Western Herbal Medicines
Excerpt from: Lee, R, Yee, P, Naing, G. Western Herbal Medicines. In Lake, J and Spiegel, D (ed.),
Clinical Manual of Complementary and Alternative Treatments in Mental Health.
Washington, DC: American Psychiatric Press, Inc. 2006.
Introduction
Historically the initial production of medicines and pharmacologic treatment of medical conditions began with the use of herbs. Until about 1930 herbal products represented a large portion the United States Pharmacoepoeia. Today, many commonly used medicines are derived from plants, for example, colchicine, digoxin, ephedrine , vincristine and others. Legislation of the medicinal uses of botanicals varies from country to country. The U. S. Congress passed the Dietary Supplement and Health Education Act in 1994, which classifies botanical medicines as food supplements. In other countries, such as Germany, botanical medicines are evaluated in a special committee comprised of experts in the field of botany, ethnobotany, pharmacology, and medicine. It is beyond the scope of this chapter to discuss these distinctions in detail. Those wishing more information can learn about this in a variety of botanical reference texts such as the ABC Clinical Guide to Herbs published by the American Botanical Council (Blumenthal 2003).
In the 1990s, sales of herbal products increased with their highest retail sales in 1998 and subsequently leveled off in 2001 (Blumenthal 2003). The decline in consumer use has been ascribed to a variety of factors including the release of negative media articles on botanicals, reports of poor quality herbal products and unreasonable consumer expectations. Yet compared to prescription medications there are fewer per capita reports of adverse events associated with herbal remedies in the U.S (Blumenthal 2003). However, a growing body of medical evidence suggests that significant pharmacologic interactions are possible with some botanical plants. It has been reported that up to 70% of patients who use alternative therapies fail to disclose this fact to their physicians ( Eisenberg 1998). Complaints of fatigue, headache, insomnia, depression and anxiety are the most frequent reasons patients seek alternative therapies (Yaeger 1999). Furthermore, many patients are reluctant to accept a diagnosis of a psychiatric disorder, making the use of botanical alternatives a frequent choice. Thus, whether or not practitioners agree with integrating botanicals in their medical practice, understanding their efficacy and potential interactions with conventional drugs is an important part of clinical training. This chapter discusses three botanicals commonly used to treat psychiatric disorders: kava (Piper methysticum), St. John's wort (Hypericum perforatum) and Ginkgo biloba.
Kava ( Piper methysticum ) (written by Roberta Lee M.D.)
Overview of historical and current uses of Kava (Piper methysticum)
Piper methysticum , commonly known as kava, kava-kava or awa is a plant of great cultural significance to Pacific islanders and has been used for centuries ( Lebot 1992). Even today, Melanesian, Polynesian and Micronesian peoples grind fresh or dried roots of this plant to prepare a traditional beverage that serves as a ceremonial centerpiece for occasions of great social and political significance including honoring a respected elder, buying a piece of land, and settling disputes. The botanist J. G. Forster (1777), who sailed with Captain James Cook on his second voyage, is credited with the first valid botanical description of this esteemed Pacific plant. However, the first scientific observations of its presence in the Pacific remain in question. The Dutch navigators, Le Maire and Schoeten observed its use in the island of Futuna as early as 1616 ( Lebot, 1989) . Writings commonly cite the eighteenth-century British explorer James Cook as the earliest person to record its Pacific presence. In his captain's log he noted that those in his crew who sampled large amounts of this beverage seemed to be sedated as if they were taking opium (Steinmetz 1960). Cook's characterization of kava's pharmacologic activity as a hallucinogen ultimately was proven to be incorrect. Kava is now recognized as a mild narcotic and hypnotic (Lewin 1924; Shultes, Hoffman 1979 ). There were many traditional medical uses of Kava, including as a treatment of inflammation of the urogenital system, gonorrhea, menstrual problems, migraine headaches, chills, vaginal prolapse, rheumatism, dermatological conditions and nervousness ( Lebot 1992). In the last one hundred and fifty years, numerous scientific publications on the chemical and pharmacologic activity of kava have given Western medicine greater insight into the potential pharmacologic value of this plant.
During the last twenty years kava has gained popularity as an herbal treatment for anxiety, nervousness, insomnia, stress, management of benzodiazepine withdrawal, and anxiety related to menopause. In 1998, kava ranked fifth in the North American botanical sales market ( Mirasol 1998). However, its use and sales rapidly plummeted beginning in the fall of 2001 after many cases of hepatotoxicity were reported. By the end of 2001 public health authorities in Germany initiated a new evaluation of the risk:benefit ratio of kava. This soon led to the withdrawal of authorization for continued sales of kava products in Germany. Other public health authorities in Europe, including Switzerland and countries around the world, soon followed Germany's example (Blumenthal 2002). Today, strict warnings exist in countries where sales of kava are permitted, dampening the public and professional use of this botanical product.
Review of the clinical evidence
a. Anxiety
Kava has been evaluated in fourteen randomized clinical trials for anxiety in studies ranging from 4 to 25 weeks in duration. A meta-analysis of randomized trials initially published in 2000 (Pittler 2000) and updated in 2002 ( Pittler 2002) and 2003 (Pittler 2003) concluded that kava had moderate efficacy in the treatment of anxiety. In the meta-analysis, fourteen clinical trials were identified but seven were excluded due to methodological flaws including duplicate reporting, concurrent benzodiazepine use or use of an isolated kavalactone. The remaining seven clinical trials were evaluated for methodology and three were selected for analysis involving a total of one hundred ninety-eight patients. Pooled data from the three studies that used a common outcome measure, the Hamilton Anxiety Rating Scale (HAM-A), found a significant reduction in the mean anxiety score in the kava group compared to placebo with a mean difference of 9.69 points (95% confidence interval )(Pittler 2000). In the 2003 updated meta-analysis eleven trials involving a total of 645 participants were eligible for inclusion (Pittler 2003). Six studies using the HAM- A rating scale as a common outcome measure showed that kava was effective for the treatment of anxiety and “relatively safe for short term treatment (1-24 weeks) (Pittler 2003).”
b. Menopausal /Perimenopausal anxiety
Three randomized placebo controlled clinical trials have evaluated kava 100mg/day with HRT as a treatment of perimenopausal and menopausal anxiety (De Leo 2000 and 2001) or kava 100 to 200mg / day plus calcium (Cagnacci 2003). All three trials used the HAM-A or State Trait Anxiety Inventory as an outcome instrument to assess changes in anxiety. In each trial anxiety reduction was more pronounced in the treatment arms with kava versus the placebo arms.
c. Equivalence trials
Several clinical trials ( Lindenberg 1990 , Woelk 1993, Boerner 2003) comparing kava to benzodiazepines have been performed. In each of the trials no significant difference was found on anxiety measures. However, the trials lacked placebo arms and the sample sizes of the earlier trials were possibly too small to measure equivalence. In the largest randomized controlled multicenter trial, one hundred and twenty nine patients were given either 400 mg of LI 150 (kava), 10 mg of buspirone, or 100 mg of opipramol daily for 8 wks. Subjects were evaluated for anxiety using the HAM-A scale , sleep quality, quality of life and measures of general well being. Approximately 70% were classified as responders with a reduction of 50% on the HAM-A scale, and 60% achieved full remission (Boerner 2003). In a small ( N=40) randomized placebo-control trial, patients with anxiety on benzodiazepines were given increasing amounts of kava ( WS 1490) up to 300 mg / day as benzodiazepines were tapered. The dose adjustments were followed by three weeks of monotherapy with kava versus placebo. Patients were monitored for benzodiazepine withdrawal, subjective well being and anxiety. The results confirmed the anxiolytic efficacy of kava ( Malsch and Kieser 2001) .
Unresolved Safety Issues
In recommended doses over short periods of time kava has been regarded as safe. However, potential hepatotoxicity of kava has become a concern as over 30 cases of liver damage associated with its use were reported in Europe as of 2001. In several cases liver transplants were required due to the extent of hepatic damage. An independent assessment of the adverse effects in these cases was undertaken by a noted expert in the field of hepatotoxicology, Donald Waller from the University of Illinois at Chicago. He concluded that there were only a few cases in which kava might be directly associated with liver damage and that those cases were likely due to hypersensitivity or idiosyncratic responses to kava (Waller 2002). At the time of writing the FDA has issued a warning to consumers, and many countries have removed kava from public access (Blumenthal 2002). The mechanism of action, doses and durations of use associated with hepatic damage remain unclear at the time of writing. Possible causes include the method of extraction of kava resulting in an increased proportion of one or more kavalactone constituents that predispose some individuals to liver damage, and contamination of kava preparations by toxic alkaloids. Serious adverse events associated with kava use are extremely rate. One published report estimated that approximately 250 million daily doses of ethanolic kava extract were administered in the 1990s with only two causally related cases of hepatotoxicity. In both cases of hepatotoxicity kava was used at doses far beyond the recommended levels. Based on these two isolated cases the rate of adverse event reports (AER) for kava was .008 in one million daily doses. In contrast, benzodiazepines have a much higher rate: .90 AERs in one million daily doses of bromazepam, 1.23 for oxazepam, and 2.12 for diazepam. The authors concluded that the transition of patients using kava to a benzodiazepine could potentially increase the risk of adverse effects (Schmidt 2002).
Guidelines for Use in Psychiatric Disorders
Uses: Kava should be used primarily for anxiety and may be considered in some cases of sleep disorders, stress and restlessness.
Safety: In December, 2001, the American Botanical Council recommended that kava should not be taken longer than one month without professional supervision ( Blumenthal 2003). Botanical preparations should be avoided in patients who have known liver disease, a history of chronic alcohol abuse, Parkinson's disease or in patients who are chronic users of benzodiazepines or other sedative-hypnotic medications.
Dosing: Typical dosing for adults using a standardized preparation of 30% kavalatones is a daily dosage equivalent of 60--120 mg of kavalactones or total dose of 70-210 mg of kava. Most controlled clinical trials are based on three 100 mg doses of a dried extract standardized to 70 mg of kavalactones or 210 mg of kavalactones/ day. The onset of response is generally 2-4 weeks, comparable to prescriptive anxiolytic medications (Blumenthal 2003). Reputable brands used in clinical trials include Kavatrol®, Laitan® , Neuronica® and WS1490®.
Toxicology: There is considerable concern over cases of hepatotoxicity as discussed above. Chronic heavy use of kava has been associated with renal dysfunction, hematologic abnormalities, pulmonary hypertension , dermopathy and choreathetosis. These conditions have been cited in case reports however the causal relationship with kava use remains unclear due to multiple confounding variables and/or incomplete reporting.
Adverse Effects:
Dermatologic: A dermatological condition known as “kava dermopathy” which appears during prolonged and heavy use. This condition is reversible upon discontinuation ( Norton 1994).
Neurologic: Several cases of extrapyramidal side effects (Meseguer 2002) and the exacerbation of Parkinsonian symptoms (Schelosky 2002) have been reported following one to four days of use. Anecdotal cases of sedation have been reported although small human trials suggest that kava does not cause neurological or psychological impairment.
Psychiatric: Apathy has been noted with long term use (Blumenthal 2003)
Pulmonary: Pulmonary hypertension was proposed as a mechanism explaining observed shortness of breath in one study where chronic users frequently complained of breathing difficulty (69%) and non users seldom reported this problem (25%) (Blumenthal 2003).
Hematologic: Anti-platelet activity was reported with kavain, a single kavalactone. Blood dyscrasias have been reported with heavy intake in Aboriginal kava users. ( Blumenthal 2003)
Gastrointestinal: Hepatotoxicity has been an on-going concern and was discussed earlier in the chapter. Gastrointestinal upset has been reported infrequently as an adverse effect in some studies (Blumenthal 2003)
Drug interactions
Pregnancy and Lactation
Pregnant or nursing women should avoid using products that contain kava.