St. John's Wort: A Mini-Review of its Pharmacokinetics
and Anti-Depressant Effects

From AccessMedicine from McGraw-Hill

By Perry V. Halushka

Posted: 12/16/2009; AccessMedicine from McGraw-Hill © 2009 The McGraw-Hill Companies

History

St. John’s wort is the common name for Hypericum perforatum , a yellow flower with a long and rich history. It was originally harvested for the feast of St. John the Baptist. The word ‘wort’ is the Old English name for plant. St. John’s wort has become one of the most popular herbal supplements for the treatment of depression.

Components of St. John's Wort

As is true for all dietary herbal supplements, [1] St. John's wort contains a vast array of chemical compounds. The major chemical components are naphthodianthrones, of which hypericin, pseudohypericin, and hyperforin are the most relevant biologically active compounds. St. John’s wort also contains quercetin, flavones and xanthoids. Many preparations are standardized to the hypericin or pseudohypericin content. As is the case with many dietary herbal supplements, the amount of active ingredients may vary significantly depending on the source, time of the year of the harvest, plant component used, and the type of preparation. For example, one study analyzed the total naphthodianthrone content of 54 commercially available preparations of St. John's wort. The measured amounts varied considerably from those claimed on the labels, from 0% to 109% for capsules and from 31% to 80% for tablets. [2] Another group reported that, whereas the amounts of pseudohypericin among 30 plants did not vary significantly, the concentrations of hyperforin did vary significantly. Such variability has significant implications for potential herbal-drug interactions and efficacy, as noted below. The component of St. John’s wort that is thought to be most responsible for its beneficial effects in the treatment of depression is hyperforin.

Pharmacology of St. John's Wort

St. John’s wort has myriad pharmacological effects, many more than can be enumerated in this mini-review. Hypericin and hyperforin have been found to inhibit the uptake of serotonin, dopamine and norepinephrine into synaptosomes. Chronic treatment of rats with St. John's wort resulted in an up-regulation of post-synaptic 5-HT1A and 5-HT2A receptors. Hypericin has also been found to have significant activity at D3 and D4 dopamine receptors. Collectively, these pharmacological effects may play a role in the efficacy of St. John's wort in the treatment of mild to moderately severe depressive disorders.

Effects on Drug Metabolism and Transport

St. John's wort is a very effective inducer of hepatic CYPs, specifically, CYP3A4, CYP2C9, and CYP1A2. Hyperforin has been found to induce CYP3A4 via activation of pregnane X, an orphan nuclear receptor. Table 1 lists drugs whose metabolism is increased by the induction of one of the CYPs. [3,4] Induction of CYPs leads to significant decreases in plasma levels of drugs that are substrates of the induced CYPs, resulting in reduced efficacy and adverse clinical outcomes. Some notable St. John's wort drug interactions are the reduction of cyclosporine levels leading to heart transplant rejection and the increased metabolism of oral contraceptives leading to unexpected pregnancies. Noted in Table 2 are several examples of functional potentiation by St. John’s wort, in which the herbal preparation acts in concert with prescription anti-depressants to enhance the blockade of neurotransmitter uptake. St. John’s wort can also induce the expression of the drug transport protein, P-glycoprotein. The induction of P-glycoprotein can cause increased efflux of digoxin into the intestinal lumen, which results in a significant decrease in its AUC and Cmax. St. John’s wort can also inhibit the activity of sulfotransferases, specifically SULT1A3. Inhibition of SULT1A3 activity may lead to an increased bioavailability for those drugs, for example ritodrine, that are metabolized by it in the intestinal epithelium.

Efficacy in the Treatment of Depression

St. John’s wort has gained considerable popularity as a dietary herbal supplement for the treatment of depression. There have been numerous trials using standardized St. John’s wort extracts. Results were variable, probably due to the heterogeneity of the presumed active components and lack of double-blind placebo-controlled trials. However, several statistically significant observations have emerged from meta-analyses of these trials. [5] For mild-to-moderate depressive disorders, it appears that St. John’s wort may be as effective as SSRIs and more efficacious than placebos. However, it has not been found to be uniformly effective in major depressive disorders. With the exception of its effects on drug transport and metabolism, St. John’s wort appears to have relatively few side effects. Although the incidence is low, the most common side effects of St. John’s wort appear to be headache, dry mouth, nausea, gastrointestinal upset and sleepiness. A rare side effect reported for St. John’s wort is photosensitivity.

Words of Caution

Because of its availability as an herbal supplement, many individuals are taking St. John's wort without consulting or informing their physicians or pharmacists. This is problematic because of the potential for an herbal-drug interaction. Most notably, taking St John's wort could lead to a loss of efficacy of a prescription drug because of the induction of one or more drug metabolizing enzymes ( Table 1 ). Because of the variable content of its components, taking St. John’s wort could also lead to changes in efficacy or potential toxicity, depending on when the pharmaceutical was started and how many different preparations of St. John's wort were consumed. Another potential concern is for those patients taking SSRIs who decide to add St. John's wort to their therapeutic regimen. They are at increased risk of experiencing the serotonin syndrome, a potentially serious adverse event which may be manifested by symptoms of lack of coordination, hyperreflexia, agitation, coma, confusion, tremor, fever, nausea and diarrhea ( Table 2 ). Patients often believe that if a drug is “natural” then it is safe. This is simply not true, and patients must be cautioned about the potential risks if they choose to treat their depression with St. John's wort.

Table 1. Examples of Effects of St. John's Wort to Induce Specific CYPs, thereby
Accelerating the Metabolism of Clinically Important Pharmaceuticals [3,4]

Table 2. Examples of Effects of St. John’s Wort to Influence Apparent Clinical Efficacy or Distribution of Important Pharmaceuticals [3,4]

References

Authors and Disclosures

Perry V. Halushka
Medical University of South Carolina

-From “ St. John's Wort: A Mini-Review of its Pharmacokinetics and Anti-Depressant Effects” by Perry V. Halushka , AccessMedicine from McGraw-Hill, Medscape, http://www.medscape.com/viewarticle/713605.

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