Monograph : Hypericum perforatum

Hypericum perforatum

St John’s wort is a native of Europe, western Asia and north Africa. It has now spread to many countries in the world. It is declared a noxious weed in parts of Australia as it causes photosensitivity in stock that eat it.

Historical use
St John's wort has a long history of usage, being used in antiquity for the treatment of burns, snake bites, fever and wounds.

The fathers of medicine, Dioscorides and Hippocrates were herbalists who recommended and used this ancient herb. Kim Fletcher in ‘The Penguin Modern Australasian Herbal’, explains how St. John’s Wort was named. “During the medieval period, St. John’s Wort was ascribed almost magical powers of protection against evil spirits because of its association with St. John the Baptist. The yellow petals when bruised show a reddish mark that symbolised the blood shed by the saint. Hung in the house or rubbed over the lintels, the herb would prevent witches and death from entering during the year.”

“Wort” is from the old English “wyrt”, meaning a plant or herb, especially one used in medicine. Paracelsus, the Swiss physician, chemist and natural philosopher who lived in the 16th century, wrote of the superior healing powers of St. John’s Wort as putting “to shame all recipes and doctors, they may yell as they wish, they will only break their teeth.”

The BHP lists the specific indication for St John's wort as menopausal neurosis; other indications listed are excitability, neuralgia, fibrositis and sciatica.¹
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¹British Herbal Medicine Association, 1983, British Herbal Pharmacopoeia, West Yorks, p 115.

ENVELOPED VIRUS (surrounded by a lipid shell)

NAKED VIRUSES (NOT surrounded by a shell)

Note: the common cold can be caused by either enveloped or naked viruses.

Cautions
Avoid excessive sunlight.

Recent research indicates that Hypericum perforatum induces the cytochrome P450 enzyme system. The UK Commitee on Safety of Medicines (UKCSM) advises that hypericum should not be used with indianvir, warfarin, cyclosporin, oral contraceptives, digoxin and theophylline.

The FDA and the UKCSM also state that interaction is expected to occur with HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors and certain anticonvulsants. There is also concern with interaction with SSRIs and other psychotropic drugs.

B. Uehleke et al evaluated the drug interaction of different formulations and dosages of hypericum with digoxin.¹ After reaching steady levels of digoxin, hypericum was co-mediciated with digoxin for a further 14 days. A standardized extract, Jarsin (900 mg) and high-dose encapsulated hypericum powder (4 g daily) reduced 24h-AUC by 24.6% and 27.1% respectively. Jarsin is standardized to hypericin, not hyperforin, yet it clearly interacts with the prescription medication.
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¹Uehleke B, 3rd International Congress on Phytomedicine, Munich 2000.

Toxicology
To investigate the safety and tolerability of hypericum extract (Remotiv), H. Woelk et al treated 440 outpatients (18-80 years) with mild to moderate depression for one year with 250 mg bid Remotiv, standardised to 0.2% hypericin and <0.2% hyperforin.¹ According to the poster, the authors concluded that of the few patients who reported adverse reactions, only 6.7% were possibly or probably related to the study drug, only 5.7% of patients dropped out of the study, the vast majority of adverse reactions were mild to moderate in intensity and completely resolved in most patients within the study period.

The authors further claimed that most patients reported significant improvements in their symptoms and that there was no convincing evidence of a significant relapse rate. No clinically relevant interaction with other drugs could be observed during the study and the authors suggest that this may be due to the fact that this particular hypericum extract has a very low level hyperforin.
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¹Woelk H, et al, 3rd International Congress on Phytomedicine, Munich 2000.

DoseDryHerb
6 to 12 g per day.

DoseExtract
15 to 40 mL per week (Std Ext).

Indications
anxiety, depression, depression, post natal, fibrositis, irritability, menopause, depression, menopause, symptoms, nervous exhaustion, neuralgia, premenstrual syndrome, sciatica, wounds (topically)

Contra Indications
cyclosporin , HIV non-nucleoside transcriptase inhibitors & protease inhibitors

Qualities
cold, pungent

Actions
antidepressant, anti-inflammatory, antiseptic (topically), antiviral (topically), anxiolytic, astringent, nervine tonic, relaxant, vulnerary

Constituents
The debate about the true active constituents of hypericum continues. The following research findings were presented at the 3rd International Congress on Phytomedicine, Munich 2000.

A study by V. Butterweck, B. Korte and H. Winterhoff suggests that the antidepressive effect of hypericum/hypericin may be, at least partly, mediated by the dopaminergic system. In patients with depression, a considerable number of endocrine abnormalities have been reported, including changes in the hypothalamic-pituitary-adrenal (HPA) axis. Hypericum extract and hypericin clearly inhibited thyroid-releasing-hormone-stimulated prolactin release in primary pituitary cell cultures in a dose dependent manner.

As companies endeavor to prove the efficacy of their botanical products, it is essential that the studies are well designed and that proper statistical analysis is applied in order to reach irrefutable conclusions. The controversy surrounding hypericum is not likely to disappear in a hurry.

The German pharmaceutical company, Bayer, sponsored a large randomized controlled study comparing the effects of their hypericum extract Remotiv (produced by Zeller in Switzerland) with Imipramine in the treatment of mild to moderate depression.

The study, recently published in the British Medical Journal¹, generated a substantial amount of comments on the BMJ website. Although the study showed that hypericum and imipramine are therapeutically equivalent, the study design, and therefore its relevance, has been criticized by other researchers.

James L. Spira, Ph.D., M.P.H., Head, Division of Health Psychology Naval Medical Center, San Diego, as well as Arthur Rifkin, MD, Attending Psychiatrist Hillside Hospital, New York, questions the choice of imipramine which is not considered the drug of choice for depression, with more side effects than the newer drugs such as the selective serotonin reuptake inhibitors, and furthermore, that the dosage used in the study is considered suboptimal. The study is also criticized for only running for six weeks, too short a time frame when exploring the efficacy of an anti-depressant drug. The statistical analysis of the study has even been criticized by an independent German biostatistician, Andreas V๖lp.

Conversely, other comments from researchers and medical doctors from around the world, expressed the view that there are sufficient data to suggest that hypericum is a safe, efficacious alternative in the treatment of mild to moderate depression and the dosage of the tri-cyclic antidepressant imipramine used in the study actually reflects the common prescribing practices of GPs, if not psychiatrists.

Other presentations by E. Schrader et al and M. Friede et al, compared Hypericum extract Ze 117 with fluoxetine. Not only was the botanical extract as effective as the drug in treating depression, it was also effective in reducing anxiety and agitation, and patients reported fewer side effects.

In conclusion, it seems that both hypericin and hyperforin show antidepressive activity and that both may contribute to hypericum extract's ability to interact with the intestinal absorption, distribution or renal excretion of digoxin. This effect seems to be mediated by the drug transporter P-glycoprotein. Hypericum extract also interacts with the drugs via its effect on hepatic cytochrome P450 enzyme systems. Until further notice, it seems prudent to caution against the use of hypericum with HIV proteases, immunosuppressants such as cyclosporin, warfarin, digoxin and SSRIs.

In view of the problems in identifying a single active constituent in hypericum, it seems essential to recommend a full-spectrum extract of hypericum. Full-spectrum extracts contain all the constituents as found in the raw herb (provided they are well extracted in the chosen solvent). However, since both hypericin and hyperforin are important constituents, they are useful as marker compounds for the purpose of quality control, and since the clinical trials have been conducted with extracts standardized to hypericin, it seems prudent to recommend products which are at least standardized to hypericin. There is also evidence to suggests that hyperforin may be unstable in liquid form.

A presentation by A. Nahrstedt et al showing that the napthadiantrone, procyanidin B2, but not procyanidin C1 or epicatechin, improved the solubility of hypericin. Nahrstedt also considers hyperoside and isoquercetin to be active constituents in hypericum. Honegger et al made the discovery that hypericum extract caused changes in the phospholipid composition in the membranes leading to greater fluidity and may therefore reduce symptoms of depression. Honegger felt that the reported ability of hypericum to inhibit the reuptake of noradrenalin and serotonin may account for its short term antidepressant activity whereas the phospholipid changes may be more significant in explaining the long term effects.

Until studied further, the importance of hyperforin and other constituents, such as the flavonoids in hypericum, and which constituents are mostly responsible for the drug interaction remains elusive.
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¹Woelk H, 'Comparison of St John's wort and imipramine for treating depression: randomised controlled trial', BMJ 2000; 321: 536-539.

alpha-pinene, beta-pinene, caffeic acid, caryophyllene, chlorogenic acid, coumarin, essential oil, flavonoids, glycosides, hyperforin, hypericin, n-alkanes, oligomeric procyanidins (OPCs), pectin, procyanidins, pseudohypericin, quercitin, resin, rutin, sesquiterpenes, tannin, xanthones

Pharmacological studies
Alcoholism Treatment of alcoholism with herbs

Central nervous system response Hypericum is anxiolytic and affects exploratory behavior in rats

Clinical studies
Depression Comparison of St John's wort and imipramine Depression in alcoholics Hypericum: depression, anxiety and agitation

Herpes infections Reduced frequency and severity

Interactions Interaction of Hypericum perforatum with cyclosporin A metabolism

Obsessive-compulsive disorder Treatment of OCD with hypericin

Author: Michael Thomsen