Drug interactions with St John's wort depend upon the product used.

Expert opinion, March 2010

Mathias Schmidt

Dr Mathias Schmidt (HerbResearch, Germany)

with Michael Thomsen

 

The clinical significance of drug interactions with Hypericum perforatum (St John's wort, SJW) depends on the type of St John's wort product used.

 

Much has been written about the drug interactions with SJW in recent years. Unfortunately the clinical significance of the reported interactions has confused health practitioners, regulators and the public alike.

Reports on pharmacokinetic interactions between SJW extracts and pharmaceutical drugs including digoxin, immunosuppressants, antiviral agents or contraceptives have been published in recent years, and extensively reviewed1-11. The knowledge on potential SJW interactions, and especially the effects on the reliability of hormonal birth control is even used as a marker of the quality of counselling in some pharmacies and health food stores 12.

A closer look at the interaction mechanisms and clinical findings, however, clearly demonstrates the need for differentiation: there is accumulating evidence that the problem of SJW interactions is not a problem of the herb as such, but related to the composition of certain special extract preparations.

The potential of these special SJW preparations to lower the blood levels of concomitantly prescribed drugs is a well-established and much discussed clinical fact. Less well-known, albeit well-examined, is the fact that the compound responsible for the interactions has been identified: according to today's knowledge, hyperforin may exclusively be held responsible for all clinically relevant SJW herb-drug interactions.

The correlation of hyperforin with drug interaction was not noted in earlier reports, and was initially attributed to a simple under-reporting. It is much more likely, however, that the lack of interaction in reports predating 1999 reflects the fact that SJW preparations studied in clincical trials did not yet include patented extracts artificially enriched with hyperforin1, 7.

The mechanisms underlying the herb-drug interaction have been amply examined. It has been confirmed beyond doubt that the mechanism is almost exclusively linked to drugs metabolized via intestinal PGP and cytochrome P450 (CyP) isoform 3A4, but also that the SJW compound responsible for the phenomenon is in fact hyperforin. The site of the interaction is not the liver, as generally assumed, but the intestinal metabolic systems. Intravenously applied concomitant drugs are therefore less likely affected by the intake of SJW preparations.

Clinical relevance of SJW-drug interactions

From the studies made to date13-21 several conclusions may be drawn:

  • Clinically relevant interactions have exclusively been observed with extracts artificially enriched in hyperforin, with hyperforin concentrations ≥ 4%. Such extracts do not reflect hyperforin ratios found in the SJW herb collected at the usual time of harvesting during full flowering as stipulated by the official monographs, but rather the picking of the herbal drug substance at the time of fructification22.
  • The higher the hyperforin content, the higher the risk of interactions with concomitantly administered CyP 3A4 of PGP substrates23, 24.
  • The interaction potential of hyperforin has been demonstrated to be dose-dependent. Obviously, hyperforin needs to exceed an as yet, not defined dose threshold, to affect drug metabolism7, 23, 24.
  • The hyperforin content is rarely mentioned in case reports or interaction trials. It can, however, be derived from publicly available product-specific information, or from analytical screenings of commercially available SJW preparations25, 26.
  • It can be quite safely assumed that the risk of clinically relevant interactions is low when preparations containing normal extracts, not enriched in hyperforin, are used. SJW preparations with normal levels of hyperforin (typically around 1.5-2.0 %) have been demonstrated not to cause clinically relevant pharmacokinetic interactions, and thus possess a better safety profile compared to special extracts enriched with hyperforin23, 24.
  • To date no clinical study has demonstrated the importance of hyperforin for clinical efficacy in depression treatment22.
  • Only a few of the interactions hitherto detected can be considered clinically relevant. In all of these cases, such as under treatment with cyclosporine, the patients are under a high level of surveillance, which should contribute to risk minimization.27-29.
  • The question of the causative constituent aside, risk-benefit assessments must necessarily also take the general therapeutic context into consideration, including the risk of potential treatment alternatives. Antidepressants of the SSRI type and nefazodone are likewise suspected to cause interactions with concomitantly taken drugs on the level of various CyP enzymes, e.g. with cyclosporine13, 30. Conventional antidepressants are therefore not necessarily a safe alternative to SJW preparations.

Bottom line

  • Hyperforin is responsible for the drug interactions attributed to SJW.
  • Clinically relevant interactions can only be expected with hyperforin-enriched products.
  • Standard products containing 1.5-2.5 % hyperforin, on average 18 mg in the daily dose, are unlikely to cause clinically significant drug interactions.
  • The solution is not to avoid St John's wort and instead use pharmaceutical antidepressants. The solution is to avoid hyperforin-enhanced SJW preparations and exercise vigilance if drugs metabolised by CYP enzymes are concomitantly prescribed.
  • Health practitioners should demand to be informed of the level of hyperforin in the products they use.

The evidence

Hyperforin is the main constituent responsible for the observed drug interactions Hyperforin has been identified as a very potent and selective inducer of CYP enzymes, more potent even than the model substance rifampicin typically used in pharmacological examinations. Despite some in vitro-data suggesting a potential effect of other SJW constituents such as hypericin or flavonoids, these compounds do obviously not make a relevant contribution to the overall clinical outcome of the metabolic induction as illustrated in figure 1.31-33.

Figure 1

Figure 1: In vitro activation of the PXR-system through St John's wort and isolated compounds34. All substances were tested in a concentration of 10 μM, with the exception of hyperforin, which had to be diluted to 1 μM due to the strong activation effect. Similar results would be observed for serum concentrations of hyperforin after intake of hyperforin rich extracts.

Clinical observations

Interactions due SJW preparations depend on the hyperforin content

Several case studies, pilot and experimental studies have shown interactions for SJW preparations with a high hyperforin content10, 35-38, 38-40.

Whereas trials performed with a preparation void of hyperforin failed to show any pharmacokinetic influence on plasma digoxin or contraceptive levels41, 42, another study reported the results of a placebo controlled group control study with 96 healthy volunteers obtaining various SJW preparations as a concomitant treatment with digoxin for 14 days. The interactions on the PGP system clearly correlated with extract dose and hyperforin content. While highly dosed and hyperforin-rich preparations triggered the interaction to a significant and relevant extent, this was not the case with preparations devoid of hyperforin, SJW tea, or low dose SJW powder and oil23. Another study also failed to demonstrate any interaction between a low hyperforin extract and digoxin in 28 healthy volunteers (verum: n = 16; placebo: n = 12)43.

Interactions due to the cytochrome P450 isoform 3A4 count among the best examined pharmacokinetic phenomena. They have been suspected in case reports and examined in clinical trials, where the pharmacokinetics of substrates of CyP 3A4 was measured under the influence of concomitantly administered SJW. In pharmacological model studies hyperforin has been identified as the most potent activator of CyP 3A4 and PGP among the constituents of SJW. Hyperforin activates both systems via the steroid-X-receptor, which explains the specificity of certain SJW preparations for these two metabolic systems24, 32, 33, 35, 44-51. The dose-dependency of interactions on the level of cytochrome P450 3A4 with hyperforin levels has been demonstrated in a clinical model trial in 42 midazolam-medicated subjects. The extent of the interaction clearly depended on the hyperforin , but not the Hypericin dose24.

Consequently, SJW preparations with normal and low hyperforin levels possess a better safety profile than hyperforin-enriched extracts.

Reports of interactions of SJW preparations at CyP 3A4 from the pharmacovigilance systems

In view of the multitude of clinical model trials demonstrating the interaction of St. John's wort extract with many drugs metabolised via cytochrome P45 3A4 one would expect to find corresponding reports from the spontaneous pharmacovigilance reporting systems. However, very little reliable information has been produced from spontaneous reporting. For the time frame of 1991 to 1999, Schulz (2001) counted 8 spontaneous reports from the German pharmacovigilance system on break-through bleedings with concomitant intake of a SJW extract rich in hyperforin and an oral contraceptive, which corresponds to 0.09 cases in 100,000 patients. From market data of the corresponding SJW preparation an incidence rate of one case of break-through bleeding in 500,000 users of oral contraceptives was calculated. This incidence rate would be by far below the usual incidence of break-through bleedings observed with the use of contraceptives even without the intake of SJW products. The relevance of such reports is thus highly questionable27.

Three reports suggest a link between SJW and break-through bleedings in women taking contraceptives (twice within one week, once within 3 months after start of SJW treatment)35. The case of menstrual break-through bleeding three months after having started SJW therapy appears an unusually long delay for an interaction usually apparent after 8-10 days of continuous application, and might therefore be unrelated to SJW. In the two women where the bleeding was observed within one week of SJW intake, the reaction fits to the general picture observed in clinical trials with preparations rich in hyperforin. It has, in addition, been demonstrated that even if hyperforin-enriched St. John's wort preparation are responsible for induction of breakthrough bleedings, the anti-ovulatory efficacy of the contraceptive is still not endangered52, 53.

On balance, a risk-benefit analysis would conclude that extracts not enriched in hyperforin carry little risk of drug interaction and as the benefits are adequately documented, SJW should continue to be the drug of choice for depression.

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