St John’s Wort and its Active Principles in Depression and Anxiety

This superb technical reference on one of the most widely studied botanical medicines is from a continuing series entitled Milestones in Drug Therapy. Suitable for basic scientists or clinicians in neuropharmacology, the volume carries great authority as it is edited by Professor Dr Walter E Müller, Director of the Institute for Natural Products Pharmacology at the University of Frankfurt Biozentrum. Müller is well known for the work of his institute on the pharmacology of herbs active in disorders of the central nervous system. His efforts combine with a noted cadré of European contributors to provide a comprehensive overview on the history, pharmacology and pharmacokinetics of Hypericum perforatum. The heavy representation by German and Italian authors, among other EU contributors, provides access to original H. perforatum work culled from journals that are not always available overseas. More importantly, the work focuses on the bioactivity of a herbal product from a medical culture where botanicals often share the same footing with prescription-only pharmaceuticals.

The strengths of this reference are many. Overall, each chapter is referenced extensively to the primary literature. Müller begins with a historical overview of H. perforatum that covers little-known study of the herb prior to its more widespread use following publication of the original 1984 German Commission E monograph. Overlooked in the years following World War II, well-documented preclinical and clinical studies of H. perforatum in depressive disorders had been published as early as 1939 by the German physician K Daniel. An excellent phytochemistry chapter examines the chemical composition of H. perforatum extracts and several chapters discuss the in vitro and in vivo biological activities of single compounds and various proprietary extracts.

The only criticism of these sections is that the editor did not push for a consensus discussion or concluding chapter on whether hyperforin alone or other compounds are responsible for the antidepressant effects of the herb. The reader is left with the equivocal conclusion that hyperforin can have antidepressant efficacy while some extracts devoid of this phloroglucinol still retain high activity in animal models. Nevertheless, the advantages and shortcomings of animal models and in vitro studies are discussed in the context of clinical management of depression. Two chapters are provided by scientists from the Dr Willmar Schwabe company that promotes a high hyperforin product, but the content is still critical, well reasoned and devoid of promotion.

Most valuable to the reader are the considerations of neurochemical receptor or transporter activities most likely to be influenced at reasonably achievable plasma concentrations of each active principle. These discussions place into proper context the concerns regarding ex vivo inhibition of monoamine oxidase A and B, activities that are highly unlikely to occur in patients ingesting even 100 times the recommended dose. Another superb chapter by Drs Wurglics and Schubert-Zsilavecz compiles all known pharmacokinetic data on hypericin, pseudohypericin, hyperforin and other components from human trials of several widely used H. perforatum products. This chapter alone is worth the rather steep cost of the volume.

Clinical trials of H. perforatum, particularly recent multicentre trials with negative outcomes, are discussed in some detail in the context of the difficulties in demonstrating antidepressant efficacy for a disorder prone to high placebo effects. These authors exercised considerable restraint in criticising the American trial of Shelton that was so harshly critical of the psychiatric expertise of EU investigators who conducted previous trials. The disappointments are few and relate primarily to inadequate discussion of potential drug–herb interactions, one of the most problematic issues with H. perforatum. These discussions fall short of the authority conferred by the remainder of the book and severely underestimate the risks of using hyperforin-enriched products. Here, the editor may have done better to relax contribution restrictions to include a chapter from one of the US groups who identified that hyperforin is the most potent activator of the PXR transcription factor that, in turn, drives inducible expression of CYP3A4 and some drug transporters.

Taken together, this is an excellent reference text with a wealth and depth of information belied by its modest composition of 188 pages. For any basic or clinical research of H. perforatum, this volume is essential in providing a compilation of diverse data for the individual investigator to draw their own conclusions. Müller has done a most admirable job.