Drug interactions with St John's wort
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 reviewed (1-11). 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 hyperforin (1;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 date (13-21) 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 fructification (22).
- The higher the hyperforin content, the higher the risk of interactions with concomitantly administered CyP 3A4 of PGP substrates (23;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 metabolism (7;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 preparations (25;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 hyperforin (23;24).
- To date no clinical study has demonstrated the importance of hyperforin for clinical efficacy in depression treatment (22).
- 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 cyclosporine (13;30). Conventional antidepressants are therefore not necessarily a safe alternative to SJW preparations.
- 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.
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