A Review of Herbal Medicines for Psychiatric Disorders

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1 A Review of Herbal Medicines for Psychiatric Disorders Gabrielle Beaubrun, M.B.B.S. Gregory E. Gray, M.D., Ph.D. Objective: This review examines herbs commonly used for psychiatric of herbal remedies by patients has symptomsSt. Johns wort, kava, ginkgo biloba, and valerian. Methods: created a need for psychiatrists and MEDLINE was searched for articles related to the use of herbs in psy- other mental health professionals to chiatry published after 1990. A secondary search examined sources cit- become familiar with the effects of ed in articles obtained from the MEDLINE search. Results: Of nine con- more commonly used herbs, includ- trolled and standardized trials of St. Johns wort, five showed the herbs ing their risks, side effects, and con- superiority to placebo, and four found no differences in effectiveness traindications. Unfortunately, this when compared with antidepressant drugs. The pharmacologically ac- topic is not covered in most medical tive components are not known. Several double-blind, placebo-con- school curricula, psychiatry residency trolled trials have demonstrated the anxiolytic efficacy of kava, but these programs, or textbooks of psychiatry studies had ill-defined patient populations, small sample sizes, and short and psychopharmacology. However, treatment duration. All but one of 40 controlled trials of ginkgo extracts this situation is beginning to change, in the treatment of dementia found clinically significant improvement in as evidenced by a recent issue of memory loss, concentration, fatigue, anxiety, and depressed mood. Most JAMA devoted to alternative medi- studies of gingko had poorly defined patient populations and small sam- cine (November 11, 1998). ple sizes and used nonstandard measures. A recent well-designed multi- Our review is intended as a brief center study showed significantly less decline in cognitive function introduction to the subject. Readers among patients with dementia receiving gingko. Valerian has been are referred to several recent texts shown to decrease sleep latency and nocturnal awakenings and improve and publications for further infor- subjective sleep quality, but placebo effects were marked in some stud- mation (37). ies, and in some cases the beneficial effects were not seen until two to four weeks of therapy. Conclusions: Although evidence of the efficacy of Methods herbal preparations in treating psychiatric conditions is growing, trans- MEDLINE was searched for articles lating the results of efficacy studies into effective treatments for patients published after 1990 related to the is hampered by the chemical complexity of the products, the lack of use of herbs in psychiatry. Search standardization of commonly available preparations, and the paucity of terms used were herb, herbal, kava, well-controlled studies. (Psychiatric Services 51:11301134, 2000) valerian, gingko, and St. Johns wort. A secondary search was performed using references obtained from arti- O nce considered a countercul- a given month (2). Four of the 12 cles identified by the MEDLINE ture phenomenon, herbal most commonly used herbal medica- search, and recent textbooks of herbal medicines are now a $4 bil- tionsSt. Johns wort, kava, ginkgo, medicine were consulted. lion industry, and herbal products are and valerianare taken for the pre- readily available in drugstores and vention or treatment of psychiatric Results supermarkets (1). It has been esti- symptoms, which is the most rapidly St. Johns wort mated that one of every three Amer- growing segment of the herbal prod- St. Johns wort (Hypericum perfora- icans has used herbal remedies (1), uct market (1). tum) is an aromatic perennial that is with 50 million people using them in The increasing interest in and use native to Europe but now grows wild in parts of Asia, North America, and South America. Its use can be traced back to the texts of the ancient Greek Dr. Beaubrun is a resident in general psychiatry at the Martin Luther King, Jr.Drew physicians Hippocrates and Galen. In Medical Center in Los Angeles. Dr. Gray is professor and chairman of the department of psychiatry and human behavior at the Charles R. Drew University of Medicine and Sci- the past decade it has become the sec- ence and director of the Augustus F. Hawkins Comprehensive Community Mental Health ond most commonly used herbal rem- Center at the King-Drew Medical Center, 1720 East 120th Street, Los Angeles, Califor- edy in Germany (3) and is currently nia 90059 (e-mail, [email protected]). Send correspondence to Dr. Gray. used in that country for the treatment 1130 PSYCHIATRIC SERVICES September 2000 Vol. 51 No. 9

2 of depression four times more often dry mouth, sedation, and headache than the most commonly used pre- (16). Photosensitivity appears to be a scription antidepressant (8). In the Editors Note: This is the sec- risk at dosages higher than those typ- United States, St. Johns wort is the ond in an occasional series of ically used to treat depression (23). second most commonly purchased articles on psychopharmaco- There do not appear to be significant herbal product. An estimated 17 per- logical treatments. The arti- adverse effects on cardiac conduc- cent of Americans have taken prod- cles were solicited by George tion (24). The use of hypericum ex- ucts containing St. Johns wort (1). M. Simpson, M.D., editor of tracts is contraindicated in pregnancy Much of the popularity of St. Johns the journals Psychopharma- and lactation due to inadequate safe- wort in the United States and other cology column, who has ty data (25). English-speaking countries followed found that some important Because the mechanism of hyper- the publication of a review article by topics require more extensive icum extracts may involve serotonin Linde and colleagues (9) in the discussion than is possible in reuptake blockade, extracts should British Medical Journal in 1996. The the relatively short space of a not be combined with monoamine article received considerable publici- column. The first article in oxidase inhibitors or selective sero- ty in the lay press (8,10). More than this series reviewed pharma- tonin reuptake inhibitors, as the two dozen reports of clinical trials of cology of depression in chil- combination could cause a serotonin hypericum extracts have been pub- dren and adolescents (see the syndrome (26). In addition, an inter- lished; the majority of trials have May 2000 issue, pages 627 action between hypericum extracts been conducted with methanol ex- 633). Another will focus on and olanzapine has been reported, tracts of the herb (3,9,11). attention-deficit hyperactivi- with a patient having a 300 percent However, if the analysis is restrict- ty disorder across the life increase in olanzapine levels after ed to well-controlled trials using stan- span. starting St. Johns wort (27). The lat- dardized dosages and standard out- ter interaction may have been due to come measures, nine studies are of an effect of some component of the interest (3). Five of these were place- extract inhibiting CYP 1A2 and thus bo-controlled studies using 900 mg interfering with the metabolism of per day of an aqueous methanol ex- St. Johns wort, the National Insti- olanzapine. tract referred to in the literature as LI tutes of Health recently funded a 160, with a treatment duration of at multisite study comparing the LI 160 Kava least four weeks. The five studies (3) preparation with sertraline and place- The kava shrub (Piper methysticum) used the Hamilton Rating Scale for bo in an eight-week trial. Results is native to Polynesia and the Pacific Depression (HAMD) as an outcome should be available in two to three Islands, and it has traditionally been measure (12). Overall, patients re- years. taken by Pacific Islanders as a bever- ceiving the extract showed a slightly The components of hypericum ex- age mixed with water and coconut greater improvement in HAMD tracts that may be responsible for any milk (3). Kava is becoming a popular scores than those receiving placebo. antidepressant actions are unknown. herbal product in the United States, When response was defined as at Extracts of St. Johns wort contain a with sales increasing rapidly (1). least a 50 percent decline in HAMD large number of compounds (3,17), Most medicinal forms are either scores, 61 percent of the patients re- and although it is often assumed that ethanol-water or acetone-water ex- ceiving the extract responded, com- hypericin is the active ingredient, it tracts (3). pared with 24 percent receiving a has not been proved. The mechanism Kava is one of the few herbal reme- placebo. of action is also unclear. Early studies dies in which the pharmacologically Four studies of St. Johns wort com- suggested that extracts of St. Johns active ingredient is known. Meyer pared a dosage of 900 mg per day of wort inhibited monoamine oxidase (28) proved that the effects of kava the LI 160 preparation of hypericum (18), but more recent studies have are due to the kavapyrones, which in against low dosages of maprotiline, failed to find such inhibition at the animal models act as muscle relaxants imipramine, and amitriptyline for pa- tissue concentrations that occur fol- and anticonvulsants, protect against tients with mild to moderate depres- lowing typical dosages (19,20). In- strychnine poisoning, and reduce lim- sion (1316). Although no statistically stead, it appears that the extract may bic system excitability. Exactly how significant differences in response block the reuptake of norepinephrine the kavapyrones produce these ef- were found, the studies were small, and serotonin and down-regulate fects is unclear, as they have a variety raising the possibility of type II error, serotonin receptors (21). of actions involving inhibition of volt- and no placebo control groups were Side effects of hypericum extracts age-dependent sodium channels, in- included, raising the question of are mild and uncommon. In a study creasing GABAA receptor densities, whether the conventional antidepres- of more than 3,000 patients taking blocking norepinephrine reuptake, sants were any better than placebo at hypericum, only 2.4 percent reported and suppressing the release of gluta- the dosages used. side effects, primarily allergic reac- mate (2932). Because of the relatively small tions and gastrointestinal upset (22). Several double-blind, placebo-con- number of well-controlled studies of Other reported side effects include trolled trials have been conducted us- PSYCHIATRIC SERVICES September 2000 Vol. 51 No. 9 1131

3 ing a standardized extract containing Ginkgo number of substances that have been 70 percent kavapyrones given in a Ginkgo trees (Ginkgo biloba) are na- found to have a variety of pharmaco- dosage of 210 mg a day (3). In two of tive to East Asia and are grown orna- logical effects (3,40). The ginkgo these studies, a significant difference mentally in Europe and North Amer- flavonoids are thought to be antioxi- in scores on the Hamilton Anxiety ica. Used in China for more than dants, and the ginkgolides, especially Rating Scale (HAMA) (33) was seen 2,000 years as a tea for treatment of ginkgolide B, inhibit platelet-activat- after only one week of treatment; in asthma, ginkgo is now the most com- ing factor. There is also evidence that the third and largest study, a signifi- monly sold herbal product in Ger- ginkgo extracts can improve vascular cant difference in HAMA scores was many and one of the top three herbals perfusion by modulating vessel wall seen after eight weeks, with the dif- in the United States, where it is taken tone. ference continuing until the study primarily to prevent or treat memory Side effects from ginkgo are rela- terminated at week 25 (3). Several problems (1,3). U.S. sales increased tively uncommon but include head- double-blind studies have also dem- markedly after a report in JAMA of a ache, gastrointestinal upset, and al- onstrated that DL-kawain, one of the clinical trial of the use of kava for pa- lergic skin reactions (40). Rarely, kavapyrones, in dosages of 200 to 600 tients with dementia (39). ginkgo preparations have been asso- mg a day is more effective than place- Standardized commercial prepara- ciated with cerebral hemorrhage bo as measured by reduced HAMA tions usually contain the active com- (42). The safety of ginkgo in preg- scores (3). ponents flavone glycosides (24 per- nancy or lactation has not been es- The major criticism of all of these cent) and terpenoids (6 percent). The tablished. studies has been their ill-defined pa- extracts most commonly used thera- Because ginkgolide B is a potent tient populations; in addition, many peutically are designated as EGb 761 inhibitor of platelet-activating fac- had small sample sizes and were of and LI 1370 (3). tor, ginkgo extracts have the poten- short duration. Although it appears A review by Kleijnen and Knip- tial to interact with platelet-antiag- that kava extracts have anxiolytic schild (40) of more than 40 controlled gregating and antithrombolytic ther- properties, it remains to be seen for trials of gingko showed that all but apies (4,42). In addition, they should which patients they may be most use- one found clinically significant im- be used with caution by patients ful and how they compare with con- provement in symptoms such as who consume alcohol or who have ventional anxiolytics in efficacy. memory loss, concentration difficul- other risk factors for hemorrhagic When kava has been taken in ties, fatigue, anxiety, and depressed stroke (42). dosages ranging from 100 to 210 mg mood. However, most of the studies of kavapyrones daily, it has been asso- had poorly defined patient popula- Valerian ciated with few adverse effects. In tions and small sample sizes and used Approximately 250 different species studies comparing kava and ox- nonstandard outcome measures. of valerian exist. The one used most azepam, kava appears not to adverse- A more recent 52-week, random- commonly for medicinal purposes ly affect cognitive function, mental ized, double-blind, placebo-con- (Valeriana officinalis) is a perennial acuity, or coordination (34,35), al- trolled, multicenter study of more that is native to Europe and Asia. Va- though slight morning tiredness and than 300 patients with Alzheimers lerian root is frequently made into a reduced reactivity while driving have disease or vascular dementia used the tea by adding 3 to 5 g of dried valer- been reported (4), as has ataxia (36). EGb 761 extract at a dosage of 120 ian root to hot water and straining af- In rare cases, kava may lead to aller- mg a day (39). The group taking gink- ter ten to 15 minutes (4). In addition, gic reactions, yellowing or scaling of go extract showed significantly less a variety of extracts and tinctures the skin, gastrointestinal complaints, decline on two of the three standard- have been prepared, with consider- pupil dilation, and blurred vision ized rating scales. The outcome able differences in composition be- (4,34). Heavy use by Australian abo- measure was improvement of 4 points tween the aqueous and ethanol ex- rigines and Pacific Islanders has been or more on the cognitive subscale of tracts (3). Preparations available in associated with hepatotoxicity, hema- the Alzheimer Disease Assessment the United States are often mixtures turia, macrocytic anemia, ataxia, in- Scale (41), which is roughly equiva- that include other ingredients such as creased patellar reflexes, weight loss, lent to a six-month reversal of symp- passion flower. hair loss, and rash (3,37). However, toms. On the basis of this measure, 27 Several studies of the effects of va- aborigines in one study ingested percent of the EGb group improved, lerian extracts on sleep have been 50,700 mg a day (37); a typical thera- compared with 14 percent of the conducted. In healthy human sub- peutic dosage is 210 mg. Kava is con- placebo group. Although these effects jects, 400 to 900 mg of valerian ex- traindicated during pregnancy and are modest, they may be valuable to tract decreased sleep latency and lactation (4). patients and families and are not un- nocturnal awakenings and improved Kava may potentiate the effects of like results from studies of cholin- subjective sleep quality (4345). alcohol, benzodiazepines, and other esterase inhibitors. More study is However, placebo effects were sedative-hypnotic agents through ad- clearly warranted to determine which marked in some studies, and in some ditive effects (4,38). Patients taking patients might benefit from this treat- cases the beneficial effects of valerian benzodiazepines should be advised ment. were not seen until after two to four not to take kava. Ginkgo extracts contain a large weeks of therapy. 1132 PSYCHIATRIC SERVICES September 2000 Vol. 51 No. 9

4 Valerian extracts contain more than Health and Education Act of 1994 Times in which samples of ten differ- 100 different constituents. Which of (5). This situation differs considerably ent brands of St. Johns wort were them are responsible for the pharma- from that in Germany, where herbal sent to an independent laboratory for cological actions is not known with preparations are regulated more like analysis (48). The amount of hyper- certainty, as the whole valerian ex- drugs (3,5). For this reason few con- icin, a component that is often used tract has been demonstrated to have trolled studies of the efficacy and for standardization purposes (3), var- central nervous system actions not at- safety of herbal preparations are pub- ied from 20 to 140 percent of the tributable to valeric acids, valepotri- lished in English-language journals, amount claimed on the label, with ates, or volatile oils (3). In laboratory making it difficult for most American half of the brands containing less animals, valerenic acids have sedative psychiatrists to gain access to infor- than 80 percent of the labeled and anticonvulsant effects, and valer- mation about these compounds. Fur- amount, and two brands containing ian extracts have been demonstrated thermore, compared with conven- more than 120 percent of the labeled to have a variety of effects on GABA- tional medications, much less is amount. Thus one cannot generalize ergic neurons, including increased re- known about the safety and efficacy from the results obtained with one lease of GABA, decreased GABA re- of these compounds. preparation to those that might be uptake, and decreased GABA degra- Another important implication of expected with a different prepara- dation (3). the less rigorous U.S. regulation is tion, even if the labels indicate that Adverse effects of valerian prepara- that herbal preparations are not they are similar. tions are rare but may include gas- standardized in the same way that trointestinal upset, contact allergies, pharmaceutical products are. Prod- Conclusions headache, restless sleep, and mydria- ucts may vary greatly in their compo- It is becoming increasingly impor- sis (4). Valerian appears to be rela- sition depending on variation in the tant for physicians to be familiar tively safe in overdose (46), with the raw plant material due to genetic with the herbal remedies commonly major effect being central nervous (varietal) factors, climate, growing used in the patient populations they system depression (47). Currently, lit- season, soil, rainfall, and other grow- serve. Our patients are frequently tle is known about its safety in preg- ing conditions; method of prepara- exposed to sketchy information nancy and lactation. tion; and the type of solvent used in about these products through the The major drug interactions of va- the extraction process (3). Thus tea media or marketing campaigns, and lerian are with other sedative-hyp- brewed from a dried herb will differ they will quite rightly expect their notics. The sedative effects of valerian in composition from an alcohol ex- physicians to be able to answer their may potentiate the effects of other tract, and both will differ from a questions about indications, risks, central nervous system depressants. volatile oil distilled from the crude interactions, and side effects of plant material. Because these herbal herbal products. Other herbal hypnotics products contain a variety of com- In addition, increasing numbers of Herbal teas have long been con- pounds, and because the active com- clients express a preference for the sumed for their presumed sedative- pounds are often unknown, it is diffi- use of remedies they perceive to be hypnotic effects. Besides valerian, cult to standardize preparations. In natural, and physicians familiar common ingredients in such teas are addition, adulteration and substitu- with the available research will be hops, lemon balm, chamomile, and tion may occur when the plant mate- better equipped to make informed passion flower, although a variety of rial is expensive. and safe decisions about whether it is other herbs have also been used (3). For all of these reasons, we cannot appropriate to recommend herbal The best studied of these is chamo- conclude, for example, that a U.S. remedies in selected cases. mile. Although chamomile has been product that is described as contain- Although evidence of the efficacy widely used as a folk remedy (3,6), ing a certain amount of ginkgo extract of certain herbal preparations in the there does not appear to be experi- would be the same as a product such treatment of psychiatric conditions is mental confirmation of its effective- as EGb 761 made in Germany, where growing, translating the results of ef- ness as a sleep aid. However, recep- standardization is more exact (5). ficacy studies into effective treat- tor-binding studies have found com- Thus it is extremely difficult to gener- ments for patients is hampered by ponents of chamomile extract to bind alize the results of European studies the chemical complexity of the prod- to GABA receptors (6). Far less is in which well-standardized prepara- ucts and the lack of standardization known of the effectiveness of the oth- tions are used to the results that of commonly available preparations, er herbs. might be obtained using American not to mention the paucity of well- preparations purchased in a drug- controlled studies of safety and effi- A note of caution store, health food store, or supermar- cacy. In particular, well-controlled The herbal preparations described ket. This difficulty is a further con- studies comparing herbal remedies here and conventional medications cern when investigators try to evalu- with conventional medications are are regulated in very different ways. ate the safety and efficacy of these few. As a result, it is premature for In the United States, herbal prepara- products. psychiatrists to recommend herbal tions are regulated as dietary supple- This problem is illustrated in a re- remedies over established conven- ments under the Dietary Supplement port published by the Los Angeles tional treatments. PSYCHIATRIC SERVICES September 2000 Vol. 51 No. 9 1133

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