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From the Townsend Letter for Doctors & Patients
October 2004

Phytotherapy Review & Commentary
by Kerry Bone
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Chaste Tree and Melatonin
The role of melatonin in human health and disease is being extensively investigated. In particular, melatonin functions in the regulation of circadian rhythms, mood and tumor growth.1 Since the effects of melatonin can be biphasic, for example some concentrations can inhibit tumor growth while other concentrations have a stimulating effect, it makes sense to investigate natural means of manipulating the melatonin output by the pineal gland. The circadian rhythm of melatonin secretion was measured in 20 healthy males aged 20 to 32 years after the intake of placebo or various doses of an extract of Vitex agnus-castus (chaste tree) for 14 days. In an open, placebo-controlled study, the doses investigated were 120 to 480 mg per day of this extract (corresponding to approximately 0.6 to 2.4 g of dried berries). The concentration of melatonin in serum showed the typical nocturnal increase, beginning approximately 1 hour after the light was turned off. Administration of chaste tree caused a dose-dependent increase of melatonin secretion, especially during the night (compared to placebo treatment). Total melatonin output was approximately 60% higher in the group receiving chaste tree. The authors observed that the feeling of fatigue or the promotion of sleepiness observed by some patients taking chaste tree during the trial might be a result of the stimulation of endogenous melatonin secretion.

Commentary: The authors speculated that chaste tree may have value in the treatment of insomnia and jetlag. If chaste tree does significantly improve nocturnal melatonin release, it could also be particularly valuable in the treatment of the type of insomnia linked to fibromyalgia, which shows a pattern suggestive of disturbed circadian rhythm.
In the meantime, in what could probably be regarded as ultimately futile research, a number of investigative teams are examining chaste tree for possible estrogenic activity. One study identified the common fatty acid linoleic acid as an estrogenic compound from chaste tree2 and another identified the relatively common flavonoid apigenin as the most active phytoestrogen in this herb.3 Since these compounds are widely found in the plant kingdom, they can hardly explain the unique clinical applications of chaste tree recognized by most Western herbalists. No doubt this sort of research will lead to a mistaken belief among the misinformed that the therapeutic effects of chaste tree can be explained in terms of its possessing estrogenic properties.

1. Dericks-Tan JS, Schwinn P, Hildt C. Dose-dependent stimulation of melatonin secretion after administration of agnus castus. Exp Clin Endocrinol Diabetes 2003; 111: 44–46
2. Liu J, Burdette JE, Sun Y et al. Isolation of linoleic acid as an estrogenic compound from the fruits of
Vitex agnus-castus L. (chaste-berry). Phytomedicine 2004; 11(1): 18–23
3. Jarry J, Spengler B, Porzel A et al. Evidence for estrogen receptor b-selective activity of
Vitex agnus-castus and isolated flavones. Planta Med 2003; 69: 945–947

Ginger and Nausea of Pregnancy: More Evidence of Safety and Efficacy
The use of ginger by pregnant women to treat nausea and vomiting is widespread, however concerns have been expressed in some circles about the safety of such a practice. In particular, the clinical trials that have been conducted in the past have only observed the use of ginger over a 4-day time period, which does not lend confidence to the safety of the extensive use of ginger during the first trimester of pregnancy.

Recently the results of three studies (two of them from Australia) have been published which provide further evidence for the safety and efficacy of ginger during pregnancy. The first study was conducted at the Royal Hospital for Women in Randwick NSW.1 The effect of a ginger extract on the symptoms of morning sickness was investigated in 120 women in a double-blind, randomized, placebo-controlled trial. Participants were less than 20 weeks pregnant who had experienced morning sickness daily for at least a week and had experienced no relief of symptoms through dietary changes. They received 125 mg of ginger extract (equivalent to 1.5 g of dried rhizome) or placebo four times per day for 4 days. The nausea experience score was significantly less for the ginger extract group relative to placebo after the first day of treatment and this difference was observed for every treatment day. While retching was reduced to some extent, there was no significant effect observed on vomiting. Follow-up of the pregnancies revealed normal ranges of birth weight, gestational age, Apgar scores (see footnote below) and frequencies of congenital abnormalities. Four participants in the ginger group withdrew from the trial due to reflux and heartburn caused by the relatively high dose of ginger used.

In the second Australian study, the effect of 1.05 g of ginger or 75 mg of vitamin B6 per day were compared using a randomized, double-blind design.2 The trial involved 291 South Australian women less than 16 weeks pregnant and either treatment was given for 3 weeks. Differences from baseline in nausea and vomiting scores were estimated for both groups at days 7, 14 and 21 of the trial. The trial found that ginger was equivalent to vitamin B6 in reducing nausea, retching and vomiting. There was no evidence of different effects between the two treatments at each of the three assessment points of the trial. Morning sickness improved in little more than half of the women in each group. No differences in congenital abnormalities were detected between the study groups and the overall risk of pregnancy complications did not differ. In addition, there were no differences found for any other birth outcomes. The authors concluded that, because of the relatively small size of the study, firm evidence of the safety of ginger in pregnancy is still required and further systematic research on the risks and benefits of ginger during pregnancy would be of great clinical relevance.

The third study was conducted in Canada.3 Rather than being a clinical trial, it was a comparative observational study where pregnant women who took ginger were compared to a control group. The outcome of 187 pregnancies where women took ginger for nausea and vomiting were compared with 187 pregnancies where no antiemetic medications were used. The study found that there were no statistical differences in pregnancy outcomes between the ginger group and the comparison group, with the exception of more infants weighing less than 2.5 kg occurring in the comparison group (12 versus 3, p £ 0.001). In addition, a total of 66 women who had used ginger alone for a minimum of 3 days completed an effectiveness score for the treatment. The mean score of 3.3 ± 2.9 indicated mild effectiveness for the ginger in the treatment of nausea and vomiting of pregnancy. However, various types of ginger were consumed by the women including capsules, ginger tea, fresh ginger, pickled ginger, candied ginger and so on. A total of 49% of the women used capsules, with the rest using the various other preparations. When the authors compared the effectiveness of the different forms of ginger they found that the capsules were significantly more effective than all the other preparations combined (4.2 ± 3.1 versus 1.7 ± 0.7, p < 0.001). No information was provided concerning the length of time that ginger was used by the women. Again the authors stressed that conclusions about the safety of ginger during pregnancy were limited by the relatively small size of their survey.

Commentary: These studies are timely given the widespread use of ginger by pregnant women throughout the world. For example, a recent survey of 400 women found that 36% had used herbal products during their pregnancy with an average of 1.7 products per woman.4 The proportion of women using herbs increased throughout the first, second and third trimesters. The most commonly used herbs were Echinacea, herbal-based iron supplements, ginger, chamomile and cranberry. The South Australian study is particularly significant because of the longer time period over which ginger was used by the pregnant women. The results of the Canadian study are also useful because the survey observed the actual usage of ginger and (although not stated), presumably ginger was used by these pregnant women for substantial periods of time.

The Apgar score was introduced in 1973 and is a method developed by Dr. Virginia Apgar to evaluate a newborn's adjustment to extrauterine life (life outside the uterus). Five items (heart rate, respiratory effort, muscle tone, reflex irritability, and color) are evaluated 60 seconds after birth and again five minutes later on a scale of 0–2, 0 being the lowest, 2 being normal. The five numbers are added for the Apgar score. A score of 0–3 represents severe distress, 4–7 indicates moderate distress, and a score of 7–10 predicts an absence of difficulty in adjusting to extrauterine life.

1. Willetts KE, Ekangaki A, Eden JA. Effect of a ginger extract on pregnancy-induced nausea: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2003; 43: 139–144
2. Smith C, Crowther C, Willson K et al. A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy.
Obstet Gynecol 2004; 103: 639–645
3. Portnoi G, Chng, LA, Karimi-Tabesh L et al. Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy.
Am J Obstet Gynecol 2003; 189: 1374–1377
4. Nordeng H, Havnen GC. Use of herbal drugs in pregnancy: a survey among 400 Norwegian women.
Pharmacoepidemiol Drug Saf 2004; 13(6): 371–380

Ginkgo and Glaucoma
While the alkaloid pilocarpine from the herb Pilocarpus jaborandi has established itself as an effective topical treatment for glaucoma, there is to date little evidence that the oral use of any herbs can help this condition. In this context, the publication of a recent clinical trial on the effect of Ginkgo biloba extract on pre-existing visual field damage in normal tension glaucoma is noteworthy.1 Normal tension glaucoma is a form of primary open-angle glaucoma in which damage to the optic nerve and visual field are present despite intraocular pressure measurements being within statistically normal ranges. The exact mechanisms behind the anatomic and functional damage in this disease are unknown, but there are two main theories: reduced blood flow to the optic nerve versus relatively high intraocular pressure. Because some patients with normal tension glaucoma can continue to experience a loss of visual field despite conventional medical treatment, the value of other treatments is worthy of investigation. Since Ginkgo biloba has been shown to improve blood flow at a tissue level, it was an obvious candidate for selection in such investigations.

In a randomized, double-blind, placebo-controlled, crossover trial, 27 patients with bilateral visual field damage resulting from normal tension glaucoma received either 120 mg of
Ginkgo biloba extract (equivalent to 6 g herb) or placebo. Since it was a crossover trial, patients acted as their own placebo controls. Visual field tests were performed at baseline and at the end of each 4-week treatment phase. The main outcome measured was any change in the visual field and the development of any ocular or systemic complications. After Ginkgo biloba treatment, a significant improvement in visual field indices was recorded, but there were no significant changes found in intraocular pressure, blood pressure or heart rate. No ocular or systemic side effects were noted in any patient during the trial. The authors concluded that their results suggest that Ginkgo biloba extract can improve pre-existing visual field damage in some individuals with normal tension glaucoma. However, they observed that the exact explanation for this effect is not currently understood.

Commentary: The results of this trial are promising, but as the authors pointed out, a longer treatment period needs to be investigated to determine whether the effects of Ginkgo biloba extract are temporary or will continue with prolonged treatment. Based on this finding, it is suggested that Ginkgo biloba may be valuable in all patients suffering from visual field damage irrespective of the type of glaucoma. However, it should be emphasized that Ginkgo biloba on its own is not an adequate treatment where intraocular pressure is significantly raised.

1. Quaranta L, Bettelli S, Uva MG et al. Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma. Ophthalmology 2003; 110: 359–364

Valerian: The Hunt for the 'Active Constituent' Continues
The sedative and anxiolytic effects of valerian have over the years been attributed to a number of phytochemicals found in the root of this plant.1 While early research concentrated on the effects of the essential oil, it is generally believed that this makes only a minor contribution to its activity (about one-third). Research on valerian in the 1950s demonstrated that the essential oil was not primarily responsible for the sedative activity. This led to the search for other components and the valepotriates were discovered about 10 years later. Attention then focused on the valepotriates and later their decomposition products. Research in the past decade has focused on the component valerenic acid and its derivatives as important sedative components unique to the European valerian. These compounds may explain the activity of a water-extracted valerian, which was noted in some clinical trials.

However, much has been made in a recent press release concerning the discovery of new components in valerian that may contribute to its sedative effect.2 The researchers say that a compound in the phytochemical class known as lignans in valerian latches onto specific receptors in the brain which control the body's sleeping and waking rhythms. Caffeine affects the same type of receptor but has the opposite effect according to the researchers.3

On the face of it, this new research suggests that valerian works on adenosine receptors targeting specifically A1 receptors and thereby triggering drowsiness. In the press release, Christa Müller, Professor of Pharmaceutical Chemistry at the University of Bonn, said: “We repeated the experiments and were able to confirm that aqueous alcoholic full extracts from the valerian root can attach themselves to the A1 receptor, at least in the brains of rats . . . What is more, we were able to show for the first time that the extract activates the receptors rather like adenosine does. Experiments with genetically produced human receptors had a similar result.”

Commentary: As can be seen from the above, the press release2in fact contains additional developments to the paper previously published in the Journal of Natural Products.3 In the published paper, the lignans in valerian were identified as mainly occurring as glycosides. These lignan glycosides would have extremely low bioavailability and would be highly unlikely to cross the blood-brain barrier. Hence this is another case of where in vitro or test tube research on herbs has been extrapolated out of proportion to the test results. In other words, due to the poor bioavailability of these compounds and the limited relevance of in vitro models, it must be concluded that any inferences drawn from this research are highly tentative. More research in both clinical and experimental models is required to validate the assertion that the lignans are partly responsible for the sedative effect of valerian. The press release also contains reference to a Swiss research team which measured the effects of valerian on the brain waves of around 50 test subjects. After caffeine was ingested the alpha waves leveled out, signalling relaxation. By contrast, the beta waves, signs of nervousness, became more marked. When valerian extract was administered, this effect of caffeine was neutralized. This could be explained in terms that the herb does in fact affect the A1 adenosine receptor, but these findings could equally be explained in terms of the general calming effect of valerian. A possible future direction for this research would be to identify the bioavailable forms of the valerian lignans and test these compounds in the in vitro models of the adenosine receptor.

Until more information is available we should resist the temptation to declare that the active components in valerian have finally been elucidated. Indeed, on current evidence, valepotriates, valerenic acid derivatives and the essential oil are still the most important quality markers for this herb.

1. Mills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. Churchill Livingstone, Edinburgh, 2000, p 583.
2. [no author listed]. Scientists unravel mechanism behind valerian's calming effect. News 13/2/2004. Available: Accessed 21 April 2004.
3. Schumacher B, Scholle S, Holzl J et al. Lignans isolated from valerian: identification and characterization of a new olivil derivative with partial agonistic activity at A(1) adenosine receptors.
J Nat Prod 2002; 65(10): 1479–1485

Herb-Drug Interactions

HDI Scares: Survey Does Not Confirm the Fears . . .
From time to time there have appeared various media articles and papers in medical journals written in alarmist terms about the dangers of herb-drug interactions. So it is refreshing to find a study which examined the reality of the potential of such interactions, rather than exaggerated concerns. The US study explored the potential incidence and severity of interactions between prescription medications and dietary supplements (including herbal products) at two outpatient practices.1

A survey was conducted on dietary supplement use by 458 veteran outpatients currently taking prescription medications. Self-reported dietary supplement use was cross-referenced with each patient's prescription medication list, and potential interactions were identified from several texts and medical literature searches.

It was found that 197 patients (43%) were currently taking at least one dietary supplement with prescription medication(s). The most common products included vitamins and minerals, garlic,
Ginkgo biloba, saw palmetto, and ginseng. Among these, 89 (45%) had a theoretical potential for drug-dietary supplement interactions of any significance. Most of these potential interactions (n=84 (94%)) were not serious, based on limited available evidence, giving an incidence of 6% (5/89) of potentially severe interactions among patients taking interacting drugs and dietary supplements and 3% (5/197) among patients taking coincident dietary supplements and medications.

Commentary: While this study is valuable, it has a major shortcoming. The potential or theoretical interactions identified were not investigated further to ascertain whether an actual interaction had occurred. One suspects, if they had done this, that the number of actual serious interactions would be lower than even a few percent, maybe even zero.

. . . And Our Knowledge Continues to Grow
A number of clinical studies and case reports on the topic of herb-drug interactions have appeared in the literature. One of these examined the potential interaction between digoxin and hawthorn (Crataegus oxyacantha).2 It found that hawthorn had no effect on the pharmacokinetic profile of digoxin. Similarly, saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 in healthy volunteers, as assessed by the test drugs dextromethorphan (CYP2D6) and alprazolam (CYP3A4).3 Neither did Ginkgo biloba using the same test drugs.4

In terms of case reports, an interaction between the anticoagulant drug phenprocoumon and ginger was recently described.5 This was reported to result in an elevated international normalized ratio (INR) of up to 10 and episodes of epistaxis. The INR returned to normal levels when the ginger (consumed as ginger tea, dosage not specified) was stopped. The basis of this possible interaction (pharmacodynamic or pharmacokinetic) is not known, but since ginger is not thought to possess anticoagulant activity, it was probably pharmacokinetic in nature. That is, more phenprocoumon reached the patient's bloodstream as a result of the patient taking ginger tea.

1. Peng CC, Glass PA, Trilli LE et al. Incidence and severity of potential drug-dietary supplement interactions in primary care patients. Arch Intern Med 2004; 164: 630–636
2. Tankanow R, Tamer HR, Streetman DS et al. Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha).
J Clin Pharmacol 2003; 43: 637–642
3. Markowitz JS. Donovan JL, Devane CL et al. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers.
Clin Pharmacol Ther 2003; 74(6): 536–542
4. Markowitz JS. Donovan JL, DeVane CL et al. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. .
J Clin Psychopharmacol 2003; 23(6): 576–581
5. Krüth P, Brosi E, Fux R et al. Ginger-associated overanticoagulation by phenprocoumon.
Ann Pharmacother 2004; 38: 257–260


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