Medical Attributes of St. John’s Wort

35 Medical Attributes of St. John’s Wort

(Hypericum perforatum)

Kenneth M. Klemow, Emily Bilbow, David Grasso, Kristen Jones, Jason McDermott, and Eric Pape Wilkes University Wilkes-Barre, Pennsylvania, U.S.A.

I. INTRODUCTION St. John’s wort, known botanically as Hypericum perforatum, is a sprawling,

leafy herb that grows in open, disturbed areas throughout much of temperate North America and Australia. St. John’s wort has been used as an herbal remedy to treat a variety of internal and external ailments since ancient Greek times. Since then, it has remained a popular treatment for anxiety, depression, cuts, and burns. Sales of products made from St. John’s wort presently exceed several billion dollars each year.

St. John’s wort produces dozens of biologically active substances, two being the most clinically effective. Hypericin and its naphthodianthrone analogs are produced by small, dark glands on the surfaces of the yellow petals, constituting 0.1–0.3% of the dry mass of the foliage. Hyperforin is a lipophilic phloroglucinol derivative derived from the buds and flowers, constituting 2–4.5% of the mass of the foliage.

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H. perforatum has been intensively studied on isolated tissue samples, using animal models, and through human clinical trials. The effectiveness of St. John’s wort as an antidepressive agent has been particularly well studied. At the cellular level, hypericin and hyperforin both inhibit uptake of key neurotransmitters like serotonin (5-HT), dopamine, noradrenaline, GABA, and L -glutamate at the synaptic cleft in the brain. Hyperforin may also increase the density of 5-HT receptors, thus providing potential long-term benefits.

Meta-analyses of clinical trials conducted in Europe since the 1980s in- dicated that St. John’s wort was more effective in alleviating depression than placebo. Moreover, St. John’s wort was shown to be as effective in treating depression as standard tricyclic synthetic drugs—with fewer adverse effects. However, two multicenter studies conducted in the United States between 1998 and 2001 did not find any difference between St. John’s wort and pla- cebo, especially in patients with moderate to severe depression. Taken together the studies indicate that St. John’s wort appears to have some effi- cacy in treating mild to moderate depression, but no proven value in treating moderate to severe depression.

St. John’s wort has value as an antibacterial and antiviral agent. Hyper- forin is particularly active against gram-positive bacteria, including metic- illin-resistant and penicillin-resistant Staphylococcus aureus. Extracts have been shown to be active against enveloped viruses, especially when activated by light. In the 1990s, St. John’s wort was examined as a therapy for HIV, though a Phase I clinical trial published in 1999 indicated no discernible effect coupled with low tolerability.

Both hyperforin and hypericin show potential as anticancer therapies. Hyperforin inhibits tumor cell growth in vitro by induction of apoptosis through the activation of caspases. In the presence of light and oxygen, hy- pericin kills tumors by generating superoxide radicals that yield cytotoxic species. Hypericin has potential to be used in photodynamic therapy (PDT) against a variety of neoplastic tissues. However, St. John’s wort extracts may interfere with the success of treatments involving the anticancer agent irinotecan.

Though generally well tolerated, especially at typically recommended doses, St. John’s wort may produce adverse effects including gastrointestinal symptoms, dizziness, confusion, restlessness, and lethargy. More significant- ly, St. John’s wort can interact adversely with a wide range of prescription and over-the-counter medications, as well as with other herbal remedies. Espe- cially noteworthy are adverse interactions with standard antidepressants, and with drugs that are metabolized by hepatic cytochrome enzymes. Individuals taking other medications or suffering from moderate to severe psychological or physical ailments should consult with their physician before taking extracts of St. John’s wort.

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II. SPECIES DESCRIPTION

H. perforatum , commonly called the common St. John’s wort, klamathweed, tiptonweed, goatweed, and enolaweed (1), is a native of Europe, but has spread to temperate locations in Asia, Africa, North and South America, and Australia (2,3). It thrives in poor soils, and is commonly found in meadows, fields, waste areas, roadsides, and abandoned mines and quarries (1,2,4).

Individuals of St. John’s wort are freely branching perennials that typically range from 40 to 80 cm tall (Fig. 1) (1,2). The stems are herbaceous, though the bases are somewhat woody. The stems and branches are densely covered by oblong, smooth-margined leaves that range from 1 to 3 cm long and 0.3 to 1.0 cm wide. The leaves are interrupted by minute translucent spots that are evident when held up to the light. The upper portions of mature plants can produce several dozen five-petaled yellow flowers that are typically 1.0–

F IGURE 1 Diagram of St. John’s wort, Hypericum perforatum. (Image from http://www.thorne.com/altmedrev/hypericum.jpg.)

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2.0 cm wide. The edges of the petals are usually black-dotted. Crushed flowers produce a blood-red pigment. By late summer, the flowers produce capsules that contain dozens of tiny dark-brown seeds. St. John’s wort reproduces both by seed and by ground-level rhizomes.

Because of concerns over phototoxicity to livestock, H. perforatum is listed as a noxious weed in seven western states in the United States. Programs promoting its eradication are underway in Canada, California, and Australia. Some of those measures include use of the Chysolina beetle, which is a natural predator (3).

III. HERBOLOGY St. John’s wort was been considered to be a medicinally valuable plant for

over 2000 years. The first-century Greek physicians Galen, Dioscorides, and Hippocrates recommended it as a diuretic, wound-healing herb, as a treat- ment for menstrual disorders, and as a cure for intestinal worms (3,5). In the sixteenth century, the Swiss herbalist Paracelsus used St. John’s wort exter- nally to treat wounds and alleviate pain (3).

The species gained a reputation during the Middle Ages as having mystical properties, and plants were collected for use as a talisman to protect one from demons and to drive away evil spirits. According to legend, the greatest effect was obtained when the plant was harvested on St. John’s day (June 24th), which is often the time of peak blooming (3). The generic name Hypericum originated from the Greek name for the plant ‘‘hyperikon.’’ Literally translated, the name is an amalgamation of the root words ‘‘hyper’’ (meaning ‘‘over’’) and ‘‘eikon’’ (meaning ‘‘image’’) (3), though its meaning is less clear.

St. John’s wort’s use as a medicinal herb continued in Europe through- out the nineteenth and twentieth centuries. It was commonly made into teas and tinctures for treatment of anxiety, depression, insomnia, water retention, and gastritis. Externally, vegetable oil preparations have been used for treatment of hemorrhoids and inflammation. Others have used St. John’s wort extracts to treat sores, cuts, minor burns, and abrasions, especially those involving nerve damage (3,6,7).

St. John’s wort enjoys a worldwide reputation as having therapeutic value for treating depression and other mood disorders. Products containing St. John’s wort in the form of tablets, capsules, teas, and tinctures accounted for $400 million in sales in 1998 in the United States (8) and an estimated $6 billion in Europe (8,9).

As noted by Barnes et al. (10), St. John’s wort has been the subject of several pharmacopoeias and monographs, including the British Herbal Pharmacopoeia (11); European Scientific Cooperative on Phytotherapy

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(ESCOP) (12); American Herbal Pharmacopoea (13); Parfitt (14); Barnes et al. (15); and the European Pharmacopoeia (16).

Pharmaceutical-grade preparations of St. John’s wort are typically comprised of dried aerial parts. One widely available extract that is commonly used in clinical trials, LI 160, is produced by Lichtwer Pharma. It is standardized to contain 0.3% hypericin derivatives, and normally comes in 300-mg capsules (17). A second preparation, Ze 117 (Zeller AG, Switzerland), is a 50% ethanolic extract with an herb to extract ratio of 4–7:1. The hyperforin content of Ze 117 is 0.2%, lower than that of LI 160, whose hyperforin content ranges between 1 and 4%. The dosage of Ze 117 is 500 mg/ day (18). The German Commission E and ESCOP monographs recommend 900 mg of standardized extract per day (7,12). Clinical trials using various H. perforatum preparations have typical dosages in the range of 300–1800 mg/ day (10).

In the United States, St. John’s wort (like all herbal remedies) is listed as

a dietary supplement by the U.S. Food and Drug Administration (FDA). Therefore, it is not subject to strict scrutiny for safety and efficacy that standard pharmaceutical drugs must pass. The FDA mandates that all herbal remedies must contain a disclaimer informing the consumer that any claims about therapeutic value have not been evaluated by that agency.

IV. CHEMICAL CONSTITUENTS Chemical investigations into the constituents of H. perforatum have detected

several classes of compounds. The most common classes include naphtho- dianthrones, flavonoids, phloroglucinols, and essential oils (10,19–21). The major active constituents are considered to be hypericin (a naphtodianthrone; Fig. 2a), hyperforin (a phloroglucinol; Fig. 2b), rutin and other flavonoids, and tannins (10). Approximately 20% of extractable compounds are consid- ered biologically active, according to standard bioanalytical techniques (22– 24).

A. Naphthodianthrones The most researched class of compounds isolated from H. perforatum is the

naphthodianthrones, which occur in concentrations ranging from 0.1% up to 0.3% (9,25,26). The most common naphthodianthrones include hypericin, pseudohypericin, isohypericin, and protohypericin (10,21). Of those, hyper- icin is the best known and, to date, the most studied. Hypericin is a reddish pigment that is responsible for the red color of St. John’s wort oils. Hypericin is found in greatest abundance in the flowers, particularly in the black dots that are located on the petals of St. John’s wort flowers (3).

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F IGURE 2 Structures of chemically active constituents of St. John’s wort, Hypericum perforatum. (a) Hypericin—a naphtodianthrone found primarily in the black dots on the flower petals. (b) Hyperforin—an acylated phloroglucinol typically derived from buds and flowers.

Hypericin is highly photoreactive, owing to its chemical structure. Biochemically, hypericin is a polycyclic quinone, having four hydroxyl groups that lie adjacent to two carbonyl groups (Fig. 2a). Owing to resonance of the molecule and the relatively short distance between oxygens (f2.5 ang- stroms), the hydroxyl hydrogen is able to transfer back and forth from the hydroxyl oxygen to the carbonyl oxygen when in the presence of fluorescent light (27). Therefore, the hydrogen is in constant flux between both oxygens when under fluorescent light (28). Studies examining the fluorescence spec- trum of hypericin and its analogs have demonstrated the existence of a ‘‘protonated’’ carbonyl group, therefore proving the H-atom transition (27). This hydrogen transfer causes acidification of the surrounding environ- ment (29,30).

B. Flavonoids Flavonoids found in H. perforatum range from 7% in stems to 12% in flowers

(21) and leaves (9). Flavonoids include flavonols (kaempferol, quercetin), flavones (luteolin), glycosides (hyperside, isoquercitrin, rutin), biflavonoids (biapigenin), amentoflavone, myricetin, hyperin, proanthocyanidins, and miquelianin (10,20). Rutin concentration is reported at 1.6% (10).

C. Lipophilic Compounds Extracts of St. John’s wort contain several classes of lipophilic compounds,

including phloroglucinol derivatives and oils, that have potential or demon- strated therapeutic value. Acylated phloroglucinols are typically derived from

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buds and flowers of H. perforatum (16). Hyperforin, found in concentrations of 2–4.5% (9,31), consists of phloroglucinol expanded into a bicyclo (2,1) nonaendionol, substituted with several lipophilic isoprene chains. Other phloroglucinols include adhyperforin (0.2–1.9%), furohyperforin, and other hyperforin analogs (9,10,21,32).

Essential oils are found in concentrations ranging from 0.05% to 0.9% (9). They consist mainly of mono and sesquiterpines, mainly 2-methyl-octane, n-nonane, a- and h-pinene, a-terpineol, geranil, and trace amounts of myrecene, limonene, caryophyllene, and others (20,32).

D. Additional Compounds Other compounds of various classes have been determined to occur in H.

perforatum . These include tannins (concentrations vary from 3% to 16%), xanthones (1.28 mg/100 g), phenolic compounds (caffic acid, chlorogenic acid, and p-coumaric acid), and hyperfolin. Other compounds include acids (nico- tinic, myristic, palmitic, stearic), carotenoids, choline, pectin, hydrocarbons, and long-chain alcohols (21). Amino acids that occur include cysteine, GABA (g-aminobutyric acid), glutamine, leucine, lysine, and others (9,19,32).

V. THERAPEUTIC USES OF ST. JOHN’S WORT The widespread popularity of St. John’s wort’s use as an herbal remedy results

from studies that appear to verify its efficacy, especially in treating mild to moderate depression. In return, its use has generated widespread interest among scientists seeking to firmly evaluate its effectiveness. Such studies have included in vitro analyses on the effects of St. John’s wort extracts on isolated tissue samples, studies using animal models, and clinical analyses and meta- analyses of humans given St. John’s wort extracts. Comprehensive reviews of the research on St. John’s wort have been recently prepared by Greeson et al. (9) and Barnes et al. (10).

A. St. John’s Wort and Depression Mood disorders are common illnesses that force individuals to seek relief by

physicians and other health care providers. Worldwide, 3–5% of the world’s population requires treatment for depression (33). The disorder brings with it

a series of symptoms such as strong feelings of sadness and guilt, a loss of interest or pleasure, irregular sleeping patterns, a loss of energy, the decreased ability to concentrate, and an increase or decrease of appetite. Even more serious symptoms are repeating thoughts of suicide and death (34).

Depression is often viewed as originating from a disruption of the normal brain neurochemistry. A primary cause is a deficiency of amine neuro-

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transmitters like acetylcholine, norepinephrine, dopamine, and serotonin [5- hydroxytryptamine (5-HT)]. Drugs used to treat depression typically raise the levels of those neurotransmitters, especially in nerve-nerve synapses (34).

Synthetic antidepressants widely used today fall into two categories: tricyclics and selective serotonin reuptake inhibitors (SSRIs). Tricyclics include amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofra- nil), nortriptyline (Aventyl, Pamelor), and trimipramine (Surmentil). Com- monly prescribed SSRIs include citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). A third category of antidepres- sants, not as commonly used as the tricyclics and SSRIs, are the monoamine oxidase inhibitors (MAOI) such as phenelzine (Nardil) and tranylcypromine (Parnate) (35).

1. Active Principles—In Vitro Studies Early research suggested that hypericin was the main antidepressant constit-

uent of H. perforatum. Those studies attributed hypericin’s mode of action as increasing capillary blood flow (21). Later, studies on rat brain mitochondria found hypericin to be a strong inhibitor of the enzyme of monoamine oxidase (MAO) A and B (10,25,36). MAO is involved in the degradation of amine neurotransmitters, and inhibiting their degradation boosts their levels in the synapse. However, further studies determined that the ability of hypericin to act as an inhibitor of MAO was not as high as originally estimated. Moreover, the levels of hypericin necessary to obtain significant MAO inhibition were far greater than those likely to be found in human brain tissue at normal doses (36,37). Hypericin has been shown to have a strong affinity for sigma receptors, which regulate dopamine levels. It also acts as a receptor antagonist at adenosine, benzodiazepine, GABA-A, GABA-B, and inositol triphosphate receptors, which regulate action potentials caused by neurotransmitters (37,38). While hypericin has been shown to have antidepressant properties, current thought is that hypericin alone cannot completely account for the antidepressant activity of St. John’s wort.

Much recent research has focused on hyperforin as an active compound in the antidepression pharmacology (39). Hyperforin has been demonstrated to be a potent reuptake inhibitor of serotonin, dopamine, noradrenaline,

GABA, and L -glutamate from the synaptic cleft (21,40–43). IC 50 values (concentration resulting in 50% inhibition) of about 0.05–0.1 Ag/mL for neurotransmitters were reported in synaptosomal preparations (44). Blocking reuptake of serotonin (5-HT) from the synaptic cleft would alleviate symp- toms of depression by allowing the serotonin to bind 5-HT receptors and elicit

a greater response (45,46). Studies show that hyperforin inhibits serotonin reuptake by elevating intracellular Na + levels (47,48). This is the first specific serotonin reuptake inhibitor (SSRI) known to do this. More recently, Mu¨ller

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et al. (42) found that hyperforin is associated with changes of ionic conduct- ance pathways.

Hyperforin has a second, and possibly additive, effect, by increasing the number of 5-HT receptors, as demonstrated in studies on the brains of rats (49). Studies have shown that the density of 5-HT receptors increased by 50% over controls in the brains of rats treated with St. John’s wort extract (49). This suggests a possible long-term therapeutic benefit of St. John’s wort treatment. Results of clinical trials also demonstrated that the level of therapeutic effects of St. John’s wort extract is directly dependent on the concentration of hyperforin (50). Despite those findings, therapeutic effects of St. John’s wort extracts may depend on other constituents besides hypericin or hyperforin (31). This is still a topic of debate among St. John’s wort advocates.

2. Clinical Studies Clinical studies of the effectiveness of St. John’s wort have been conducted

since the 1980s. Some of the studies have compared populations receiving St. John’s wort to controls. Others have compared populations receiving St. John’s wort to those receiving standard antidepressants. Other studies are three-legged, comparing populations receiving St. John’s wort to a second population receiving a standard antidepressant and a third receiving a placebo. Excellent reviews of the clinical literature through 2001 have been provided by Greeson et al. (9) and Barnes et al. (10).

Several meta-analyses, integrating the results of numerous studies mostly performed in Germany, have been conducted to help gain a broader perspective on the efficacy of St. John’s wort (51–53). A study prepared by Linde and Mulrow (53) was published as a Cochrane Review, and has received considerable attention from individuals researching St. John’s wort. Using computerized searches of several databases, Linde and Mulrow investigated whether extracts of Hypericum were more effective than placebo and as effective as standard antidepressants in the treatment of depressive disorders in adults, and whether they have fewer side effects than standard antidepressant drugs. To be included in their analysis, trials had to be randomized; include patients with depressive disorders; compare prepara- tions that included St. John’s wort with placebos or other antidepressants; and include an objective clinical assessment of symptoms. The Linde and Mulrow analysis included 27 trials containing a total of 2291 patients who met inclusion criteria. Seventeen trials with 1168 patients were placebo-con- trolled, while 10 with 1123 patients compared Hypericum with other antide- pressant or sedative drugs. Most trials were 4–6 weeks long. Participants usually had ‘‘neurotic depression’’ or ‘‘mild to moderate severe depressive disorders.’’ Linde and Mulrow (53) found that preparations containing H.

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perforatum extracts were significantly superior to placebo and as effective as standard antidepressants. Only 26.6% of the patients taking Hypericum single preparations reported side effects, compared to 44.7% given standard anti- depressants. Based on that evidence, the authors concluded that extracts of Hypericum are more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. However, they felt that the evidence was inadequate to establish whether Hypericum is as effective as other antidepressants, and suggested that additional studies be done (53).

Barnes et al. (10) reported on seven additional clinical studies examining mono-preparations of St. John’s wort. Two compared St. John’s wort against

a placebo. Three studies compared St. John’s wort against each of one standard antidepressant including fluoxetine, sertraline, and imipramine. One study compared St. John’s wort to both a placebo and imipramine. St. John’s wort extracts were standard preparations, including LI 160, ZE 117, WS 5572, WS 5573, and LoHyp-57. Dosages varied from 500 to 900 mg/day, and typically ran for 6 weeks. Outcomes were assessed by objective criteria, typically through a Hamilton Depression Scale. In general, patients receiving St. John’s wort extracts reported a higher reduction in depression scores than those taking the placebo. Likewise, studies comparing St. John’s wort to standard antidepressants found little difference between the two. Fewer side effects were reported among the St. John’s wort group than the group taking the synthetic antidepressants. One of the studies, conducted by Laakmann et al. (50), found that individuals receiving preparations containing 5% hyper- forin responded better than those receiving 0.5% hyperforin or a placebo. Reports of adverse events were similar among the three groups, however.

Barnes et al. (10) note that the trials comparing St. John’s wort to synthetic antidepressants have been criticized because the dosages of the latter were unrealistically low (54). Other criticisms [e.g., Spira (55)] point to the study’s usage of somewhat outdated tricyclics and a short (6-week) duration of the analysis. Barnes et al. (10) acknowledged that trials comparing St. John’s wort to more modern SSI antidepressants were also needed.

Two recent studies conducted in the United States did not support the idea that St. John’s wort is effective in treating moderate to major depression. The first was conducted between 1998 and 2000 by Shelton et al. (56). Their study included 200 adult outpatients diagnosed as having major depression [defined as having a baseline Hamilton Rating Scale for Depression (HAM-

D) score of at least 20] in 11 academic medical centers in the United States. After a 1-week, single-blind run-in of placebo, participants were randomly assigned to receive either St John’s wort extract (n = 98; 900 mg/day for 4 weeks, increased to 1200 mg/day in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. Outcomes measured included rates of change on the HAM-D over the treatment period, and four other tests

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as secondary determinants. The study found that significantly more patients administered St. John’s wort reached remission of illness than those taking placebo ( p =.02). Unfortunately, the rates were very low in the full-intention- to-treat analysis 14.3% vs. 4.9%, respectively. Shelton et al. (56) agreed that St. John’s wort was safe and well tolerated, with headache being the only adverse reaction that was higher than with the placebo. The authors con- cluded, however, that St. John’s wort was not effective for treatment of major depression, and even called into question its efficacy for treating moderate depression (56). The Shelton et al. study was critiqued by Hawley and Gale (57), who expressed concern that the methodology did not use a three-arm approach in which St. John’s wort would have been compared against both a placebo and a reference agent of known efficacy.

A second study, conducted by the Hypericum Depression Trial Study Group (58), was a double-blind multicenter investigation aimed at determin- ing whether St. John’s wort (LI-160) was useful in treating major depression. Their study had the benefit of being three-armed, involving comparisons against a control group receiving a placebo and a second receiving the SSRI sertraline. The study involved 340 adult outpatients at 12 academic and community psychiatric research clinics in the United States. Patients were randomly assigned daily doses of H. perforatum that ranged from 900 to 1500 mg, sertraline from 50 to 100 mg, or a placebo for 8 weeks. The study found that the overall response rates of patients receiving the St. John’s wort were 38.1%, actually lower than those receiving the placebo (43.1%) and the sertraline (48.6%). Perhaps most noteworthy was the finding that neither H. perforatum nor sertraline yielded response rates higher than the placebo. The authors concluded that the findings failed to support any claims for efficacy of

H. perforatum in treating moderately severe major depression. They admitted that their results might have been due to low assay sensitivity of the trial. However, the three-armed design of the test was significant, because without a placebo group, one might conclude that St. John’s wort was as effective as an established synthetic antidepressant.

The lack of statistical difference between Hypericum and placebo contrasted markedly with findings of previous studies that did find such a difference (53). Likewise, the lack of difference between the sertraline and placebo was also striking. Rather than showing a lack of efficacy for either the St. John’s wort or the sertraline, Kupfer and Frank (59) attributed the lack of statistical difference to an unusually high placebo response. They expressed concerns that variability in placebo response from trial to trial may obscure interpretation of controlled experiments on natural and synthetic antidepres- sants alike.

Other critiques of the Hypericum Depression Trial Study Group suggested that the study included individuals with untreatable, long-term

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depression (60,61), that an inappropriate placebo was selected because it did not mimic the side effects of the treatments (especially the sertraline) (61), and that bias on the part of clinicians confounded results (62). Linde et al. (63) speculated that the difference between the U.S. and German studies may be due to the latter’s focus on patients with mild to moderately severe depression. They suggested studies may be needed to determine whether St. John’s wort appears to be particularly effective in Germany, but not elsewhere.

The research evidence to date indicates that the application of H. perforatum for the treatment of depression can be helpful in cases that are mild to moderate; however, it is still uncertain if using it to treat major depression is appropriate. The consequences that may result from inadequate therapies of major depression, like suicide, are too dangerous to risk. In the case of severe depression, patients should stay with the traditional treatments of synthetically derived prescription antidepressants.

B. Antibacterial and Antiviral Activities As noted, extracts of H. perforatum have been used for millennia to treat cuts,

abrasions, and other wounds. Its usefulness in reducing inflammation is well known, and appears related, at least in part, to its ability to serve as an anti- bacterial agent. Recent research also suggests that it is useful in combating viruses.

1. Antibacterial Antibacterial properties of H. perforatum extracts were reported by Russian

scientists in 1959 (64). The main antibacterial principle was determined to be hyperforin and its chemical structure was elucidated in 1975 (65). Recent studies have shown that hyperforin inhibited growth of certain types of microorganisms. Growth inhibition occurred for all gram-positive bacteria that were tested, though no growth-inhibitory effects were seen in the gram-negative bacteria tested (65). Meticillin-resistant (MRSA) and penicil- lin-resistant (PRSA) Staphylococcus aureus were especially susceptible to hyperforin. The MRSA strain was shown to be resistant to several types of penicillins, ofloxacin, clindamycin, erythromycin, cephalosporins, and gen- tamicin (65). Little toxicity of purified hyperforin in vitro has been observed in peripheral blood mononuclear cells (65). Oral administration of hyper- forin-containing extract of St. John’s wort was well tolerated and this sup- ports the potential systemic use of hyperforin (66).

In Russia, acetone extracts of St. John’s wort have been used to treat bacterial infections. This extract, novoimanine, is commonly used as an antibiotic preparation for treatment of gram-positive bacteria (67). Various teas showed antibacterial effects against gram-positive bacteria, especially

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toward MRSA Staph. aureus (67). These results provide a rationale for topical treatment of wounds and skin lesions with preparations of St. John’s wort.

2. Antiviral Extracts of St. John’s wort have long been regarded as being effective against

various classes of viruses. Studies by Mishenkova et al. (68) indicated that flavonoid- and catechin-containing fractions of St. John’s wort were active against influenza virus. Since 1988, the virucidal activities of hypericin extract have been investigated against many other forms of viruses (69). Two common characteristics have been established for the antiviral activities of hypericin compounds. First, these compounds are effective against enveloped viruses, but have no effect against nonenveloped viruses (69). Second, the virucidal potential of hypericin is greatly enhanced by light against certain enveloped viruses (70–72). Studies have shown that hypericin inactivates enveloped viruses at different points in the viral life cycle (73). Degar et al. (74) suggested that the inactivation of enveloped viruses by hypericin was attri- buted to alterations in viral proteins. This form of inactivation contrasts to the antiviral nucleoside treatments that target viral nucleic acids (74). Other studies suggest that the inactivation of enveloped viruses by hypericin is due to the inhibition of fusion. Fusion is a membrane-specific process that all enveloped viruses must perform and loss of the ability to fuse to may be a direct result of hypericin (73,74). Lack of the fusion function may be the reason that hypericin inactivates enveloped viruses rather than nonenveloped.

These promising in vitro results have begun to promote various in vivo studies of certain viruses in mice. These include: LP-BMS murine immuno- deficiency viruses, murine cytomegalovirus (MCMV), Sindbis virus, Friend virus, and Ranscher leukemia virus (75–77). Hypericin has also shown in vitro activity against influenza and herpes viruses (78), vesiculostomatitis and Sendai viruses (73), and duck hepatitis B virus (79).

Hypericin has been used to inactivate several enveloped viruses present in human blood and to treat AIDS patients (76,80). AIDS is a retrovirus that uses reverse transcriptase activity to replicate. Degar et al. (74) observed changes in the p24 protein and the p24-containing gag precursor, p55, by Western blot analysis. They also observed that a recombinant p24 formed an anti-p24 immunoreactive material. This indicated that alterations of p24 occurred, and such alterations may be able to inhibit the release of reverse transcriptase activity (74).

Gulick et al. (81) conducted a Phase I clinical trial of 30 HIV-infected patients with CD4 counts less than 350 cells/mm 3 . Hypericin was adminis- tered intravenously at doses of 0.25 or 0.5 mg/kg of body weight twice weekly, or 0.25 mg/kg three times weekly, or orally at 0.5 mg/kg daily. Sixteen of the thirty patients who were enrolled discontinued treatment early because of

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toxic effects, often due to severe cutaneous phototoxicity. None of the param- eters examined, including HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts, showed improvement significant to warrant hypericin as being effective in treating HIV, even for those patients who could tolerate the side effects at the doses given.

Hypericin impacts other viruses. It completely inactivated bovine diarrhea virus (BVDV) in vitro in the presence of light (82). BVDV, a pestivirus, has structural similarities to hepatitis C virus (HCV) (83,84). Jacobson et al. (85) examined the effects of hypericin on HCV, and found that in the doses studied, hypericin demonstrated no detectable anti-HCV activity. Plasma HCV levels were not lowered in HCV-infected patients nor was any effect seen on improving serum liver enzyme levels in the patients studied (85). These results provide significant evidence that, in the doses administered, hypericin is not an effective treatment of HCV (85). While some studies have shown that hyperforin and hypericin may be effective in treating various microbial or viral infections, one should consult a physician before taking these extracts to treat pathogen-induced disease.

C. Anticancer Properties In addition to their use as antidepressants and antimicrobial compounds,

hyperforin and hypericin have been examined for their anticancer properties. According to Schempp et al. (86), hyperforin inhibits tumor cell growth in vitro by induction of apoptosis (programmed cell death) through the activa- tion of caspases. Caspases are cysteine proteases that play a central role in the apoptotic process and trigger a cascade of proteolytic cleavage occurrences in mammalian cells. Hyperforin also causes the release of cytochrome c from isolated mitochondria. Mitochondrial activation is an early event during hyperforin-mediated apoptosis and hyperforin inhibits tumor growth in vivo (86). Schempp and his colleagues agree that since hyperforin has significant antitumor activity, is readily available in high quantities (since it is naturally occurring in abundance), and has a low toxicity in vivo, hyperforin holds ‘‘promise of being an interesting novel antineoplastic agent.’’

Hypericin has also been investigated as an anticancer agent, owing mainly to its photodynamic properties. In the presence of light and oxygen, hypericin acts as a powerful natural photosensitizer, generating superoxide radicals. In turn, those superoxide radicals often form peroxide or hydroxyl radicals, or singlet oxygen molecules that kill tumor cells.

Photodynamic therapy (PDT) consists of systemic administration of a photosensitizer and targeted delivery of light to tumor lesions. At first this therapy was only used for skin lesions, but is becoming increasingly accepted as treatment for many types of tumors. Reactive oxygen species lead to tumor

Medical Attributes of St. John’s Wort 771

destruction, as well as extreme changes in the vasculature of the tumor (87). Since hypericin is photodynamic, its application as a potential photosensitizer and cancer therapeutic agent has been investigated (87). Agostinis et al. recommend that it be introduced into clinical trials because it has powerful photosensitizing and tumor-seeking characteristics, as well as having minimal dark toxicity.

Fox et al. (88) found that hypericin inhibits the growth of cells derived from a variety of neoplastic tissues including glioma, neuroblastoma, adeno- ma, mesothelioma, melanoma, carcinoma, sarcoma, and leukemia. Photo- activation of hypericin with white light and/or ultraviolet light promotes its antiproliferative effect (88). Hypericin could induce near-complete apoptosis (94%) in malignant cutaneous T cells and lymphoma T cells when photo- activated with white or ultraviolet light (88).

Exposing tumors cells to hypericin in conjunction with laser irradiation led to toxic effects on human prostatic cancer cell lines (89), human urinary bladder carcinoma cells (90), and pancreatic cancer cell lines (91) in in vitro systems. Experiments using nude mice receiving implants of pancreatic cancer cells and human squamous carcinoma cells showed reductions in cancer pro- liferation following laser photodynamic therapy using hypericin (10,91,92).

In contrast, extracts of St. John’s wort, when given in conjunction with the anticancer drug irinotecan, reduces the plasma levels of the active metabolite SN-38—a derivative of irinotecan (93). Reduction in the plasma levels of SN-38 may have an adverse effect on irinotecan-based cancer treatments. Treatments based on compounds similar to irinotecan may be similarly compromised if St. John’s wort compounds are included.

While hyperforin and hypericin both show promise as anticancer agents, more research is clearly needed to evaluate their efficacy, mode of action, and deleterious interactions.

VI. ADVERSE EFFECTS/INTERACTIONS As with any pharmacologically active substance, treatments involving St.

John’s wort may lead to adverse effects, either when used alone or in conjunction with other medications.

A. Adverse Effects As noted earlier, normal dosages of St. John’s wort have relatively few side

effects. Indeed many of the clinical trials indicated that rates of adverse effects were lower than for patients using synthetic tricyclic or SSRI antidepressants.

Reviews of adverse drug reactions (ADR) were presented by Greeson et al. (9) and Barnes et al. (10), and readers seeking a detailed account are

772 Klemow et al.

referred to those sources. In general, the most common adverse effects include gastrointestinal symptoms, dizziness, confusion, restlessness, and lethargy. Woelk et al. (94) reported ADR rates of 2.4% for 3250 patients taking St. John’s wort for mild depression. An analysis by Lemmer et al. (95) reported an ADR rate of 0.125% among 6382 patients. Isolated instances of subacute toxic neuropathy and induced mania have also been reported (96,97).

Extracts of St. John’s wort have been found to lack genotoxic potential and mutagenic activity, based on in vivo and in vitro studies (10). Hypericin has a unique phototoxic effect when taken in high doses. The toxic effects are attributed to an acidification of the surrounding environment caused by the transfer of hydrogen between hydroxyl groups upon receiving light energy (98,99). A growing body of literature states that this drop in pH affects viral replication (27). However, while phototoxicity is being studied for its possible therapeutic benefits, excessive phototoxicity can result in photo- dermatitis. Excessive phototoxicity is usually observed only with high doses of hypericin (0.5 mg/kg of body weight) such as those associated with AIDS treatments. As noted, clinical trials on high-dose hypericin AIDS treatments resulted in 48% of the participants displaying severe cutaneous phototoxicity (81). Normal doses of St. John’s wort taken for mild depression (300 mg extract containing 0.3% hypericin taken 3 times daily) do not have any significant associated phototoxic effects (21,38).

B. Drug Interactions While adverse drug reactions are relatively rare for individuals taking St.

John’s wort extracts alone, interactions with other drugs are more commonly reported, and should be a source of concern for those taking St. John’s wort along with other medications. Greeson et al. (9) and Barnes et al. (10) provide excellent reviews of drug interactions. The herb in some cases can increase the effectiveness of other compounds when taken together. This increase may be helpful to the individual or may increase the reaction of the compound to the point of toxicity. Conversely, the herb may decrease or even cancel the effectiveness of another compound (100).

The compounds thought to be effective in the treatment of depression are believed to act similar to selective serotonin reuptake inhibitors as well as monoamine oxidase inhibitors. The use of St. John’s wort in association with other antidepressants containing the active ingredients sertraline or nefazo- done, clorgyline, clomipramine, lithium, carbamazepine, benzodiazepine, bromocriptine, L -dopa/carbidopa, levothyroxine, and others can create po- tential serotonin syndrome (100). Typical symptoms include changes in mental state and autonomic changes, as well as neuromuscular changes. Clinical studies have shown an increased rate of hypersensitivity, nausea,

Medical Attributes of St. John’s Wort 773

vomiting, anxiety, confusion, dizziness, hyperactivity, lethargy, and diapho- resis when St. John’s wort is taken concomitantly with synthetic antidepres- sants (101).

St. John’s wort extracts may lead to an increase in hair loss when taken in conjunction with other tricyclic antidepressants as well as selective SSRIs (38). Microscopic examination of patients showing hair loss revealed a mixed telogen and normal anagen morphology that suggests drug interaction (100).

St. John’s wort extracts apparently induce some cytochrome (CYP)- drug-metabolizing enzymes in the liver, while inhibiting others. Those changes may lead to alterations in serum levels of a variety of drugs such as calcium blockers, chemotherapeutic agents, antifungal agents, glucocorti- coids, cisapride, fentanyl, losartan, midazolam, omeprazole, ondansetron, and fexofenadine (38). Extracts of the herb have also been shown to induce intestinal P-glycoprotein drug transporter, which would decrease oral bio- availability of cyclosporine. The concomitant use can decrease plasma cyclosporine levels by up to 61%. This decrease can cause the rejection of organs during a transplant. Stopping St. John’s wort treatment and starting antithymocyte globulin (ATG) will lead to a resolution of the rejection episode (102).

St. John’s wort when taken with non-nucleoside reverse transcriptase inhibitors (NNRTIs) can decrease serum levels of the NNRTIs, which in turn decreases the plasma concentrations of the protease inhibitor indiavir. This is associated with therapeutic failure, development of viral resistance, and development of drug class resistance (38). St. John’s wort causes this to happen by inducing intestinal and hepatic cytochrome 3A4 and intestinal P- glycoprotein/MDR-1, a drug transporter (38).

Use of St. John’s wort concomitantly with other herbs taken as dietary supplements may lead to other interactions. The documented cases of concomitant use of St. John’s wort with herbs that have sedative properties where the combination may have enhanced both the therapeutic and the adverse effects include interactions with calamus, canendula, California poppy, catnip, capsicum, celery, couch grass, elecampane, Siberian ginseng, German chamomile, goldenseal, gotu kola, hops, Jamaican dogwood, kava, lemon balm, sage, sassafras, scullcap, shepherd’s purse, stinging nettle, valerian, wild carrot, wild lettuce, ashwaganda root, and yerba mensa (38). Another herb known to show side effects when used in conjunction with St. John’s wort is foxglove or members of the digitalis family of herbs. Concom- itant use has been shown to decrease the therapeutic effects of the digitalis by about 25% (38).

St. John’s wort usage along with oral contraceptive may decrease steroid concentrations and induce the cytochrome P450 3A4 enzymes. This

774 Klemow et al.

can result in breakthrough bleeding and irregular menstrual bleeding. When use of the herb was discontinued, the menstrual cycles returned to normal although alternate forms of birth control are suggested if the use of St. John’s wort is continued (38).

St. John’s wort taken in conjunction with barbiturates and narcotics may enhance sleep time. Likewise, when taken with foods containing try- maine, hypertensive crisis may occur (38).

VII. CONCLUSIONS St. John’s wort has a long history of use as an herbal treatment for a variety of

ailments. During the past 20 years, it has become a mainstream alternative treatment for depression, as well as holding promise as a therapy for cancer, bacterial and viral infections, and other disorders.

Thanks to its popularity, the effectiveness of St. John’s wort has been intensively studied since the mid-1980s. Those studies have focused on the pharmacology of its constituents, and on clinical trials. Pharmacological investigations show that extracts of St. John’s wort do have neuroactive properties. Interestingly, those properties appear to derive primarily from the constituent hyperforin, rather than hypericin, which has been investigated for

a longer period of time.

A large number of studies conducted in Germany in the 1990s indicate that individuals showing mild to moderate depression who take St. John’s wort show improvement in mood at rates higher than those taking placebo. Moreover, rates of improvement were seen as being similar to those experi- enced by individuals taking synthetic antidepressants. Those clinical studies comparing the effects of St. John’s wort against synthetics have been criti- cized, however, on the basis of their short duration and a claim that the dosage of the synthetics was below typical dosage. Two recent studies, conducted in the United States, failed to show a clear benefit of St. John’s wort over a synthetic antidepressant and a placebo. At least the latter study was criticized because the response rate of the placebo seemed abnormally high.

Therefore, while a substantial body of literature points toward the efficacy of St. John’s wort toward treating mild to moderate depression, more recent studies argue that the case is far from conclusive. It is interesting to note that the greatest clinical success for the herbal remedy was achieved in Europe, where the use of herbal therapies is standard, compared to the find- ings for the United States, where reliance on synthetic medicines is highest.

St. John’s wort does appear to be an effective treatment for other dis- orders, particularly some skin ailments and possibly cancer. However, its once-promising use as an anti-HIV therapy has not been borne out by clinical studies.

Medical Attributes of St. John’s Wort 775

The preponderance of clinical studies point toward St. John’s wort as being relatively safe, especially at typical dosages. However, high dosages might lead to phototoxicity in susceptible individuals. Extracts of St. John’s wort do appear to interact with other medications, especially owing to impact on liver enzyme function. Therefore, individuals taking St. John’s wort along with other medications should be cognizant of such potential drug interactions.

As with any herbal remedy, any individual using St. John’s wort is advised to consult with his or her physician to ascertain that is the best course of action when seeking the most efficacious remedy for any condition.

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