,31 Suppl 1:54-9
82. Brinker F: Herb Contraindications and Drug Interactions., 1997, Eclectic Press, ISBN 0-9659135-0-3
83. Bove GM: Acute Neuropathy After Exposure to Sun in a Patient Treated with St John''s Wort [letter], Lancet, Oct 3, 352 (9134):1121-2
84. Woelk H, Burkard G, Grunwald J: Benefits and Risks of the Hypericum Extract LI 160: Drug Monitoring Study with 3250 Patients., J Geriatr Psychiatry Neurol, 1994, Oct,7 Suppl 1, S34-8
85. Kumper H: Hypericum Poisoning in Sheep (Hypericismus bei Schafen). Tierarztl Prax , 1989, 17 (3). 257-61 (Published in German)
86. Gullick R. et.al, Annals of Internal Medicine 1999;130:510-514.
87. Ernst E. The Lancet 354:2014-6, 11 Dec 1999
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"While studies suggest fewer adverse effects compared with conventional antidepressants, there have been several recent reports suggesting important drug interactions with OCs, warfarin, cyclosporin and theophylline. Hypericum-containing products appear to induce hepatic enzymes of the cytochrome P450 group. In each of the reported cases, the patient has been female, though more women than men take hypericum extracts. Levels of the coadministered agent were reduced in each case report, and all such agents are metabolised by the P450 enzymes. Four in-vitro studies indicate hypericum extracts are capable of inducing and approximately doubling cytochrome P450 activity. In one study involving human volunteers, area under the curve for phenprocoumon was markedly reduced when patients were pretreated with hypericum extract compared with placebo. In another similar study serum digoxin levels that were previously stable fell increasingly with number of days on coadministered hypericum extract. Last year there were reports of central serotonin excess in five patients taking SSRIs as well as hypericum extracts. Patients were elderly and in each case symptoms such as altered mental status, tremor, GI upset, headache, myalgia and restlessness were serious." ⁸⁷

• According to information available on herb interactions, St. John's Wort extracts should not be used while taking other prescription anti-depressants or narcotics without physician approval. ⁸²

• St. John's Wort may not be effective in severe depression (risk of suicide, inability to function, etc.) - no clinical data available.
• May cause phototoxicity, photsensitivity or photoallergy (See Adverse reactions) ^{45 86}
• No not use if pregnant (no clinical data available - there is some information available suggesting it may have emmenagogue and abortifacient effects) ⁸²
• Do not use if nursing (no clinical data available)
• Should not be used for children under the age of 2 years old (no clinical data available)
• Use only with physician approval if utilizing with children over the age of 2 years old.
• St. John's Wort, as with any herbal or prescription drug, may interact with other medications you are be taking. If taking other medications, please consult your physician.
• Taking St. John's Wort in conjunction with another antidepressant should be done under the advice of a physician. (See Drug Interactions)
• Like many antidepressants, it is w.s. to avoid alcohol consumption.
• St John's Wort has been proven to be poisonous in very large quantities to animals. Also, photsensitivity in animals had been demonstrated. (See Adverse reactions)
• Solutions of St. John's Wort may stain clothing and skin
• St. John's Wort may lower blood levels of indinavir (used in the treatment of AIDS) leading to treatment failure. (Lancet - Feb 2000)

USAGE IN PREGNANCY

Do not use if pregnant - Safety for use in pregnancy has not been established. - there is some information available suggesting it may have emmenagogue and abortifacient effects . ⁸²

General

The possibility of an allergic reaction (see Adverse effects) to the herb should be kept in mind during therapy. Symptoms of a reaction may take 12-24 hours before they manifest. If a reaction does occur, discontinue using the herb, consult your physician and stay out of the sun until the symptoms clear. Hypericin may trigger severe skin reactions in AIDs patients ⁸⁶

Laboratory Tests

You should always notify your physician when undertaking any herbal therapy for a prolonged period. It is always recommended that periodic assessments occur during any therapy, some of which may include laboratory testing.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in animals on Impairment of fertility and Carcinogenesis have not been adequately performed with this herb.

Mutagenic Potential

"St. John's Wort (Hypericum perforatum) contains hypericin and hypericin-like substances as well as flavonoids, of which particularly Quercetin has generated a wide-spread controversial discussion with respect to mutagenic action." Using standardized aqueous ethanolic hypericum extracts the genotoxicity was studied using in-vivo and in-vitro test systems with mamalian cells. " Both the in-vitro tests as well as the in-vivo tests--fur spot test of the mouse and the chromosome aberration test with the bone marrow cells of the chinese hamster—were negative, giving completely no indication of a mutagenic potential of Hypericum extract. These investigations lend support to the view that results from bacterial short-term tests are of very limited transferability to human." ⁷⁶

Pregnancy

No not use if pregnant - Safety for use in pregnancy has not been established. - there is some information available suggesting it may have emmenagogue and abortifacient effects. ⁸²

Labor and Delivery

Studies have not been conducted on the effect of this herb on Labor and Delivery therefore Extreme Caution should be taken and a physician consulted before usage.

Nursing Mothers

Studies in animals have not been performed with this herb. As many ingested substances are excreted in human milk, caution should be exercised and a physician consulted before using the herb while nursing.

Pediatric Use

Studies have not been conducted on the effect of this herb on children therefore Extreme Caution should be taken and a physician consulted before usage with children.

ANIMAL TOXICOLOGY

Mutagenic potential

"St. John's Wort (Hypericum perforatum) contains hypericin and hypericin-like substances as well as flavonoids, of which particularly Quercetin has generated a wide-spread controversial discussion with respect to mutagenic action." Using standardized aqueous ethanolic hypericum extracts the genotoxicity was studied using in-vivo and in-vitro test systems with mamalian cells. h" Both the in-vitro tests as well as the in-vivo tests--fur spot test of the mouse and the chromosome aberration test with the bone marrow cells of the chinese hamster—were negative, giving completely no indication of a mutagenic potential of Hypericum extract. These investigations lend support to the view that results from bacterial short-term tests are of very limited transferability to human." ⁷⁶

"Sheep given different dosages and frequencies of Hypericum perforatum had decreased hemoglobin, red blood cell count, packed cell volumes, total protein ,glucose, cholesterol, triglycerides, and serum alkaline phosphotase activities. Blood urea nitrogen, sodium, potassium, bilrubin (total and direct), and the activities of aspartate aminotransferase, alanine aminotransferase, lactatedehydrogenase and gamma glutamyltransferase increased. Hemato- biochemical assays were useful diagnostic a.d. to determine the severity of this plant''s toxic effects." ⁷⁷

Photosensitivity Disease (see also adverse effects)

"A report about a case of St. John's Wort poisoning in German Blackface sheep is given. After the ingestion of St. John''s Wort (Hypericum perforatum) all slightly pigmented parts of the skin, that were rarely covered with hair, were photosensitized. In summer many sheep suffered from inflammatory skin alterations at the ears, the bridge of the nose and at the surroundings of the eyes." ⁷⁸

• St. John's Wort is contraindicated in cases of genetic predisposition or history of photosensitivity.
• Due to it's photosensitizing effects it is not advised if undertaking ultraviolet or solarium treatments.
• It is contraindicated if currently taking an antidepressant unless otherwise specified by a physician.
• St. John's Wort, as with any herbal or prescription drug, may interact with other medications you are be taking. If taking other medications, please consult your physician.
• No not use if pregnant (no clinical data available - there is some information available suggesting it may have emmenagogue and abortifacient effects) ⁸²
• It has been suggested that foods or substances that interact with MAO or serotonin uptake inhibitors should be avoided. ⁸²
• Hypericin may trigger severe skin reactions in AIDs patients ⁸⁶

Pharmacodynamics:

General (See Studies listed in this section below):

It is not clear how Hypericum Perforatum works in its ability to treat some kinds of depression but there are several theories that are being investigated. One theory is that Hypericum Perforatum inhibits an enzyme called monoamine oxidase (MAO) and catechol methyl-transferase (COMT). Another is that it may raise the levels of a neurotransmitter called serotonin. Still another theory suggests that Hypericum lowers levels of the stress hormone cortisol or affects GABA receptors in the brain.

Along with the debate on it’s action is also the question of which constituent is responsible. Hypericin, pseudohypericin, amentoflavone, xanthones, and hyperforin are all being investigated as the possible active ingredient or combination of ingredients.

Studies:

Influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT

"The influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT, prepared in vitro from pork liver, were investigated in several concentration steps. An inhibition of MAO could be shown in the following concentrations (extract correlated to a mean molecular value of 500): hypericin to 10(-3) mol/L, hypericum total extract to 10(-4) mol/L, one extract fraction up to 10(-5). A COMT inhibition could not be shown for hypericin, with hypericum extract to 10(-4) mol/L and with two extract fractions also up to 10(-4) mol/L. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT- inhibition fraction being mainly flavonols and xanthones. The concentrations of inhibition shown might not be sufficient to explain the clinically proven antidepressive effect of hypericum particularly with regard to the inhibition of MAO activity." ²⁸

Inhibition of monoamine oxidase (MAO)

"The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as p.r. substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoids showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using p.r. hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition." ²⁹

Inhibits uptake of serotonin and norepinephrine:

"Because known mechanisms of antidepressant activity include inhibition of serotonin and/or norepinephrine uptake, we investigated the effects of standardized extracts of Hypericum LI 160 on the transport of these monoamine neurotransmitters into astrocytes, cells which surround synaptic terminals and regulate neurotransmission by means of their uptake systems. We found that LI 160 inhibited both serotonin and norepinephrine uptake in a dose-dependent manner. The two monoamine transport systems were affected differently by LI 160: for serotonin, the main effect was a 50% decrease in the rate of maximal transport, whereas for norepinephrine, the main effect was a 4.5 fold reduction in the apparent affinity of norepinephrine for its uptake sites. Upon removal of LI 160, uptake was restored, thereby indicating that the inhibition was not due to a toxic effect of Hypericum on the cells. These findings suggest that the ability of LI 160 to inhibit serotonin and norepinephrine uptake may underlie the antidepressant activity of this Hypericum extract." ³⁰

Hypericum extract causes a 50% inhibition (IC50 value) of serotonin uptake

"In the present study it is reported that the methanolic Hypericum extract LI 160 (Jarsin 300) exerts no protective effect against N- methyl-D-aspartate (NMDA-) or gp120- (from the HIV virus) induced cytotoxicity. Moreover, it is established that Hypericum extract causes no activation of arachidonic acid release from neurons activated by gp120; hence it displays no sensitization effect on the NMDA receptor channel. The main outcome of this study is the finding that Hypericum extract causes a 50% inhibition (IC50 value) of serotonin uptake by rat synaptosomes at a concentration of 6.2 microglml. Therefore it is concluded that the antidepressant activity of Hypericum extract is due to an inhibition of serotonin uptake by postsynaptic receptors. Future studies might focus on the effect of Hypericum extract on serotonin binding to neurons, serotonin storage in granules, the rate of synthesis of serotonin, and on the activity of monoamine oxidase." ³¹

Hypericum extract on the expression of serotonin receptors

"The influence of hypericum extract LI 160 on the expression of serotonin receptors was investigated using a neuroblastoma cell line to establish a model for the regulation of neurotransmitters by immunologically active compounds s.c. as cytokines. The cells were incubated with hypericum extract LI 160 in kinetic form for 2, 4, 6, 8, and 10 hours, then washed. The serotonin receptor expression analysis was compared to that of a placebo control solution. The neuroblastoma cells showed a clearly reduced expression of the serotonin receptors under treatment with hypericum extract. First stimulation experiments with interleukin-1 (IL-1) and hypericum extract suggest that a further reduction of the serotonin receptors is possible when IL-1 is added." ³²

MAO inhibitors and selective 5-HT reuptake inhibitors (SSRI) and alpha receptor binding:

"The present study examined the affinity of hypericin at 30 receptor or uptake sites; [At 1.0 microM] it inhibited less than 40% of specific radiolig and binding at all sites except mAChR and alpha receptors. The alpha receptor finding is novel and is a potentially important clue to the mechanism of action of St. John’s Wort, as these receptors have been found to have an association with the antidepressant action of synthetic agents s.c. as MAO inhibitors and selective 5-HT reuptake inhibitors (SSRI). Though the efficiency of St. John’s Wort as an antidepressant may be attributed to the concerted activity of several mechanisms, the affinity of hypericin for alpha receptors presents new possibilities for the cause of this extract’s clinical success." ³³

Photocytotoxic effect of pseudohypericin versus hypericin

" Pseudohypericin and hypericin, the major photosensitizing constituents of Hypericum perforatum, are believed to cause hypericism. Since hypericin has been proposed as a photosensitizer for photodynamic cancer therapy, the photocytotoxicity of its congener pseudohypericin has been investigated. The presence of foetal calf serum (FCS) or albumin extensively inhibits the photocytotoxic effect of pseudohypericin against A431 tumor cells, and is associated with a large decrease in cellular uptake of the compound. These results suggest that pseudohypericin, in contrast to hypericin, interacts strongly with constituents of FCS, lowering its interaction with cells. Since pseudohypericin is two to three times more abundant in Hypericum than hypericin and the bioavailabilities of pseudohypericin and hypericin after oral administration are similar, these results suggest that hypericin, and not pseudohypericin, is likely to be the constituent responsible for hypericism. Moreover, the dramatic decrease of photosensitizing activity of pseudohypericin in the presence of serum may restrict its applicability in clinical situations." ³⁴

Inhibition of benzodiazepine binding in vitro by amentoflavone

"Hypericum perforatum, H. olympicum, H. patulum, and H. hirsutum on the binding of radio labeled flumazenil to rat brain benzodiazepine bin"The effects of various constituents, including hypericin and amentoflavone, of flower and leaf extracts of ding sites of the GABAA receptor were studied in vitro. The results showed that amentoflavone, in contrast to hypericin, was a very active inhibitor of radio labeled flumazenil binding in vitro." ³⁵

Modulation of cytokine expression by hypericum extract

"The effect of hypericum extract LI 160 on the stimulated cytokine expression was investigated in vitro in a whole blood culture system. Blood samples were taken from five healthy volunteers and four depressive patients. The release of interleukin-6 (IL-6), interleukin- 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the interleukin-6 release was found for PHA-stimulated hypericum extract. Possible relations to the antidepressive effects of hypericum extract are discussed." ³⁶

Hypericum perforatum inhibits the binding of mu- and kappa-opioid receptor

"The effects of Hypericum perforatum extracts on in vitro [3H] naloxone binding to the human mu- and rat kappa-opioid receptors were studied in chinese hamster ovary (CHO) cells using the Semliki Forest virus (SFV) expression system. Binding of [3H] naloxone to the mu- and kappa-opioid receptor was inhibited in the presence of Hypericum extracts showing IC50 values of approximately 25 and 90 micrograms/ml, respectively. In contrast, extracts of Valeriana officinalis did not inhibit binding to the mu-opioid receptor. Also, single constituents of H. perforatum like the flavonoids quercetin and kaempferol and the glycosilated flavonoid quercitrin did not inhibit [3H]naloxone binding to the mu-opioid receptor up to a concentration of 10 microM. The present in vitro data may suggest a new possible mechanism for the anti-depressant effect of H. perforatum." ³⁷

Significant increase in 3-methoxy-4-hydroxyphenylglucol

"A monotherapy with the active hypericine complex (Psychotonin M). In all patients there was a significant increase in 3-methoxy-4-hydroxyphenylglucol which is considered an expression of a beginning antidepressive reaction." ³⁸

Inhibition of some phosphorylation involved by protein kinase C

"In the course of screening specific inhibitors of protein kinase C we have found that both compounds specifically inhibit protein kinase C with IC50 values 1.7micrograms/ml and 15 micrograms/ml, respectively, and show anti-proliferative activity against mammalian cells. These data suggest that antiretroviral activity of hypericin and pseudohypericin could be attributable to the inhibition of some phosphorylation involved by protein kinase C during viral infection of cells." ³⁹

Immunotropic activity

"We carried out a systematic study of immunotropic activity of John''s Wort on the level of integrated fractions including all basic active substances of this plant. Both types of substances capable of increasing and suppressing the immunity were found in John''s Wort. Polyphenol fraction exhibits the immunostimulating activity with respect to the system of mononuclear phagocyte system, cellular and humoral immunity, and is capable of recovering the immune response in conditions of high-zone tolerance. Lipophilic fraction of this plant exhibits immunosuppressing properties with respect to cellular and humoral immune response. Immunotropic activity of polyphenol and lipophilic fractions correlate with their low toxicity. " ⁴⁰

Inhibition of cellular phosphodiesterase

"Characterization of the main components of each fraction was performed by UV- and mass spectroscopy. Their biological activity was tested in porcine isolated coronary arteries. All PC fractions antagonized histamine- orprostaglandin F2 alpha-induced arterial contractions. In contrast, vasorelaxation was insignificant in KCl-precontracted coronary arteries except with the higher oligomeric PC fraction 3. Vasoactive properties of the PC seem to be dependent on their relative molecular mass. An inhibition of cellular phosphodiesterase might be involved in the underlying mechanism of action." ⁴¹

Pharmacokinetics

" After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 h, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively.". "Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed.." ⁴²

Single-dose and steady-state pharmacokinetics of hypericin (H) and pseudohypericin (PH) were studied in 13 healthy volunteers by administration of St. John''s Wort extract LI 160. " Both H and PH were initially distributed into a central volume of 4.2 and 5.0 liter, respectively. The mean distribution volumes at steady state were 19.7 liters for H and 39.3 liters for PH, and the mean total clearance rates were 9.2 ml/min for H and 43.3 ml/min for PH. The systemic availability of H and PH from LI 160 was roughly estimated to be 14 and 21%, respectively." ⁴³
 

12 healthy male subjects were studied forsingle and multiple-dose pharmacokinetics of the naphthodianthrones hypericin and pseudohypericin derived from St. John''s Wort (Hypericum perforatum, LI 160, Lichtwer Pharma GmbH, Berlin). Single oral doses of 300, 900, or 1800 mg of dried hypericum extract (250, 750, or 1500 micrograms hypericin and 526, 1578, or 3156 micrograms pseudohypericin)were given. Serum half lives of hypericin measured were 24.8 to 26.5 hours, and varied for pseudohypericin from 16.3 to 36.0 hours. ⁴⁴

 In 25 HIV infected patients IV synthetic Hypericin exhibited the following pharmacokinetic properites:

Area under the curve (AUC) : 26 +/- 5.0 mcg/hr/ml following .25mg/kg IV with peak levels of 4.2 +/- 1.1 mcg/ml and an elimination half lifeIn of 23.7 +/- 7.3 hours. ⁴⁵

Clinical Studies:

Depression:

Hypericum Perforatum has been favorably compared to numerous antidepressant drugs s.c. as amitriptyline, maprotiline, and imipramine. These studies have revealed equivalent results yet with reduced incident and severity of side effects. ^13/14 /15 To date, there have been 23 randomized trials conducted which included 1757 patients with mild or moderate depressive disorders. The data collected and reviewed from these studies showed Hypericum extracts to be "significantly superior to a placebo" and "similarly effective as standard antidepressants". ¹⁸

" In a randomized, double-blind, placebo-controlled, multicenter study, the clinical efficacy and safety of two different extracts of St. John''s Wort were investigated in 147 male and female outpatients suffering from mild or moderate depression according to DSM-IV criteria. Following a placebo run-in period of three to seven days, the patients were randomized to one of three treatment groups: During the 42-day treatment period, they received 3 x 1 tablets of either placebo, Hypericum extract WS 5573 (300 mg, with a content of 0.5% hyperforin), or Hypericum extract WS 5572 (300 mg, with a content of 5% hyperforin)." "…These results show that the therapeutic effect of St. John''s Wort in mild to moderate depression depends on its hyperforin content." ⁵⁵

A systematic review and meta-analysis of 23 randomized trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders was carried out. "Hypericum extracts were significantly superior to placebo (ratio =2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78to 2.94)." ⁵⁶

"…The main outcome of this study is the finding that Hypericum extract causes a 50% inhibition (IC50 value) of serotonin uptake by rat synaptosomes at a concentration of 6.2 mcg/ml. Therefore it is concluded that the antidepressant activity of Hypericum extract is due to an inhibition of serotonin uptake by postsynaptic receptors. Future studies might focus on the effect of Hypericum extract on serotonin binding to neurons, serotonin storage in granules, the rate of synthesis of serotonin, and on the activity of monoamine oxidase." ⁵⁷

The excretion of urinary metabolites of noradrenaline and dopamine was measured after a monotherapy with the active hypericine complex (Psychotonin M).in 6 women aged 55-65 years. " In all patients there was a significant increase in 3-methoxy-4-hydroxyphenylglucol which is considered an expression of a beginning antidepressive reaction" Clinical improvement over a 4-6 wek period was also demonstrated. ⁵⁸
 

"Hypericum extract enhanced the exploratory activity of mice in a foreign environment, significantly prolonged the narcotic sleeping time dose-dependently, and within a narrow dose range exhibited reserpine antagonism. Similar to most other antidepressants, hypericum extract enhanced significantly the activity of mice in the water wheel test and after a prolonged daily administration decreased aggressiveness in socially isolated male mice." ⁵⁹

97 outpatients were treated with 100-120 mg hypericum extract bid In a multicenter, placebo-controlled double-blind trial to measure the effects of a hypericum concentrate. "Treatment resulted in an appreciable improvement in the symptoms of depression, and the 70% response rate (n = 43), corresponded to that of chemical antidepressants. The preparation also showed an anxiolytic effect. The substance was extremely well tolerated, and no side-effects were reported by any of the patients." ⁶⁰

66.6 % of St.John''s Wort treated outpatients with mild to moderately severe depression showed an improved response as compared to 26.7% of placebo treated patients. ⁶¹

In a double-blind study with either 3 x 300 mg hypericum extract or placebo with 105 outpatients with mild depressions of short duration the patients receiving the extract showed statistically significant improvement in symptoms over placebo. ⁶²

Studying sleep polysomnograms of healthy subjects given Hypericum perforatum the authors concluded that the mechanism of action of St. John''s Wort may be similar to that of conventional antidepressant medications. ⁶³

Several other studies also reported signifcant differences between St John''s Wort and placebo with comparable efficacy to tricyclic antidepressants with very few side effects ^{15 64 65 66}

SAD

A controlled single-blind study of seasonal affective disorder (SAD) diagnosed patients showed equal efficacy between hypericum (900mg/d) and bright light therapy, which has become the standard for this type of depression. The authors suggest that hypericum " may be an efficient therapy in patients with seasonal affective disorder. " ⁶⁷

Baldness
Topically applied extract of St.John''s Wort is being investigated for the potential treatment of alpecia (baldness). ⁶⁸

Antioxidant