DEPARTAMENTO DE DIDÁCTICA DE LAS MATEMÁTICAS

Historical and Current Uses

Hypericum perforatum, commonly known as St. John’s wort, is a perennial plant common in the United States, Europe, and Asia. Its traditional uses date back to the fifth century B.C.E., when Hippocrates first documented the medicinal qual-

ities of St. John’s wort in healing wounds. The herb has also been traditionally used to treat afflictions of the nervous system (e.g., hysteria, neurosis) and a wide of range of disorders (e.g., spinal injuries, rheumatism); has been used as a neu- ralgesic, diuretic, and astringent; and has been given for dysentery and parasites (Mills and Bone 1999).

St. John’s wort has recently gained popularity as an herbal treatment, mostly for depression but also for mood disorders associated with premenstrual syn- drome, seasonal affective disorder, perimenopausal symptoms, obsessive-com- pulsive disorder, and anxiety. In 1998, St. John’s wort was the second highest- selling dietary supplement in the United States, but it fell to fifth place in 2000 because of negative publicity surrounding its potential for adverse interactions with many conventional drugs (Blumenthal et al. 2000).

Description and Standardization

St. John’s wort is made using the dried tops, leaves, and stems procured during flowering season, which are prepared as standardized extracts, teas, alcohol- based tinctures, capsules and tablets, and topical oil infusions. These preparations may vary in constituents, depending on growing conditions and on climate, har- vesting, and extraction methods, yielding products that vary significantly in con- tent from manufacturer to manufacturer and batch to batch. St. John’s wort is often standardized to 0.3% hypericin extract or 2%–4.5% hyperforin (Bruneton 1999). In earlier studies, hypericin was thought to be the primary constituent possessing antidepressant efficacy, but recent studies have indicated that hyper- forin probably plays a more significant role. To date it is not known whether the antidepressant efficacy of St. John’s wort comes from one or a combination of constituents present in the whole herb. A practical consequence of this uncer- tainty is that standardization is not a critical factor in determining the probable clinical effectiveness of different preparations (Linde and Mulrow 2002).

Pharmacology

The biologically active constituents that may contribute to the antidepressant ef- fects of St. John’s wort include the compounds naphthodianthrones (hypericin

and pseudohypericin), phloroglucinols (hyperforin and adhyperforin), fla- vonoids, xanthones, oligomeric procyanidins, and amino acids (Nahrstedt and Butterweck 1997). As noted above, it is not yet clear which constituents have beneficial effects on mood; however, the research focus has recently shifted to hyperforin as the principal antidepressant constituent. St. John’s wort exerts its effects on several neurotransmitters, specifically by inhibiting reuptake of sero- tonin (5-hydroxytryptamine [5-HT]), norepinephrine, dopamine, GABA, and

L-glutamate in vitro. Animal models have demonstrated serotonin receptor (5-

HT1 and 5-HT2) upregulation and downregulation of β1-adrenergic receptors

when St. John’s wort is used for a long period (De Smet 2002; Di Carlo et al. 2001). In vitro binding to GABA_A, GABA_B, benzodiazepines, inositol, and MAO A and B receptors has also been confirmed (Cott 1997). There is a report of dose-dependent potentiation of animal behaviors affected by CNS serotonin levels, with the greatest effect being with a 38.8% hyperforin extract, in contrast to a more dopaminergic-mediated behavior with an extract of 4.5% hyperforin (Bhattacharya et al. 1998). A small study of healthy volunteers demonstrated in- creased cortisol levels after oral administration of 600 mg of WS 5570 (an extract of St. John’s wort), suggesting central norepinephrine or serotonin activity (Schule et al. 2001).

Pharmacodynamics and Pharmacokinetics

In humans, the mean plasma concentration (150 ng/mL) of hyperforin is reached approximately 3.5 hours after oral administration of 5% hyperforin ex- tract. The elimination half-life is 9 hours (Biber et al. 1998). Clinical studies have demonstrated the induction of cytochrome P450 (CYP) enzymes by St. John’s wort, resulting in increased metabolism and reduced plasma concentra- tions of many drugs. More recently, it has been suggested that the drug trans- porter P-glycoprotein, found in the gastrointestinal tract and the CNS, may also alter the bioavailability of many drugs (Zhou et al. 2004). Hyperforin, but not hypericin, has been found to induce CYP 3A4 expression in human hepatocytes (Moore et al. 2000; Wentworth et al. 2000). CYP 3A4 is the most clinically im- portant member of the CYP family of hepatic enzymes and is involved in the metabolism of many common pharmaceuticals. Induction of intestinal P-glyco- protein/multidrug resistance 1 (Pgp/MDR1) transport by St. John’s wort and hepatic CYP 3A4 decreases intestinal absorption and increases first-pass clear- ance of many drugs (Dressler et al. 2003).

Review of Clinical Evidence

Depression

Many randomized controlled trials have been conducted using St. John’s wort; at the time of this writing, six systematic reviews and meta-analyses have found the

herb to be superior to placebo and as effective as conventional antidepressants for the short-term treatment of mild-to-moderate depression (Gaster and Holroyd 2000; Kim et al. 1999; Linde and Mulrow 2002; Linde et al. 1996; Whiskey et al. 2001; Williams et al. 2000). However, negative results were found in two recent studies evaluating the effectiveness of St. John’s wort in severely depressed individ- uals, with Hamilton Rating Scale for Depression (Ham-D) scores higher than 20. Shelton et al. (2001) conducted a multicenter randomized, double-blind, placebo- controlled trial in 200 subjects over 4 weeks using LI 160, a preparation standard- ized to 0.3% hypericin, and concluded the herb had no effect on severe depressed mood. The study was criticized for the unusually low remission rates in both groups and the lack of a conventional antidepressant arm to ensure sensitivity. More re- cently, the Hypericum Depression Trial Study Group compared St. John’s wort with sertraline and placebo for major depression. In that trial, 340 subjects were randomized to receive LI 160 (900–1,500 mg), sertraline (50–100 mg), or placebo over 8 weeks; outcomes were based on the Ham-D and Clinical Global Impression (CGI) scores (Hypericum Depression Trial Study Group 2002). Improvement was seen in all three groups, with no significant differences among the groups. In both studies, the significance of the findings was limited by the short study duration and the lack of adequate statistical power on which to base strong conclusions. In view of the above findings, the evidence supporting the use of St. John’s wort for the treatment of severe depressed mood remains inconclusive; however, there is com- pelling evidence of the herb’s beneficial effects in mild-to-moderate depression.