by Kerry Bone, BSc (hons), Dip. Phyto, FNIMH, FNHAA, MCPP

Introduction

The metabolic interaction of the herb St. John's wort (Hypericum perforatum) with a range of pharmaceutical drugs is both widely known and well-documented.

Hyperforin Is the Culprit

It was not long after the first documented cases of metabolic drug interactions involving St. John's wort that the evidence began to emerge suggesting one phytochemical constituent could be largely responsible for this effect. This constituent is hyperforin, a notoriously unstable compound that is only found in some St. John's wort subspecies, such as Hypericum perforatum ssp perforatum.² For example, in 2001, a letter by Kroll and co-workers to the journal Alternative Therapies highlighted the importance of hyperforin in causing the drug interactions.³

The most compelling case for the culpability of hyperforin came from receptor studies which showed that hyperforin is a potent activator of the pregnane or steroid X receptor.

This significant discovery was made in 2000 by two independent research teams.^{4, 5} The human steroid X receptor (SXR) is activated by a wide range of endogenous and synthetic steroids, and its counterpart in mice is the pregnane X receptor (PXR).⁵ However, it is now recognized that the SXR also is activated by other drugs and results in potent induction of CYP3A enzymes, including CYP3A4.⁵ In fact, PXR and SXR function to protect the body against foreign chemicals or xenobiotics. In an article in the prestigious journal Science, the CYP3A system was described as the "garbage disposal" system of the liver and small intestine.⁶

St. John's wort, and specifically hyperforin, also stimulate a second "garbage disposal" mechanism, namely P-glycoprotein (P-gp), probably again by activating PXR and SXR. P-gp is one of several multidrug resistance (MDR) pumps that are found in many living organisms and act to pump out chemicals from cells. For example, MDRs are one mechanism bacteria use to become resistant to antibiotics. In fact, another name for P-gp is MDR1. P-gp is said to be "promiscuous" in that it can recognize and export a diverse range of structurally unrelated compounds from cells. Experimentally it has been verified that it is indeed hyperforin and not hypericin that increases the expression of P-gp in vitro.⁷

Clinical Proof

The natural conclusion to draw from these findings is that the metabolic drug interactions can be avoided by using a St. John's wort preparation devoid of hyperforin. Indeed, several clinical trials have demonstrated that low-hyperforin St. John's wort extracts do not interact with key drugs such as cyclosporin, digoxin and the oral contraceptive pill. In the case of cyclosporin, the effect of two St. John's wort preparations on the pharmacokinetics of cyclosporin was investigated in 10 renal transplant patients using a crossover design.⁸ The decrease in cyclosporin bioavailability was 52 percent for the high-hyperforin preparation, but only a clinically insignificant 7 percent for the low-hyperforin product.

The pharmacokinetic interaction between a low-hyperforin St. John's wort extract and alprazolam, caffeine, tolbutamide and digoxin was evaluated in two randomized, placebo-controlled studies with 28 healthy volunteers. The participants received St. John's wort extract (240 mg per day containing 3.5 mg hyperforin) or placebo on days 2 to 11. The test drugs were administered on days one and 11. No significant differences in bioavailability were found for all the test drugs between the placebo group and the St. John's wort group at the end of the study.⁹

In an unpublished study, the effect of a hyperforin-free extract of St. John's wort was investigated in 16 women ages 18 to 43 years who were taking a low-dose oral contraceptive pill.¹⁰ No significant effect on the serum levels of the pill components, namely ethinylestradiol and 3-keto desogestrel (the active metabolite of desogestrel), were observed. In addition, intracyclic bleedings were not reported.

Hyperforin or None When Treating Depression?

If avoiding the use of St. John's wort preparations high in hyperforin will alleviate the drug interactions, a key question is whether this will compromise the antidepressant activity. An important issue in this regard was highlighted in a recent review of hyperforin in St. John's wort drug interactions¹¹ – namely that the extraction process used to make the most clinically tested extract of St. John's wort, namely LI160, was modified in 1998 to target better levels of hyperforin when research became available suggesting hyperforin was important for the herb's antidepressant activity.^12,13 As the review points out, there were no reports of drug interactions with St. John's wort prior to 1998.¹¹

There is still considerable debate concerning the relevance of hyperforin to the antidepressant effects. Several clinical studies show that low-hyperforin extracts are superior to placebo or equivalent to fluoxetine in the treatment of mild to moderate depression.¹¹ Another clinical study demonstrates that a low-hyperforin extract is ineffective compared to a high-hyperforin extract.¹²

Which preparations of St. John's wort are low in or free of hyperforin? As mentioned above, hyperforin is unstable in extracts of St. John's wort, even in the dry extracts found in tablets and capsules. But it is most unstable in solution and rapidly decomposes at an acidic pH.¹⁴ Tinctures and fluid extracts (galenicals) of St. John's wort which are older than a few months contain no hyperforin at all.¹⁵ So, the most sure and obvious way to avoid the drug interactions with St. John's wort is to use the traditional liquid dosage forms.

Total Dose Is Important

As well as the hyperforin content, the actual dose of St. John's wort also should come into consideration. A randomized, placebo-controlled, parallel-group study investigated the pharmacokinetic interaction of various St. John's wort formulations and doses with digoxin in 96 healthy volunteers.¹⁶ Like the other studies quoted, this study also found that the interaction with digoxin varied with the hyperforin content in the administered dose. But what the study highlighted was that the hyperforin dose is a function of two variables, namely the hyperforin percentage in the preparation and the action actual dose of that preparation. When using the same preparation (powdered dried herb in capsules), a clear dose-response relationship was demonstrated for the drug interaction. No effect on digoxin bioavailability compared to placebo was observed for herb doses of 0.5 and 1 g/day containing the daily doses of hyperforin of 2.6 and 5.3 mg, respectively. Significant effects were seen at doses of 2 and 4 g/day of herb (containing 10.6 and 21.1 mg/day hyperforin respectively); although the authors noted that the effect from 2 g/day was borderline and potentially not clinically relevant.

Conclusions

The research has shown that pharmacokinetic drug interactions should not be an issue for doses of St. John's wort smaller than 2 gm per day (or its equivalent) or any doses of a St. John's wort preparation low in hyperforin (such as a tincture or fluid extract). These preparation and dose guidelines should be followed whenever there is a requirement to recommend St. John's wort to patients taking medications known to interact with this herb. In particular, the guidelines should be observed strictly in all patients taking any form of the oral contraceptive pill. However, for depressed patients not taking any of the problem drugs, it is best to recommend a preparation which delivers a reasonable dose of hyperforin (in the range 15 to 30 mg/day). By necessity, this will be a tablet or capsule.

There is still considerable debate concerning the relevance of hyperforin to the antidepressant effects. Several clinical studies show that low-hyperforin extracts are superior to placebo or equivalent to fluoxetine in the treatment of mild to moderate depression.

Due to media attention and in some cases, warnings on labels, many patients are concerned about the drug interaction issue with St. John's wort. Sometimes, they have received advice from their medical doctor on this matter. Hence, the above recommendations need to take into consideration the informed consent of the patient.

The issue of pharmacokinetic herb-drug interactions with St. John's wort is highly complex, and the bulk of the literature on this topic has been prematurely eager to make unjustified generalizations about the responsible use of this herb. What the research highlights is that the safety and efficacy issues for any herb will depend on how it has been made and the dosage administered. Generalizations about St. John's wort or any herb should always be regarded with great suspicion.