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Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of their constituents
General Hospital Psychiatry 24 (2002) 430 – 435
Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of their constituents Ka Fai Chung, MBBS (HK), MRCPsych (UK), FHKAM (Psychiatry)*, Claire K.Y. Lee, BNurs(HKU) Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China
Abstract This study examined the composition of over-the-counter (OTC) sleeping pills in Hong Kong and reviewed the current knowledge about the hypnotic efficacy and safety of their major herbal and dietary supplement constituents. We conducted a cross-sectional survey of OTC sleep aids at drug stores in a residential district of 0.3 million population and literature search using MEDLINE, EMBASE, PsycINFO, China Journal Net, China Biomedical Database and relevant English and Chinese literature. We identified 17 brands of OTC sleeping pill: eleven of them were composed of mixtures of Chinese and Western herbal agents and six brands contained 3 mg of melatonin. The Chinese herbal mixture suanzaorentang, comprising zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma and glycyrrhizae radix in ratio of 7:5:2:1:1, was the most common OTC sleeping pill available in the survey. Our literature review showed that kava, valerian and melatonin were the better-researched herbs and dietary supplements, however, the data on hypnotic efficacy and safety was inadequate to support their clinical use. More rigorous investigations of the risk-benefit relationship of herbal agents and dietary supplements used for insomnia are needed. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Over-the-counter medications; Traditional Chinese medicine; Herbs; Insomnia; Hypnotics
1. Introduction Insomnia is one of the most frequent health complaints brought to the attention of health care practitioners. Epidemiological surveys have suggested that 10 to 20% of adults have moderate to severe insomnia [1]. A WHO collaborative survey of 25,916 primary care attendees found that 29% of those with poor sleep had tried over-the-counter (OTC) medications for sleep [2]. Johnson et al. [3] found that use of alcohol, prescription drugs and OTC medications as sleep aids was fairly common. The past-year prevalence of any substance use to aid sleep in a sample of 18 – 45 years’ old adults was 26% [3]. A substantial minority of users reported regular use for longer than 1 month: 9% for OTC medications and 36% for prescription drugs [3]. Mellinger et al. [4] reported that 3.1% of the adult population in the past year had used OTC sleeping pills and 4.3% had taken prescribed psychotropic drugs for sleep. The use of OTC sleep aids is often for short duration but a substantial number of individ* Corresponding author. Tel.: ⫹852-285-54487; fax: ⫹852-28551345-. E-mail address: [email protected] (K.F. Chung).
uals use an agent regularly on a long-term basis [3,5,6]. Antihistamines, herbs and dietary supplements are the most frequent components of OTC sleeping pills in Western countries. In light of the growing trend in alternative medicine use in the general population [7], it is common to have patients using herbs and dietary supplements as sleep aids inquire about their efficacy, side effects and adverse drug interactions. In the U.S. herbal agents and dietary supplements are not permitted to be labeled as a drug nor to claim they treat, cure, or prevent any disease. In some European countries however, herbal medicines have a long legal history and are integrated into medicine [8]. In 1978 the German Ministry of Health established Commission E, a panel of experts responsible for evaluating the safety and efficacy of herbal products. Commission E published a therapeutic guide to herbal medicines in 1998, which is one of the major references in herbal medicine [8]. Similarly in Asia, traditional Chinese medicine also has a long history of use and many OTC drugs in Asian countries are made up of Chinese herbal agents. We conducted a survey of OTC sleeping pills in Hong Kong. We examined the composition of OTC sleep aids and
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systematically reviewed the literature related to efficacy, side effects and adverse drug interactions of those constituents purported to have hypnotic effects.
Table 1 Composition of the over-the-counter (OTC) sleeping pill in Hong Kong Type 1.**
2. Methods In July 2000, the author (KYL) located all pharmacies and grocery stores that sold packaged OTC medications in a residential district in Hong Kong. The district was within the catchment area of the study center, consisted of mainly middle and lower social class families, and had an approximate population of 0.3 million. There were a total of 42 stores; 6 had registered pharmacists at the store; 36 had no qualified pharmacist to dispense drugs. Drug stores that had registered pharmacists were generally more organized and larger in size. We randomly selected 50% of each type of store to be included in this study. We identified all OTC sleeping pills for sale at the stores and recorded the compositions mentioned on the drug packages. We used MEDLINE 1966 –2000, EMBASE 1974 –2000, PsycINFO 1967– 2000, China Biomedical Database 1981–2000 and China Journal Net 1997–2000 as database to search English and Chinese language literature. The China Biomedical Database includes more than 900 journals published in China and the China Journal Net covers 6600 major journals in full-test. The keywords used for literature review were the herbal and dietary supplement components of the OTC sleeping pills identified in the survey, ‘herbs,’ ‘natural products,’ ‘traditional Chinese medicine,’ ‘TCM,’ ‘insomnia,’ ‘sedatives,’ and ‘hypnotics.’ We also hand searched the Chinese Joural of Integrated Traditional and Western Medicine from 1983 to 2000, which contains a greater number of high quality randomized controlled trials than other Chinese language journals [9]. In addition, we reviewed relevant English and Chinese reference books on herbal medicine and traditional Chinese medicine. We thus examined the major relevant literature on the efficacy and safety of the herbs and dietary supplements that are purported to have hypnotic effects.
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2.** 3.**
4. 5. 6. 7. 8. 9. 10. 11. 12–17.
Composition* Zizyphi Spinosi Semen; Anemarrhenae Rhizoma; Ligusticum Wallichii; Poria Cocos; Glycyrrhizae Radix Natural alkaloid Zizyphi Spinosi Semen; Biotae Semen; Ophiopogonis Radix; Anemarrhenae Rhizoma; Atractylodis Macrocephalae Rhizoma; Schizandrae Fructus; Miltiorrhizae Radix; Glycyrrhizae Radix; Mori Fructus; Polygalae Radix; Ginseng; Poria. Natural alkaloid Natural alkaloid Motherwort; Hops; Kelp; Thiamine; Riboflavin; Nicotinamide; Passion flower; Wild lettuce Valerian; Passion flower; Wild lettuce; Vervain; Hops Kava Mullein; Chamomile; Passion flower; Blue Vervain; Scullcap; Hops; Oatstraw. Valerian Valerian; Kava; Hops; Passion flower; Scullcap Melatonin
* Information obtained from packages of the OTC sleeping pill; ** Three most commonly available OTC sleeping pills
Table 2 summarizes the efficacy and safety data for the herbal and dietary supplement components of the OTC sleeping pill in Hong Kong.
Table 2 Efficacy and safety data of herbs and dietary supplements with purported hypnotic effect Herbs and dietary supplements
Data score*
Efficacy score**
Safety score†
3. Results
Valerian [10–15) Kava‡ [25] Hops [16] Passion flower [16] Suanzaorentang§ [35,41–45] Melatonin [48–54]
A A D D B A
3 4 2 2 3 3
3 3 2 2 3 3
Twenty of the 21 randomly selected drug stores participated in the survey. Twelve of the 20 stores (60%) stocked OTC sleeping pills. We identified 17 brands of OTC sleeping pill (Table 1). The majority of OTC sleep aids were composed of a combination of herbs. Three agents (OTC sleeping pill 2, 4, and 5 in Table 1) did not have information regarding their composition. Six brands of OTC sleep aids were a 3-mg melatonin tablet. The herbs that were most commonly present in the OTC sleeping pills were zizyphi spinosi semen, anemarrhenae rhizoma, poria cocos, glycyrrhizae radix, valerian, kava, hops, passion flower, scullcap, and vervain.
* A ⫽ Published data including at least two placebo-controlled, doubleblind studies; B ⫽ published data including at least one placebo-controlled, double-blind study or at least three non-placebo-controlled trials; C ⫽ double-blind, nonplacebo-controlled trial; D ⫽ one open, nonplacebocontrolled trial; ** 5 ⫽ Appears very efficacious (ⱖ50% of patients); 4 ⫽ generally positive reports regarding efficacy; 3 ⫽ possibly efficacious, more data required; 2 ⫽ does not appear efficacious; 1 ⫽ generally not beneficial; † 5 ⫽ Appears generally safe and well tolerated; 4 ⫽ generally safe with some adverse effects that may limit use; 3 ⫽ generally safe but may have common adverse effects that may limit use; 2 ⫽ frequent adverse effects, at least one of which may be serious; 1 ⫽ does not appear safe (after Keck et al. [64]); ‡ Efficacy data for treatment of anxiety. No studies were performed on subjects with insomnia alone; § Zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma, and glycyrrhizae radix in ratio of 7:5:2:1:1.
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3.1. Valerian Valerian was the most researched herbal product with purported hypnotic effect. There are approximately 250 valerian species and Valeriana officinalis is the species most commonly used for medicinal purposes. Four of six randomized placebo controlled trials showed that valerian in doses of 400 to 900 mg had a subjective hypnotic effect [10 –13]. However, two recent studies did not find significant differences in subjective measures of sleep between subjects taking valerian or placebo [14,15]. In polysomnography, valerian did not have significant effects on sleep onset latency nor time awake after sleep onset, but there was a significant increase in slow wave sleep immediately and for one and two weeks after valerian use [14,15]. Schulz et al. [16] commented that valerian might have a delayed onset of action with improvements in sleep and mood after 28 days’ treatment. Valerian was postulated to act mainly as a GABA agonist [17]. Side effects of valerian, consisting of headache and morning grogginess, were uncommon [13, 15]. The herb appeared to be relatively safe even after overdose [18]. It was suggested that valerian could potentiate the effects of other CNS depressants [19,20] and cause “disinhibitation” when combined with fluoxetine [21]. In addition, hepatotoxicity was reported after taking valerian with skullcap [22]. One recent report suggested a possible withdrawal reaction upon abrupt discontinuation of valerian, which was reversed by benzodiazepine [23]. There were concerns about cytotoxicity of valepotriates contained in valerian, however in vivo studies failed to show carcinogenic effects [17] There was insufficient information to recommend valerian in pregnancy and during lactation, although no reports of teratogenicity were found [24]. In conclusion, the studies suggested that valerian increased slow wave sleep and had few adverse reactions, but its efficacy as a treatment for insomnia was doubtful [25]. Further studies using larger samples and examining the long-term effects of valerian would give a better picture of its hypnotic efficacy and undesirable effects. 3.2. Kava A meta-analysis [26] showed that kava, in daily doses of 60 to 240 mg of kavapyrones equivalent, was beneficial in the management of anxiety, however, no clinical data were available on the herb’s hypnotic action. Adverse effects of kava in therapeutic doses, consisting of mild gastrointestinal complaints, were uncommon [27]. There were case reports of extrapyramidal symptoms with use of kava [28,29]. It was suggested that the herb could potentiate the effect of CNS depressants and there was a report of a semicomatose state after kava was ingested with alprazolam [30]. Longterm heavy use of kava was reported to cause scaly rash, weight loss, liver and renal dysfunction, hematological abnormalities and possibly pulmonary hypertension [31]. The German Commission E recommended kava be used for less
than 3 months [8]. In conclusion, kava was shown to have a tranquilizing effect but its action on sleep was unclear and merits further investigation. 3.3. Hops and passion flower There were no randomized controlled trials of hops or passion flower as a single agent to treat insomnia. The German Commission E [8] recommended the two herbs for nervousness and sleep disturbance. However, Schulz et al. [16] reported that hops as a single agent had no sleepinducing effect in human subjects and that passion flower alone produced an hypnotic effect but also showed signs of hepatotoxicity and pancreatotoxicity. Adverse effects of hops included allergy and disruption of menstrual cycle [32] and hypersensitivity vasculititis was reported with passion flower use [33]. Studies suggested that both herbs should be avoided in pregnancy and during lactation [32,33] and that care should be taken when hops and passion flower is used with other CNS depressants [32,33]. One report advised that the use of hops should be avoided in depression [32]. 3.4. Zizyphi spinosi semen and glycyrrhizae radix One of the commonest ancient Chinese remedies for insomnia was a preparation consisting of zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma, and glycyrrhizae radix in ratio of 7:5:2:1:1, which is known as suanzaorentang (OTC sleeping pill 1 in Table 1). In ancient times the herbs were prepared in liquid form or “tang,” but nowdays the herbal preparation is mostly in capsules. In animals, zizyphi spinosi semen was shown to inhibit caffeine-induced excitation and prolong hexobarbital-induced sleep, however tolerance occurred after 6 days’ use [34,35]. Open studies of zizyphi spinosi semen or glycyrrhizae radix in combination with other Chinese herbs in the treatment of insomnia were all favorable. The case reports showed that the herbal mixture resulted in significant improvement of sleep in over 50% of patients with insomnia of various etiologies and only 10% of subjects showed no response [36 – 45]. There was only one published placebo-controlled trial of suanzaorentang for treatment of insomnia [46]. Sixty poor sleepers were given placebo during the first and fourth week and suanzaorentang for the second and third week. Subjective sleep measures were significantly better during suanzaorentang use, however no objective sleep parameters were assessed in the study [46]. The hypnotic effect of zizyphi spinosi semen was postulated to be due to the anticholingeric and antihistamine actions of betulic acid, an active compound in zizyphi spinosi semen [47]. Adverse reactions of zizyphi spinosi semen and glycyrrhizae radix were not systematically examined in any study. Side effects of zizyphi spinosi semen, consisting of gastrointestinal symptoms, dizziness and skin rash, were uncommon [36,46,47]. However, Ma et al. [36] reported that systolic and diastolic blood pressure in one patient with
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essential hypertension dropped significantly after taking zizyphi spinosi semen and cautioned the use of the herb in patients with hypotension and bradycardia. Adverse reactions of glycyrrhizae radix including high blood pressure, edema, muscle weakness, dizziness, and headache were dose-related and postulated to be the result of water and sodium retention [35,48]. Effects of overdose of the Chinese herbs and their use in pregnancy and during lactation were not clearly recorded. There were case reports suggesting that a combination of the Chinese herbs with Western psychiatric medications, including tricyclic antidepressants and benzodiazepines, could enhance the hypnotic efficacy of the herbs [49,50], however adverse interactions between the herbs and the CNS depressants were not mentioned in the reports. In conclusion, zizyphi spinosi semen and glycyrrhizae radix in combination with other Chinese herbs appeared to have short-term hypnotic efficacy, however longterm efficacy and safety data were limited and this merits further investigation. 3.5. Melatonin There were mixed findings in randomized placebo-controlled trials examining the hypnotic effect of melatonin qhs doses of 0.5 to 5 mg [51–57]. Two studies on middle-aged patients with persistent insomnia did not find significant improvement in subjective [51,52] nor objective [52] measures of sleep. Hughes et al. [53] did not detect any beneficial effects of melatonin on subjective sleep parameters in 14 elderly people with insomnia, however the drug significantly shortened sleep latency by polysomnography. Studies which examined the hypnotic efficacy of melatonin by objective measures alone found significant improvements in sleep efficiency [54 –57], reduction of wakening after sleep onset [54] and shortening of sleep latency [55,57] in elderly subjects with insomnia [54,55], patients with schizophrenia and insomnia [56] and healthy young subjects [57]. Side effects of melatonin, consisting of sleepiness, headache, giddiness, and nausea, were uncommon [58]. There were concerns that possible contaminants in melatonin manufacturing process could cause hypersensitivity reactions [59]. Case reports suggested that melatonin might increase seizure frequency [60], disturb sleep-wake pattern [61] and result in optic neuropathy when used with sertraline and a high-protein diet [62]. Our review did not find sufficient efficacy and long-term safety data to recommend melatonin for most patients with insomnia [63]. 3.6. Poria cocos, linusticum wallichii, radix ophiopogonis, semen biotae, rhizoma atractylodis, schizandrae, radix salviae miltiorrhizae and polygala All these Chinese herbs inhibited caffeine-induced excitation and prolong hexobarbital-induced sleep in animals, but data on their hypnotic effect and safety profile in humans was limited [34,35].
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3.7. Scullcap, kelp, motherwort, mullein, wild lettuce, vervain, oat straw, chamomile flower (German), anemarrhenae rhizoma, morus and ginseng Scullcap (skullcap) has been traditionally used as sedative and anticonvulsant, however no clinical data were found for its hypnotic effect [33]. The other herbs had no animal nor clinical evidence for sedative action [33–35]. The German Commission E did not approve scullcap, kelp, motherwort, mullein, wild lettuce, and vervain for any therapeutic purpose [8].
4. Discussion We found many brands of OTC sleeping pill at pharmacies in the study area. A significant proportion of OTC sleep aids were composed of a combination of Chinese or Western herbal agents. Melatonin was a frequently found OTC sleeping pill in Hong Kong, but sedative antihistamines were not commonly available. Our literature review identified limited evidence-based human data on the hypnotic efficacy and safety profile of the herbal agents and melatonin. The commonest type of OTC sleeping pill in our survey was made up of a mixture of Chinese herbal agents, zizyphi spinosi semen, glycyrrhizae radix, anemarrhenae rhizoma, ligusticum wallichii and poria cocos. There were many publications on the hypnotic efficacy of the Chinese herbs, however, most of the studies were open, uncontrolled and lacked systematic information on adverse reactions. Both zizyphi spinosi semen and glycyrrhizae radix were reported to affect blood pressure and there was insufficient data to recommend the herbs for patients with insomnia. Valerian, kava, hops and passion flower were approved by the German Commission E for treatment of nervousness and insomnia [8]. Based on our literature review, valerian and melatonin had the most evidence-based data for efficacy in insomnia among the herbs and dietary supplements with purported hypnotic effects, but their efficacy was not clear and therefore more data are required. Polymedicine is not often practiced in Western medicine as multiple drug interactions can lead to unexpected adverse effects. Nevertheless, since using a combination of herbs is a common traditional Chinese medicinal and Western herbal practice, evidence that herbal mixtures are superior in efficacy to a single agent and reasonably safe is required. Another major concern of OTC medications is their batchto-batch variability and impurities that can cause hypersensitivity reactions as reported in a melatonin preparation [59]. One of the major limitations of this study is that our review was restricted to English and Chinese language literature. It is possible that some relevant literature in other languages, such as Japanese and German, have been missed. Large differences in study subjects, design and outcome measures of the previous studies have limited meta-analyses of the data. Our survey was limited to one district of Hong
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Kong and it is likely that some OTC sleep aids consumed by Hong Kong people were not examined. However, we were able to sample 17 brands of OTC sleeping pill of various compositions and have largely reviewed the major constituents with purported hypnotic effects. In conclusion, the efficacy and safety data of the herbal and dietary supplement components of the OTC sleeping pill in Hong Kong was insufficient. Although the use of OTC sleep aids is common [3,4] it is premature to comment on the merits and risks of the OTC medications for individuals with insomnia and subsequent impact upon the public health care system. Future studies examining the efficacy and safety of herbs and dietary supplements in community samples of poor sleepers will enrich our knowledge about the use, value and risks of the agent. Acknowledgments We thank Grainne McAlonan for her editorial advice. References [1] Partinen M. Epidemiology of sleep disorders. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine. Philadelphia: WB Saunders, 1994. p.437–52. [2] Silva JA Costa E, Chase M, Sartorius N, Roth T. Special report from a symposium held by the World Health Organization and the World Federation of Sleep Research Societies: an overview of insomnias and related disorders - recognition, epidemiology, and rational management. Sleep 1996;19:412– 6. [3] Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep 1998;21: 178 – 86. [4] Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment, prevalence and correlates. Arch Gen Psychiatry 1985;42:225–32. [5] Pillitteri JL, Kozlwski LT, Person DC, Spear ME. Over-the-counter sleep aids: widely used but rarely studied. J Sub Abuse 1994;6:315– 23. [6] Ohayona MM, Cauleta M, Priest RG, Guilleminault C. Psychotropic medication consumption patterns in the UK general population. J Clin Epidemiology 1998;51:273– 83. [7] Eisenberg DM, Davis RB, Ettner SL, et al. Trends in complementary medicine use in the United States, 1990 –1997; results of a follow-up national survey. JAMA 1998;280:1569 –75. [8] Blumenthal M, Busse WR, Goldberg A, et al. The Complete German Commission E Monographs - therapeutic guide to herbal medicines. Austin, Texas: American Botanical Council, 1998. [9] Tang JL, Zhan SY, Ernst E. Review of randomised controlled trials of traditional Chinese medicine. BMJ 1999;319:160 –1. [10] Leathwood PD, Chauffard F, Heck E, Munoz BR. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65–71. [11] Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med 1985;50:144 – 8. [12] Balderer G, Borbely AA. Effect of valerian on human sleep. Psychopharmacol 1985;87:406 –9. [13] Lindehl O, Lindwall L. Double blind study of a valerian preparation. Pharmcol Biochem Behav 1989;32:1065– 6. [14] Schulz H, Stolz C, Muller J. The effect of a valerian extract on sleep polygraphy in poor sleepers: a pilot study. Pharmacopsychiatr 1994; 27:278 –9.
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Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of their constituents Ka Fai Chung, MBBS (HK), MRCPsych (UK), FHKAM (Psychiatry)*, Claire K.Y. Lee, BNurs(HKU) Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China
Abstract This study examined the composition of over-the-counter (OTC) sleeping pills in Hong Kong and reviewed the current knowledge about the hypnotic efficacy and safety of their major herbal and dietary supplement constituents. We conducted a cross-sectional survey of OTC sleep aids at drug stores in a residential district of 0.3 million population and literature search using MEDLINE, EMBASE, PsycINFO, China Journal Net, China Biomedical Database and relevant English and Chinese literature. We identified 17 brands of OTC sleeping pill: eleven of them were composed of mixtures of Chinese and Western herbal agents and six brands contained 3 mg of melatonin. The Chinese herbal mixture suanzaorentang, comprising zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma and glycyrrhizae radix in ratio of 7:5:2:1:1, was the most common OTC sleeping pill available in the survey. Our literature review showed that kava, valerian and melatonin were the better-researched herbs and dietary supplements, however, the data on hypnotic efficacy and safety was inadequate to support their clinical use. More rigorous investigations of the risk-benefit relationship of herbal agents and dietary supplements used for insomnia are needed. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Over-the-counter medications; Traditional Chinese medicine; Herbs; Insomnia; Hypnotics
1. Introduction Insomnia is one of the most frequent health complaints brought to the attention of health care practitioners. Epidemiological surveys have suggested that 10 to 20% of adults have moderate to severe insomnia [1]. A WHO collaborative survey of 25,916 primary care attendees found that 29% of those with poor sleep had tried over-the-counter (OTC) medications for sleep [2]. Johnson et al. [3] found that use of alcohol, prescription drugs and OTC medications as sleep aids was fairly common. The past-year prevalence of any substance use to aid sleep in a sample of 18 – 45 years’ old adults was 26% [3]. A substantial minority of users reported regular use for longer than 1 month: 9% for OTC medications and 36% for prescription drugs [3]. Mellinger et al. [4] reported that 3.1% of the adult population in the past year had used OTC sleeping pills and 4.3% had taken prescribed psychotropic drugs for sleep. The use of OTC sleep aids is often for short duration but a substantial number of individ* Corresponding author. Tel.: ⫹852-285-54487; fax: ⫹852-28551345-. E-mail address: [email protected] (K.F. Chung).
uals use an agent regularly on a long-term basis [3,5,6]. Antihistamines, herbs and dietary supplements are the most frequent components of OTC sleeping pills in Western countries. In light of the growing trend in alternative medicine use in the general population [7], it is common to have patients using herbs and dietary supplements as sleep aids inquire about their efficacy, side effects and adverse drug interactions. In the U.S. herbal agents and dietary supplements are not permitted to be labeled as a drug nor to claim they treat, cure, or prevent any disease. In some European countries however, herbal medicines have a long legal history and are integrated into medicine [8]. In 1978 the German Ministry of Health established Commission E, a panel of experts responsible for evaluating the safety and efficacy of herbal products. Commission E published a therapeutic guide to herbal medicines in 1998, which is one of the major references in herbal medicine [8]. Similarly in Asia, traditional Chinese medicine also has a long history of use and many OTC drugs in Asian countries are made up of Chinese herbal agents. We conducted a survey of OTC sleeping pills in Hong Kong. We examined the composition of OTC sleep aids and
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systematically reviewed the literature related to efficacy, side effects and adverse drug interactions of those constituents purported to have hypnotic effects.
Table 1 Composition of the over-the-counter (OTC) sleeping pill in Hong Kong Type 1.**
2. Methods In July 2000, the author (KYL) located all pharmacies and grocery stores that sold packaged OTC medications in a residential district in Hong Kong. The district was within the catchment area of the study center, consisted of mainly middle and lower social class families, and had an approximate population of 0.3 million. There were a total of 42 stores; 6 had registered pharmacists at the store; 36 had no qualified pharmacist to dispense drugs. Drug stores that had registered pharmacists were generally more organized and larger in size. We randomly selected 50% of each type of store to be included in this study. We identified all OTC sleeping pills for sale at the stores and recorded the compositions mentioned on the drug packages. We used MEDLINE 1966 –2000, EMBASE 1974 –2000, PsycINFO 1967– 2000, China Biomedical Database 1981–2000 and China Journal Net 1997–2000 as database to search English and Chinese language literature. The China Biomedical Database includes more than 900 journals published in China and the China Journal Net covers 6600 major journals in full-test. The keywords used for literature review were the herbal and dietary supplement components of the OTC sleeping pills identified in the survey, ‘herbs,’ ‘natural products,’ ‘traditional Chinese medicine,’ ‘TCM,’ ‘insomnia,’ ‘sedatives,’ and ‘hypnotics.’ We also hand searched the Chinese Joural of Integrated Traditional and Western Medicine from 1983 to 2000, which contains a greater number of high quality randomized controlled trials than other Chinese language journals [9]. In addition, we reviewed relevant English and Chinese reference books on herbal medicine and traditional Chinese medicine. We thus examined the major relevant literature on the efficacy and safety of the herbs and dietary supplements that are purported to have hypnotic effects.
431
2.** 3.**
4. 5. 6. 7. 8. 9. 10. 11. 12–17.
Composition* Zizyphi Spinosi Semen; Anemarrhenae Rhizoma; Ligusticum Wallichii; Poria Cocos; Glycyrrhizae Radix Natural alkaloid Zizyphi Spinosi Semen; Biotae Semen; Ophiopogonis Radix; Anemarrhenae Rhizoma; Atractylodis Macrocephalae Rhizoma; Schizandrae Fructus; Miltiorrhizae Radix; Glycyrrhizae Radix; Mori Fructus; Polygalae Radix; Ginseng; Poria. Natural alkaloid Natural alkaloid Motherwort; Hops; Kelp; Thiamine; Riboflavin; Nicotinamide; Passion flower; Wild lettuce Valerian; Passion flower; Wild lettuce; Vervain; Hops Kava Mullein; Chamomile; Passion flower; Blue Vervain; Scullcap; Hops; Oatstraw. Valerian Valerian; Kava; Hops; Passion flower; Scullcap Melatonin
* Information obtained from packages of the OTC sleeping pill; ** Three most commonly available OTC sleeping pills
Table 2 summarizes the efficacy and safety data for the herbal and dietary supplement components of the OTC sleeping pill in Hong Kong.
Table 2 Efficacy and safety data of herbs and dietary supplements with purported hypnotic effect Herbs and dietary supplements
Data score*
Efficacy score**
Safety score†
3. Results
Valerian [10–15) Kava‡ [25] Hops [16] Passion flower [16] Suanzaorentang§ [35,41–45] Melatonin [48–54]
A A D D B A
3 4 2 2 3 3
3 3 2 2 3 3
Twenty of the 21 randomly selected drug stores participated in the survey. Twelve of the 20 stores (60%) stocked OTC sleeping pills. We identified 17 brands of OTC sleeping pill (Table 1). The majority of OTC sleep aids were composed of a combination of herbs. Three agents (OTC sleeping pill 2, 4, and 5 in Table 1) did not have information regarding their composition. Six brands of OTC sleep aids were a 3-mg melatonin tablet. The herbs that were most commonly present in the OTC sleeping pills were zizyphi spinosi semen, anemarrhenae rhizoma, poria cocos, glycyrrhizae radix, valerian, kava, hops, passion flower, scullcap, and vervain.
* A ⫽ Published data including at least two placebo-controlled, doubleblind studies; B ⫽ published data including at least one placebo-controlled, double-blind study or at least three non-placebo-controlled trials; C ⫽ double-blind, nonplacebo-controlled trial; D ⫽ one open, nonplacebocontrolled trial; ** 5 ⫽ Appears very efficacious (ⱖ50% of patients); 4 ⫽ generally positive reports regarding efficacy; 3 ⫽ possibly efficacious, more data required; 2 ⫽ does not appear efficacious; 1 ⫽ generally not beneficial; † 5 ⫽ Appears generally safe and well tolerated; 4 ⫽ generally safe with some adverse effects that may limit use; 3 ⫽ generally safe but may have common adverse effects that may limit use; 2 ⫽ frequent adverse effects, at least one of which may be serious; 1 ⫽ does not appear safe (after Keck et al. [64]); ‡ Efficacy data for treatment of anxiety. No studies were performed on subjects with insomnia alone; § Zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma, and glycyrrhizae radix in ratio of 7:5:2:1:1.
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3.1. Valerian Valerian was the most researched herbal product with purported hypnotic effect. There are approximately 250 valerian species and Valeriana officinalis is the species most commonly used for medicinal purposes. Four of six randomized placebo controlled trials showed that valerian in doses of 400 to 900 mg had a subjective hypnotic effect [10 –13]. However, two recent studies did not find significant differences in subjective measures of sleep between subjects taking valerian or placebo [14,15]. In polysomnography, valerian did not have significant effects on sleep onset latency nor time awake after sleep onset, but there was a significant increase in slow wave sleep immediately and for one and two weeks after valerian use [14,15]. Schulz et al. [16] commented that valerian might have a delayed onset of action with improvements in sleep and mood after 28 days’ treatment. Valerian was postulated to act mainly as a GABA agonist [17]. Side effects of valerian, consisting of headache and morning grogginess, were uncommon [13, 15]. The herb appeared to be relatively safe even after overdose [18]. It was suggested that valerian could potentiate the effects of other CNS depressants [19,20] and cause “disinhibitation” when combined with fluoxetine [21]. In addition, hepatotoxicity was reported after taking valerian with skullcap [22]. One recent report suggested a possible withdrawal reaction upon abrupt discontinuation of valerian, which was reversed by benzodiazepine [23]. There were concerns about cytotoxicity of valepotriates contained in valerian, however in vivo studies failed to show carcinogenic effects [17] There was insufficient information to recommend valerian in pregnancy and during lactation, although no reports of teratogenicity were found [24]. In conclusion, the studies suggested that valerian increased slow wave sleep and had few adverse reactions, but its efficacy as a treatment for insomnia was doubtful [25]. Further studies using larger samples and examining the long-term effects of valerian would give a better picture of its hypnotic efficacy and undesirable effects. 3.2. Kava A meta-analysis [26] showed that kava, in daily doses of 60 to 240 mg of kavapyrones equivalent, was beneficial in the management of anxiety, however, no clinical data were available on the herb’s hypnotic action. Adverse effects of kava in therapeutic doses, consisting of mild gastrointestinal complaints, were uncommon [27]. There were case reports of extrapyramidal symptoms with use of kava [28,29]. It was suggested that the herb could potentiate the effect of CNS depressants and there was a report of a semicomatose state after kava was ingested with alprazolam [30]. Longterm heavy use of kava was reported to cause scaly rash, weight loss, liver and renal dysfunction, hematological abnormalities and possibly pulmonary hypertension [31]. The German Commission E recommended kava be used for less
than 3 months [8]. In conclusion, kava was shown to have a tranquilizing effect but its action on sleep was unclear and merits further investigation. 3.3. Hops and passion flower There were no randomized controlled trials of hops or passion flower as a single agent to treat insomnia. The German Commission E [8] recommended the two herbs for nervousness and sleep disturbance. However, Schulz et al. [16] reported that hops as a single agent had no sleepinducing effect in human subjects and that passion flower alone produced an hypnotic effect but also showed signs of hepatotoxicity and pancreatotoxicity. Adverse effects of hops included allergy and disruption of menstrual cycle [32] and hypersensitivity vasculititis was reported with passion flower use [33]. Studies suggested that both herbs should be avoided in pregnancy and during lactation [32,33] and that care should be taken when hops and passion flower is used with other CNS depressants [32,33]. One report advised that the use of hops should be avoided in depression [32]. 3.4. Zizyphi spinosi semen and glycyrrhizae radix One of the commonest ancient Chinese remedies for insomnia was a preparation consisting of zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma, and glycyrrhizae radix in ratio of 7:5:2:1:1, which is known as suanzaorentang (OTC sleeping pill 1 in Table 1). In ancient times the herbs were prepared in liquid form or “tang,” but nowdays the herbal preparation is mostly in capsules. In animals, zizyphi spinosi semen was shown to inhibit caffeine-induced excitation and prolong hexobarbital-induced sleep, however tolerance occurred after 6 days’ use [34,35]. Open studies of zizyphi spinosi semen or glycyrrhizae radix in combination with other Chinese herbs in the treatment of insomnia were all favorable. The case reports showed that the herbal mixture resulted in significant improvement of sleep in over 50% of patients with insomnia of various etiologies and only 10% of subjects showed no response [36 – 45]. There was only one published placebo-controlled trial of suanzaorentang for treatment of insomnia [46]. Sixty poor sleepers were given placebo during the first and fourth week and suanzaorentang for the second and third week. Subjective sleep measures were significantly better during suanzaorentang use, however no objective sleep parameters were assessed in the study [46]. The hypnotic effect of zizyphi spinosi semen was postulated to be due to the anticholingeric and antihistamine actions of betulic acid, an active compound in zizyphi spinosi semen [47]. Adverse reactions of zizyphi spinosi semen and glycyrrhizae radix were not systematically examined in any study. Side effects of zizyphi spinosi semen, consisting of gastrointestinal symptoms, dizziness and skin rash, were uncommon [36,46,47]. However, Ma et al. [36] reported that systolic and diastolic blood pressure in one patient with
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essential hypertension dropped significantly after taking zizyphi spinosi semen and cautioned the use of the herb in patients with hypotension and bradycardia. Adverse reactions of glycyrrhizae radix including high blood pressure, edema, muscle weakness, dizziness, and headache were dose-related and postulated to be the result of water and sodium retention [35,48]. Effects of overdose of the Chinese herbs and their use in pregnancy and during lactation were not clearly recorded. There were case reports suggesting that a combination of the Chinese herbs with Western psychiatric medications, including tricyclic antidepressants and benzodiazepines, could enhance the hypnotic efficacy of the herbs [49,50], however adverse interactions between the herbs and the CNS depressants were not mentioned in the reports. In conclusion, zizyphi spinosi semen and glycyrrhizae radix in combination with other Chinese herbs appeared to have short-term hypnotic efficacy, however longterm efficacy and safety data were limited and this merits further investigation. 3.5. Melatonin There were mixed findings in randomized placebo-controlled trials examining the hypnotic effect of melatonin qhs doses of 0.5 to 5 mg [51–57]. Two studies on middle-aged patients with persistent insomnia did not find significant improvement in subjective [51,52] nor objective [52] measures of sleep. Hughes et al. [53] did not detect any beneficial effects of melatonin on subjective sleep parameters in 14 elderly people with insomnia, however the drug significantly shortened sleep latency by polysomnography. Studies which examined the hypnotic efficacy of melatonin by objective measures alone found significant improvements in sleep efficiency [54 –57], reduction of wakening after sleep onset [54] and shortening of sleep latency [55,57] in elderly subjects with insomnia [54,55], patients with schizophrenia and insomnia [56] and healthy young subjects [57]. Side effects of melatonin, consisting of sleepiness, headache, giddiness, and nausea, were uncommon [58]. There were concerns that possible contaminants in melatonin manufacturing process could cause hypersensitivity reactions [59]. Case reports suggested that melatonin might increase seizure frequency [60], disturb sleep-wake pattern [61] and result in optic neuropathy when used with sertraline and a high-protein diet [62]. Our review did not find sufficient efficacy and long-term safety data to recommend melatonin for most patients with insomnia [63]. 3.6. Poria cocos, linusticum wallichii, radix ophiopogonis, semen biotae, rhizoma atractylodis, schizandrae, radix salviae miltiorrhizae and polygala All these Chinese herbs inhibited caffeine-induced excitation and prolong hexobarbital-induced sleep in animals, but data on their hypnotic effect and safety profile in humans was limited [34,35].
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3.7. Scullcap, kelp, motherwort, mullein, wild lettuce, vervain, oat straw, chamomile flower (German), anemarrhenae rhizoma, morus and ginseng Scullcap (skullcap) has been traditionally used as sedative and anticonvulsant, however no clinical data were found for its hypnotic effect [33]. The other herbs had no animal nor clinical evidence for sedative action [33–35]. The German Commission E did not approve scullcap, kelp, motherwort, mullein, wild lettuce, and vervain for any therapeutic purpose [8].
4. Discussion We found many brands of OTC sleeping pill at pharmacies in the study area. A significant proportion of OTC sleep aids were composed of a combination of Chinese or Western herbal agents. Melatonin was a frequently found OTC sleeping pill in Hong Kong, but sedative antihistamines were not commonly available. Our literature review identified limited evidence-based human data on the hypnotic efficacy and safety profile of the herbal agents and melatonin. The commonest type of OTC sleeping pill in our survey was made up of a mixture of Chinese herbal agents, zizyphi spinosi semen, glycyrrhizae radix, anemarrhenae rhizoma, ligusticum wallichii and poria cocos. There were many publications on the hypnotic efficacy of the Chinese herbs, however, most of the studies were open, uncontrolled and lacked systematic information on adverse reactions. Both zizyphi spinosi semen and glycyrrhizae radix were reported to affect blood pressure and there was insufficient data to recommend the herbs for patients with insomnia. Valerian, kava, hops and passion flower were approved by the German Commission E for treatment of nervousness and insomnia [8]. Based on our literature review, valerian and melatonin had the most evidence-based data for efficacy in insomnia among the herbs and dietary supplements with purported hypnotic effects, but their efficacy was not clear and therefore more data are required. Polymedicine is not often practiced in Western medicine as multiple drug interactions can lead to unexpected adverse effects. Nevertheless, since using a combination of herbs is a common traditional Chinese medicinal and Western herbal practice, evidence that herbal mixtures are superior in efficacy to a single agent and reasonably safe is required. Another major concern of OTC medications is their batchto-batch variability and impurities that can cause hypersensitivity reactions as reported in a melatonin preparation [59]. One of the major limitations of this study is that our review was restricted to English and Chinese language literature. It is possible that some relevant literature in other languages, such as Japanese and German, have been missed. Large differences in study subjects, design and outcome measures of the previous studies have limited meta-analyses of the data. Our survey was limited to one district of Hong
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