St. John’s Wort: Safe and Effective?

Jerry Cott, PhD
Research Pharmacologist,
Scientific Advisor to the Health Professions,
College Park, MD.

St. John's Wort (Hypericum perforatum; SJW) is a common roadside plant that has gained much popularity in Europe and the United States as an alternative to synthetic antidepressants. The market for SJW in 1998 was $330 million in Europe and $210 million in the U.S. Hypericum appears to be an effective antidepressant with an excellent safety profile (with the interaction caveat discussed here). The NIH has just completed a multi-centre study comparing the efficacy of SJW to sertraline and placebo for treating patients with moderate to severe depression. This study was completed in December 2000, and results should be available in the summer of 2001.

Although SJW has been shown to inhibit monoamine oxidase (MAO) in vitro, this effect has not been demonstrated in vivo, nor have there been any reported cases of MAOI-associated hypertensive crises in humans using SJW.¹ Although SJW has been reported to inhibit uptake of serotonin, norepinephrine and dopamine in vitro,² the concentrations required to attain these effects are quite high and the chance of a patient attaining equivalent blood concentrations is low. In fact, a recent study suggests that the uptake inhibition is only an artifact of the assay since, in contrast to other inhibitors, it does not bind to the serotonin uptake site but does deplete storage vesicles in a similar fashion to reserpine.³

Cytochrome P450 and P-glycoprotein
The Cytochrome P-450 (CYP450) system is a family of enzymes, particularly concentrated in the liver and intestinal mucosa but also found in the kidneys, skin, lung and other tissues. While 12 gene families have been identified, three categories of these enzymes are significant in humans--the most important are the CYP2C, 2D6, and 3A4.^4,5 CYP 3A4 is the most abundant hepatic enzyme and accounts for the oxidation of over half of all the medications that are subject to oxidative metabolism. There is significant variation of enzyme activities among individuals and diet plays a major role both daily and in the long-term. Orally administered substrates of CYP 3A4 undergo significant extrahepatic metabolism in the intestine prior to absorption.

Foods and herbal products may contain a number of pharmacologically active constituents which may potentially participate in pharmacokinetic interactions.

Many foods and medications induce or inhibit the activity of CYP450 enzymes. Induction is a slow process; it depends on the rate of synthesis of new enzyme and is usually noticeable after only a few days, and may be maximal after two weeks. Inhibition is more rapid and can become maximal within the first 24 hours of exposure to the inhibitor--but likewise may reverse more rapidly. Foods and herbal products may contain a number of pharmacologically active constituents including essential oils, tannins, coumarins, anthraquinones, saponins, glycosides, anthocyanins, alkaloids and flavonoids, all of which may potentially participate in pharmacokinetic interactions.

The flavonoid, quercetin, a constituent of many herbal products including SJW, has been shown to inhibit CYP 3A4 in vitro.⁶ The bioflavonoid constituents (naringenins and/or coumarins) in grapefruit juice inhibit intestinal CYP 3A4.^7,8,9 Cruciferous vegetables such as Brussel sprouts and broccoli induce CYP1A2.^10,11

Although in vitro screening is a common and non-invasive means of screening for potential drug interactions mediated by the CYP system, its limitations prevent generalization to the clinical situation. For instance, drug and enzyme concentrations in the test tube must accurately reflect those attained in vivo since enzyme specificity for inhibition may be lost at elevated concentrations. Another problem is that crude extracts incubated directly with human liver