Abstract
Objectives:
To evaluate the traditional use of Chinese herbal medicine (CHM) for insomnia in pre-contemporary times.
Materials and methods:
The Encyclopedia of Traditional Chinese Medicine (fifth edition) was systematically searched using seven Chinese medicine disease nomenclatures to identify insomnia citations. Citations were coded, and frequently used herbal formulae specific for insomnia were analyzed.
Results:
Insomnia treatments were mentioned in 940 citations, and insomnia diagnosis treated with Chinese herbal formulae was specifically described in 800 citations. The traditional use of CHM appeared to be individualized based on the cause, pathogenesis, phase, phenotype, demographics, and concurrent medical conditions of insomnia. The most common herbal formulae for insomnia included Wen dan tang, Suan zao ren tang, Ban xia shu mi tang, and Gui pi tang. The most frequently cited herb was suan zao ren (Ziziphi spinosae semen).
Conclusions:
A number of herbal formulae for insomnia were cited in the historical literature. The commonly cited formulae such as Wen dan tang and Suan zao ren tang are consistent with current clinical practice and are good prospects for further therapeutic development.
Introduction
Insomnia is the most common sleep disorder. 1 Chinese medicine (CM), including Chinese herbal medicine (CHM), has a long history of being used for insomnia. 2 It holds a holistic view of the human body and focuses on the physiologic functions. 3 –5 CM philosophy believes that yin, yang, and qi regulate the sleep–wake cycle, 3 –5 and Mind includes a broad range of consciousness, thoughts, cognition, and emotions. 3 –5 Three CM theories explain the pathogenesis of insomnia, 6 –8 namely (1) disharmony between yin (sleep) and yang (awakening), (2) irregular circulation of defensive qi, and (3) disturbance of Mind caused by the dysfunction of the Heart. These theories inform the principle of herb selection and formula development to improve sleep.
Systematic reviews of randomized controlled trials have demonstrated that CHM can improve subjective sleep. 9 However, there is no specific formula that outperforms the others. To identify a formula candidate for further research, the historical literature of CM may provide leads. One such gift is the discovery and development of artemisinin (qinghaosu). The herb qing hao was discovered as an ancient remedy with antimalarial properties, and through further research, the active compound artemisinin was extracted, which is now the leading treatment for malaria. 10
In the past few years, our research team has been developing the methodology to evaluate the historical literature of CM. 11 –15 Based on the established methodology, we systematically collected, appraised, and analyzed the pre-contemporary Chinese text on CHM for insomnia.
Materials and Methods
Search strategy
To obtain a representative sample of the ancient and premodern medical literature, we conducted a search of Zhong Hua Yi Dian CD 5.0 [中华医典第五版] (ZHYD 5.0; Translation: The Encyclopedia of Traditional Chinese Medicine, fifth edition). It is the most comprehensive electronic collection of CM texts, containing 1158 medical books with a wide range of topics spanning
In ancient China, five Chinese words were commonly used to describe sleep, including Mei [寐] (definition: good sleep maintenance), Mian [眠] (definition: falling asleep), Ming [瞑] (definition: closing the eyes), Wo [卧] (definition: laying down), and Shui [睡] (definition: sleep). 16 –18 To select CM disease nomenclatures related to insomnia, we consulted dictionaries, monographs, medical nomenclatures, and textbooks. 2,4,6–7,16 –29 Bu de wo [不得卧] (definition: inability to lay in the bed) and mu bu ming [目不瞑] (definition: inability to close the eyes) were the earliest recorded terms for insomnia, 2 but they were not included among our search terms because the preliminary search and analyses suggested that they also refer to a large number of other disorders, such as breathing-related sleep disorders, night symptoms of heart failure, and disorders of ophthalmology.
To balance sensitivity and specificity, seven search terms were used, consisting of bu mei [不寐], bu mian [不眠], bu shui [不睡], wu mei [无寐], wu mian [无眠], shi mian [失眠], and shi mei [失寐].
A citation, a distinct passage of text, was defined as the unit of text. Each term was entered into the ZHYD search fields to identify relevant text. Then, the texts were sorted by citations. A duplicate was defined as the same citation in the same book. After removing duplicates, the citation was categorized by authors, book titles, publishing year, and types of content. Exclusion criteria were then applied to remove citations that were considered irrelevant to insomnia, contained no treatment information, books written after 1949, or translated from other languages.
Coding tree
Codes on clinical characteristics of insomnia
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was consulted to identify the essential clinical characteristics of insomnia. 30 The texts were coded on importance of insomnia complaints in clinical scenarios, duration, impairment, types of insomnia, and differential diagnosis. Demographics such as gender and age were also coded. The coding system is specified in Table 1.
Codes on Clinical Characteristics of Insomnia
Codes on treatment and outcomes
The codes of treatment had two levels. The first level of codes comprised the type of treatment, including CHM, acupuncture, and other therapies (e.g., dietary therapy, meditation, and combination therapies). Only the citations related to CHM were included for further coding. The second level of codes consisted of specific categories of CHM treatment, including a multi-herb formula, single herb, and several formulae used together for one case. Codes of outcomes included insufficient information to decide, effective and ineffective.
Data set development
Two data sets were derived in line with two levels of insomnia definition. The primary data set included all citations in the coding procedure. Insomnia in this data set was considered a complaint, in which insomnia could be the main focus or a concurrent symptom.
The secondary data set aimed to include information about treatments specific to insomnia, and only citations with insomnia as primary diagnosis (Code 1.2, Table 1) were included. Differential diagnosis codes were reviewed, and citations codes 5.2–5.7 were excluded. Insomnia in this data set was considered a main clinical focus, and the treatment was specific to it.
Information about formula names, herb ingredients, preparation methods, administration routes, and treatment frequency and duration was collected where available. The citation without a formula name was replaced by a substituted name whose ingredients were the same. For the formula without herbal ingredients, other texts in the same book or texts written by the same author were searched. To ensure precision of the data, no further imputations of the missing data were undertaken.
Data analysis procedure
The primary data set was used to gain an overview of citations, including treatment information and insomnia descriptions. The secondary data set was used to investigate clinical characteristics of insomnia diagnosis in pre-contemporary times, such as which population was more likely to experience insomnia, which type of impairment was commonly derived from insomnia, and which herbal formulae was the most popular. Descriptive statistics such as frequency calculation was applied. To further evaluate the relationship between treatment popularity and demographics, cross-tabulation and association analysis were used.
Results
Search results
The initial search found 5204 citations. Citations found by bu mian accounted for the biggest proportion, and citations identified by bu mei was the second largest. The number of citations in the primary data set, which defined insomnia as a complaint, was 3694, whereas the count in the secondary data set was decreased to 940 when insomnia was referred to as a primary diagnosis. Table 2 includes the search terms and results.
Citations per Insomnia Terms
Insomnia citations
Books
These citations came from 540 distinct books. The books published between the Chinese Ming (1369–1644) and Qing (1645–1911) dynasties accounted for the largest proportion (90.4%), followed by the Chinese Minguo dynasty (1912–1949) (6.0%), Chinese Song and Jin (961–1271) and Yuan dynasties (1272–1368) (3.3%), and the times before the Song dynasty (0.3%).
The books with the most citations on insomnia included Indispensable Tools for Pattern Treatment [证治准绳] (n = 110), Continuation of Classified Case Histories by Renowned Physician [续名医类案] (n = 110), Formulae of Universal Benefits [普济方] (n = 94), Direct Interpretations to Cold Damages [伤寒直指] (n = 91), Collected Treatises of Jing-Yue [景岳全书] (n = 84), Treatment Decisions Categorized According to Pattern [类证治裁] (n = 83), Case Histories of Wang Meng-Ying [王孟英医案] (n = 69), Wondrous Lantern for Peering into the Origin and Development of Miscellaneous Disease [杂病源流犀烛] (n = 66), Introduction to Medicine [医学入门] (n = 64), and Systematic Great Compendium of Medicine Past and Present [古今医统大全] (n = 48).
Insomnia diagnosis
Among the citations by insomnia diagnosis level, some were descriptions of treatment types and some were case reports. The frequency of insomnia onset was seldom reported, and insomnia duration could be only described in a few citations. Acute insomnia was described in 44 citations. For instance, “Being physically and mentally tired, the complaint of difficulty initiating sleep continues for ten days.” Chronic insomnia was mentioned in 52 citations. For example, “Overthinking induced insomnia lasts for two years.” Only 31 citations clearly described the insomnia-associated impairments, such as “inability to fall into sleep at all night which leads to fatigue and being emaciated.”
Six hundred and six treatment citations reported insomnia alone and 334 described comorbid insomnia. Comorbidities included the following: Concurrent pain such as “eye conditions with painful and swelling eyes and blurred vision may cause inability to fall asleep day and night.” Concurrent arrhythmia such as “insomnia accompanied by palpitation is due to the disorders of heart meridians.” Concurrent digestive disorders such as “adverse rising of stomach qi resulting in disturbance of qi-blood, dysfunctions of viscera, and consequent insomnia.”
Several special groups of people with insomnia were mentioned, including: Women particularly those in postpartum, such as “the syndrome of postpartum insomnia referring to sleeplessness the whole night initially, followed by being irritable, sweating, thirsty and red face.” Children with “poor appetite and insomnia due to diarrhea or insomnia caused by itchiness after chicken pox.” Elderly people “being susceptible to insomnia.”
Chinese herbal therapy for insomnia
Therapeutic principle
CHM for insomnia was described in 840 citations. The insomniacs sharing the same characteristics were often grouped to guide treatment selection. As the Indispensable Tools for Pattern Treatment stated: Generally, there were two causes of insomnia. One was weakness right after recovering from an illness or deficient blood in the elderly; the other was phlegm blocking the gallbladder meridian. Liu jun zi plus zao ren was commonly used for the deficient scenario while Ban xia tang originated from Ling Shu for those identified as phlegm pattern.
In addition, the book Treatment Decisions Categorized According to Pattern detailed 25 Patterns and their corresponding treatments. Pattern encompassed a broad range of insomnia relevant factors, including: Causes such as “insomnia commonly caused by overthinking affecting mind, being frightened, annoyed and angry, depressed qi producing phlegm, where Ban xia tang should be used.” Pathogeneses such as “stomach disharmony causes insomnia and restlessness. Because phlegm-fire blocks the downwards of stomach qi, which results in irritability and then insomnia. Ju hong, fu ling, shi hu, ban xia, zhi cao, zhi shi, zha rou, and shen qu can be used for this condition.” Phases such as “when insomnia is induced by inexplicable anxiety right after recovering from a disease, Zhu ye shi gao tang or Fu ling bu xin tang can be applied.” Phenotypes such as “for frequently wakening up after sleep, Bie jia qiang huo wan can be used, and for no sleep for the whole night, An wo ru shen tang.” Demographics such as “the elderly with insomnia is caused by deficient blood when Sheng yu tang could be used, obese women commonly suffer from depression when emetic therapy could be used for insomnia by removing the phlegm-fire.” Concurrent medical conditions such as “menopausal insomnia with deficiency of spleen-blood, was caused by overthinking and worry which can be relieved by Gui shao liu jun zi tang or Yi qi an shen tang.”
Multi-herb formulae for insomnia
A multi-herb formula, the most common prescription of CHM, is not only a quantitative collection of herbs but also a complex recipe of interrelated substances. The essence of CHM formula is that each component has its own role, and it is believed to be more effective and less harmful when being used together. Insomnia treated with multi-herb formulae was described in 729 citations.
The most common formula was Wen dan tang [温胆汤]. One citation stated that “Insomnia referred to a restless sleep. When it is caused by phlegm blocking heart meridian and the deficiency of gallbladder qi, Wen dan tang should be used to generate the heart blood and then to regain a sound sleep.” The second most common formula was Suan zao ren tang [酸枣仁汤]. “For those difficult in falling in asleep induced by unexplained irritability, Suan zao ren tang can be utilized.” The third most common formula was Gui pi tang [归脾汤]. “Gui pi tang is for those who cannot return to sleep after wakening up, which is caused by overthinking induced Spleen impairment.” The fourth most common formula was Ban xia shu mi tang [半夏秫米汤], also called Ban xia tang [半夏汤] or Ling shu ban xia tang [灵枢半夏汤], which was also one of the earliest recoded treatments for insomnia. Their ingredients are listed in Table 3.
Multi-Herb Formulae for Insomnia
The herbal ingredients are presented as per the Chinese pinyin followed by their English name. The English name is taken from the Pharmacopoeia of the People's Republic of China. 31 The use of some herbs such as mu xiang may be restricted in some countries. Readers are advised to comply with relevant regulations.
Other common formulae were Liu wei di huang wan [六味地黄丸], Huan lian e jiao tang [黄连阿胶汤], Xiao chai hu tang [小柴胡汤], Liu jun zi tang [六君子汤], Yang xin tang [养心汤], and Zhi zi chi tang [栀子豉汤].
Excluding citations of comorbid insomnia, the top four formulae in the subgroup were the same as those in the overall insomnia citations. In the citations describing comorbid insomnia, Wen dan tang continued to rank first.
Single-herb formulae for insomnia
There were 101 citations that described insomnia treated with 24 single-herb formulae. For instance, “If someone cannot fall asleep at night, fried suan zao ren can be used.” Suan zao ren was the most common herb specific to insomnia (n = 71 citations) and was cited far more frequently than other herbs. Preparation techniques were considered critical to maintain the herb property. For example, “raw suan zao ren was used for sleepiness while the fried was for insomnia.”
Multiple formulae for an insomnia case
Ten citations explained a more complicated approach to treating insomnia such as different formulae for different periods over a long-term follow-up or multiple formulae taken for one day. There were 13 clinical cases of insomnia successfully treated with CHM formulae.
Example 1
A 14-year-old boy, studying extremely hard, could not fall asleep at all at night, and then had poor appetite. He took Bu zhong yi qi tang in the morning and Yi gong san in the afternoon, which improved his appetite and sleep gradually. After continuing using this therapy, all symptoms completely disappeared.
This case depicted the therapeutic strategy that treated insomnia in line with its dynamic nature, and it is considered that the timing of therapeutic administration is important to achieve the satisfactory outcomes.
Example 2
A man suffering irritability, a sensation of heat, weight loss and insomnia has lasted for three years. Taking around one thousand packs of herbs cannot cure it, and he cannot have a sound sleep for the whole night. The pulse related to the function of “Liver” is deep and fast. This may be caused by the long-term accumulation of Liver fire, and the strategy “soothing the Liver and relieving depression” can be used. The prescribed formula consists of chaihu (2 qian), baishao (2 qian), danpi (2 qian and 5 fen), gancao (5 fen) and guizhi (4 fen). Once the formula is administrated, the man falls asleep straightway and the sound sleep last for the whole day and night. In the following visit, Xiao yao san combined with Ren shen wan is used, and then all the symptoms dissolved. [qian, a unit of weight in ancient China ( = 5 grams); fen, a unit of weight in ancient China ( = 1/2 gram)]
This case highlighted the importance of pulse diagnosis in prescribing an effective formula for the people with insomnia, and the sequential application of different herbal formulae can consolidate the therapeutic effect.
Example 3
A woman in pregnancy expectorates phlegm in the morning, has a fever at night, and she cannot fall asleep day and night. Initially, she was treated by the herbs clearing phlegm and suppressing fire; however, she lost her appetite and weight day by day. I state that expectoration in the morning is caused by the deficiency of Spleen Qi; the fever at night is caused by the deficiency of Liver blood; sleeplessness day and night was due to the short of Spleen blood. Hence, Liu jun zi tang, modified Xiao yao san and modified Gui pi tang are administrated one by one. Then she is cured for less than one month.
This case showed the therapeutic strategy for comorbid insomnia. Distinct formulae targeting various symptoms caused by different pathogenesis should be used together.
Other factors contributing to formula selection
Among the citations on CHM for women with insomnia (n = 42), Gui pi tang was the most widely used (n = 10). As for the elderly with insomnia (n = 15 citations), Liu wei di huang wan (n = 3) and Liu jun zi tang (n = 3) were most frequently used. Twenty-three citations explained various formulae for children with insomnia and their therapeutic mechanism from the perspective of CM theory. For example: There are always predisposing factors to insomnia. Liu wei wan is indicated for the deficiency of Kidney meridian with heat, Zhen zhu mu wan for deficiency of Heart blood and Yang rong tang for lack of Qi or Spirit. Suan zao ren tang is used for insomnia after recovering from a disease, Ren shen zhu ye tang for insomnia due to deficient Gallbladder with bitter mouth, modified Xiao chai hu tang for liver-fire induced insomnia followed by anxiousness, and Si jun zi tang adding sheng jiang and zao ren for palpitation induced insomnia.
Original Chinese characters of all quotations were included in the Supplementary Table S1 (Supplementary Data are available online at
Discussion
The analysis of the historical literature suggests that insomnia in CM is defined as the persistent dissatisfaction with sleep quantity or quality, which is similar to the modern understanding of insomnia. However, CM diagnosis seldom quantified the frequency and duration of insomnia. The historical texts include descriptions of people who were weak, suffering from chronic disease and the elderly, to be more likely to experience insomnia, which is also supported by epidemiological studies. 32
The analysis of the historical literature revealed that the traditional use of CHM for insomnia was likely individualized based on the cause, pathogenesis, phase, phenotype, demographics, and concurrent medical conditions. Zheng [证], also translated to Syndrome or Pattern, was applied to this situation. 33 Although the statements of Zheng in CM differ from biomedical nomenclature, system biology has bridged them for some conditions, such as rheumatologic arthritis and coronary heart disease. 34
Specifically to insomnia, a cross-sectional survey of people with primary insomnia identified a correlation between Zheng and the changes of intracranial neurotransmitters, including 5-hydroxytryptamine and γ-aminobutyric acid (GABA). 35 The belief that CHM treatments based on individualized syndrome differentiation [辨证论治] performed better than nonsyndrome therapy is supported by current clinical evidence. 36
The four most common formulae identified in the historical literature were Wen dan tang, Suan zao ren tang, Ban xia shu mi tang, and Gui pi tang. Gui pi tang has been developed into Guipi pill, an over-the-counter product for insomnia, 37 and it has been recommended in the Chinese evidence-based clinical guideline. 23 Ban xia shu mi tang has a long history of use, but it is less commonly used in contemporary clinical practice for insomnia, rather its effects may relate to irritability and memory impairment. 38
Therefore, Wen dan tang and Suan zao ren tang are the most promising formulae options for treating insomnia identified in the historical literature. They should be the focus of further therapeutic research to improve their application in clinical practice.
The earliest use of Wen dan tang for insomnia was traced in the book Unification of the Three Aetiologies, published c. 1174. 39 It was likely to be used for the Zheng “disharmony between the stomach and gallbladder with phlegm-heat obstructing the qi dynamic” in people with insomnia. 37 Wen dan tang has also been analyzed in preclinical studies to evaluate its potential mechanism of action. In a sleep-deprived rat model, Wen dan tang reduced insomnia-related anxiety in terms of open-field text via preventing a decrease in ghrelin levels and increasing microRNA expression of ghrelin receptors, one of the brain-gut peptides associated with mood disorder. 40 It also improved negative emotions of a sleep-deprived model by upregulating orexin-A and leptin, one of the key regulators of the sleep–wake cycle. 41
The key ingredient in Wen dan tang, Pinelliae Rhizom apraeparatum [Pinyin: Ban xia, Chinese: 半夏], can transform phlegm and regulate stomach qi according to the traditional CM theory. 42 It showed a synergic effect on pentobarbital-induced sleeping by increasing the numbers of mice falling asleep and reducing sleep latency and prolonged sleep time, possibly via the GABAergic system. 43
CM clinicians make modifications according to individual patient's complaints. Huang lian wen dan tang [黄连温胆汤], a variation of Wen dan tang, is utilized for insomnia with severe phlegm-heat. 23 Shi wei wen dan tang [十味温胆汤] is prescribed for insomnia accompanied by dreams attributed to excess phlegm, 39 and its modern preparation Wen dan ning xin granule [温胆宁心颗粒] presents greater improvements of subjective sleep quality and daytime functioning in people with primary insomnia compared with estazolamin. 44 Shen hu wen dan tang [参胡温胆汤] and Jia wei wen dan tang [加味温胆汤] are considered more suitable for insomnia triggered by unexplained anxiety. 45 However, clinical evidence comparing the effectiveness of Wen dan tang with its variations for insomnia is required.
Suan zao ren tang, the second most popular formula for insomnia in the historical literature, originated from the book Essentials from the Golden Cabinet [金匮要略] in c. 220
Animal experiments indicated that high doses of Suan zao ren tang increased nonrapid eye movement sleep, rather than altering rapid eye movement sleep, which may be mediated through serotonergic activation 49 and GABA-A receptors. 50
Clinical research evidence showed that Suan zao ren tang was superior to placebo in improving the overall sleep quality and well-being in the people with sleep disorders. 51 A systematic review of 12 randomized controlled trials suggested that Suan zao ren tang appeared safe and potentially enhance sleep. 52 A recent randomized, double-blind, and placebo-controlled trial showed that a 4-week treatment of Suan zao ren tang significantly improved subjective sleep in terms of the Pittsburgh Sleep Quality Index and improved the sleep efficiency in sleep disturbance during methadone maintenance and resulted in mild adverse events. 53 Also, Suan zao reng tang safely improved daytime function of climacteric women with poor sleep quality, in a prospective observational study. 54 In addition, there are a few ongoing clinical trials investigating variations of Suan zao ren tang for primary insomnia. 55,56
Overall, preclinical and clinical evidence suggests that Suan zao reng tang can improve sleep, but further clinical trials are needed to confirm its efficacy on the target type of insomnia.
The results of this research may be limited by searching only one source. The ZHYD is the largest electronically searchable resource, but it does not contain every historical CM text and some classical books may have been missed. We included seven search terms to locate insomnia citations; however, searching more terms may have found more citations.
Conclusions
The analysis of the historical literature identified various CHM formulae that might be used for different types of insomnia. Suan zao ren tang and Wen dan tang were commonly cited in the historical literature, and experimental evidence suggests that they have biological activities relevant to insomnia. These two formulae should be the focus of further therapeutic research to improve their application in clinical practice with the potential to be developed into commercial products for insomnia.
Footnotes
Authors' Contributions
X.N. conceived the study, coded the citations, and wrote the article. X.N. and J.L.S. designed the study and analyzed the data. A.L.Z., X.G., C.L., and Y.L. contributed to data interpretation. C.C.X. contributed to the overall design, quality control, and data interpretation. All authors critically reviewed the article and approved the submission.
Acknowledgments
The project is jointly supported by the China–Australia International Research Centre for Chinese Medicine (CAIRCCM)—a joint initiative of the RMIT University, Australia, and the Guangdong Provincial Academy of Chinese Medical Sciences, China, with additional funding support from the Ministry of Science and Technology of China (International Cooperation Project, Grant No. 2012DFA31760). We acknowledge Dr. Fuchang Lu, Dr. Chen Zhou, and Dr. Yuan Ming Di for their assistance with the citation categorization. We also acknowledge Ms. Shengnan Gan for checking the translation of ancient Chinese texts.
Author Disclosure Statement
No competing financial interests exist.
References
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