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  5. 中药治疗失眠症的态靶辨证体系与作用机制探析

中药治疗失眠症的态靶辨证体系与作用机制探析

深度研究匿名用户发表于 2026年01月11日 11:533阅读
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1. 态靶辨证理论在失眠症治疗中的内涵界定

1.1 态靶辨证的核心概念与理论框架

态靶辨证是中医辨证论治理论与现代医学精准靶向治疗理念相结合的产物，旨在更全面、深入地理解疾病的发生发展机制，并指导临床实践。其核心在于阐释“态”与“靶”的辩证关系，并在中医“整体观”和“辨证论治”的框架下进行延伸和发展。“态”指的是患者的整体功能状态，涵盖了中医所强调的体质、脏腑功能、气血津液运行、精神情志以及临床上呈现的各种证候表现等宏观层面。例如，失眠患者可能表现出心脾两虚、肝郁化火等不同的证候类型，这些都是“态”的具体体现1。“靶”则指具体的病理生理靶点，包括现代医学研究中揭示的神经递质失衡（如5-HT、GABA）、肠道菌群紊乱、炎症因子（如IL-6、TNF-α）通路异常、内分泌紊乱（如HPA轴功能异常）等微观分子或细胞层面的异常改变。这些“靶点”是疾病发生发展的关键环节，也是中药发挥作用的重要通路。

“态靶辨证”的理论框架强调“由表及里，由宏观至微观”的认知路径。中医的辨证论治首先是对患者“态”的辨识，通过望、闻、问、切等方法全面收集信息，归纳出证候类型。在此基础上，结合现代医学对疾病发病机制的认识，深入探究与该证候“态”相对应的具体“靶点”。这种“态-靶”结合的思维模式，使得中医对疾病的理解不再局限于宏观表象，而是能进一步阐明其深层的分子机制。例如，在传统中医整体观指导下，中药的“自洽”现象反映了其多成分在药性、药效、体内过程和中医功效上的协调一致性，这为理解“态”的整体调节作用提供了基础2。同时，中医的整体观也强调了人体内部各系统、脏腑之间的紧密联系，疾病的发生往往是多系统功能失调的体现3。因此，“态靶辨证”不仅关注单一靶点的改变，更注重中药通过多成分、多靶点、多途径的协同作用，实现对患者整体“态”的调节和平衡45。这种全面的调节，如调节肠道菌群、改善炎症反应等，最终有助于疾病的康复和稳态的维持678。

1.2 失眠症态靶辨证的特殊性

失眠症在中医学中素有“阳不入阴”之核心病机论述，即指阳气当入于阴而未能入藏，导致阴阳失衡，神魂不安，从而出现入睡困难、寐而不酣或时寐时醒等症状。在态靶辨证体系下，理解失眠症的特殊性，需要将这一传统病机与现代医学对睡眠障碍的认识进行深度融合，构建“态-靶-药”的映射模型。

1.2.1 “阳不入阴”与“态”的关联逻辑
“阳不入阴”作为失眠的根本病机，其“态”的表现多种多样。具体而言，阳气亢盛、阴血亏虚、脏腑功能失调等，皆可导致阳不入阴。例如：

  • 肝郁化火：肝失疏泄，气郁化火，扰动心神，阳气不得潜藏。其“态”表现为烦躁易怒、口苦、胁胀、脉弦数等。
  • 心脾两虚：思虑劳倦伤及心脾，气血生化不足，心神失养，脾虚运化不健，均可导致心神不安，阳无所依。其“态”表现为面色萎黄、倦怠乏力、心悸健忘、纳差便溏等。研究表明，心脾两虚型失眠患者的TCM证型分布显著，尤其是在阴证中最为常见 9。
  • 痰热内扰：脾失健运，生湿酿痰，郁而化热，痰热上扰清窍，蒙蔽心神。其“态”表现为胸闷、痰多、头重、苔黄腻、脉滑数等。

这些不同的“态”，本质上都是“阳不入阴”在不同脏腑、不同病理阶段的体现，反映了机体整体功能状态的失衡。

1.2.2 “阳不入阴”与“靶”的关联机制
在现代医学视角下，“阳不入阴”的病理过程与多种具体的分子、细胞或系统“靶点”密切相关：

  • 神经递质异常：如γ-氨基丁酸（GABA）受体功能不足导致神经兴奋性增高；5-羟色胺（5-HT）代谢紊乱影响睡眠-觉醒周期的调控；以及腺苷（Adenosine）代谢异常，作为内源性睡眠驱动因子，其累积不足或受体功能障碍均可能影响睡眠启动和维持 10。
  • 脑肠轴失调：肠道菌群紊乱可通过产生神经活性物质或影响炎症通路，进而影响中枢神经系统的功能，导致睡眠障碍。例如，肠道菌群失调可影响色氨酸代谢，进而影响5-HT的合成，而5-HT是调节睡眠的重要神经递质 11。
  • 神经炎症：慢性炎症因子（如IL-6、TNF-α）的升高可穿过血脑屏障，激活脑内小胶质细胞，引起神经元损伤和神经递质紊乱，从而导致失眠。
  • 自主神经功能紊乱：失眠患者常表现出交感神经过度活跃，心率变异性降低等现象，这种持续的生理性高觉醒状态会抑制睡眠的发生和维持，与中医“阳不入阴”的病机有内在联系 12。
  • 基因遗传背景：失眠具有遗传性，基因组关联研究（GWAS）已识别出数百个与失眠相关的基因位点，这些位点可能涉及代谢和精神病理通路，为失眠的“靶”提供了更深层次的遗传学基础 13。

1.2.3 “态-靶-药”映射模型
基于上述分析，我们可以构建一个“态-靶-药”的映射模型，以指导失眠症的中药治疗（见表1）。该模型强调根据患者的宏观“态”象，推导其潜在的微观“靶”点，进而选择具有多靶点协同作用的“药”物，以达到整体调节与精准干预相结合的目的。

表1 失眠症“态-靶-药”映射模型示意

失眠证型（“态”）典型临床表现潜在病理生理靶点（“靶”）常用中药/方剂（“药”）作用机制（示例）
肝郁化火烦躁易怒、口苦、胁胀、入睡困难神经递质失衡（5-HT、GABA）、自主神经功能紊乱、炎症因子升高龙胆泻肝汤、丹栀逍遥散调节神经递质平衡，抑制炎症反应，稳定自主神经功能
心脾两虚面色萎黄、倦怠乏力、心悸健忘、纳差便溏脑源性神经营养因子减少、肠道菌群紊乱、免疫功能下降归脾汤、酸枣仁汤促进神经营养，调节肠道微生态，增强免疫功能
痰热内扰胸闷、痰多、头重、苔黄腻、时寐时醒炎症因子升高（IL-6、TNF-α）、脂质代谢紊乱、肠道代谢物异常温胆汤、黄连温胆汤清热化痰，调节炎症通路，改善代谢紊乱

这个映射模型旨在提供一个思考框架，使得临床医生在辨识患者具体证型（“态”）的同时，能够结合现代研究成果，理解其背后的分子机制（“靶”），从而更精准地选择中药方剂（“药”），实现多维度、深层次的治疗效果。例如，半夏、黄芩在治疗痰火郁结所致顽固性失眠方面具有独特优势 14，其作用可能涉及多靶点协同。

2. 失眠症常见中医证型的态靶特征解析

2.1 肝郁气滞型：态的表现与靶的定位

肝郁气滞型失眠是临床上常见的证型，其“态”的表现与现代医学所定义的应激、焦虑等精神心理因素密切相关。中医理论认为，肝主疏泄，调畅气机，情志抑郁或过激均可导致肝气郁结，进而影响心神，使阳气不得入阴而发为失眠。

2.1.1 态的表现：典型症状与体质特点
肝郁气滞型失眠患者的“态”主要体现在以下几个方面：

  • 典型症状： 患者常表现为入睡困难或入睡后易醒、醒后难以再睡，多梦。伴随症状包括情绪急躁易怒、精神紧张，或情志抑郁，胸胁胀满疼痛、脘腹胀闷，口苦咽干，嗳气叹息，女性可见月经不调。这些症状反映了肝失疏泄、气机郁滞、肝火内扰的病理状态。
  • 体质特点： 气郁质个体更易发展为肝郁气滞型失眠。这类人群常性格内向、敏感多虑、情志不畅，对刺激反应敏感。舌象多见舌质暗红或淡红，苔薄白或薄黄；脉象多为弦脉。

2.1.2 靶的定位：现代医学机制解析
肝郁气滞型失眠的“态”与现代医学研究中的多个“靶点”存在紧密关联：

  • 神经递质失衡：
    • 5-羟色胺（5-HT）： 肝郁气滞常伴随情绪问题，如焦虑、抑郁。5-HT是一种重要的神经递质，与情绪、睡眠和应激反应密切相关。肝郁气滞可能导致5-HT代谢紊乱，影响其在大脑中的水平和活性，从而干扰睡眠的正常调节。有研究指出，色氨酸（5-HT的前体）的摄入与抑郁和睡眠时长呈负相关和正相关 15，提示5-HT系统在调节情绪和睡眠中的重要作用。
    • 去甲肾上腺素（NE）： 情绪应激时，交感神经系统被激活，释放去甲肾上腺素，导致机体处于高警觉状态，不利于睡眠。肝郁气滞型患者的烦躁易怒、精神紧张可能与去甲肾上腺素水平升高，交感神经兴奋性增强有关。
    • GABA： GABA是主要的抑制性神经递质，其功能减弱会导致神经系统兴奋性增加。肝郁气滞状态下，可能存在GABA能系统功能受损，从而影响睡眠的启动和维持。
  • 下丘脑-垂体-肾上腺（HPA）轴功能异常： 慢性应激和情绪障碍是失眠的重要诱因 1617。肝郁气滞与长期的精神压力密切相关，可导致HPA轴的过度激活。HPA轴的激活会引起皮质醇（Cortisol）等应激激素水平升高。高水平的皮质醇可能直接干扰睡眠结构，抑制褪黑素分泌，从而影响睡眠质量。例如，某些适应原（如南非醉茄）的制剂被发现能够显著改善压力和焦虑症状，并提高睡眠质量，其机制可能涉及对HPA轴的调节 17。
  • 炎症反应与氧化应激： 长期情绪应激和肝气郁结可能诱发或加重全身性炎症反应和氧化应激。炎症因子（如IL-6、TNF-α）的升高可影响大脑功能，干扰睡眠-觉醒周期。一些研究也表明，睡眠障碍与肝功能生物标志物（如ALT、AST、GGT等）异常存在关联，提示睡眠问题可能与肝脏炎症和损伤有关 18。此外，胆汁酸水平升高也可能诱发慢性肝病患者的昼夜节律睡眠障碍 19。
  • 自主神经功能紊乱： 肝郁气滞患者常伴有心烦、易怒等症状，这提示自主神经系统失衡，表现为交感神经张力增高，副交感神经活性降低，使得身体处于持续的“战斗或逃跑”模式，难以放松入睡。
  • 肠道菌群失调： 情绪应激和肝郁气滞也可能通过脑-肠轴影响肠道菌群的组成和功能，而肠道菌群失调反过来又会影响神经递质的合成和释放，形成恶性循环，进一步加重失眠。
  • 褪黑素分泌异常： 褪黑素是调节睡眠-觉醒周期的重要激素。肝郁气滞可能通过HPA轴紊乱、交感神经兴奋等机制，间接影响褪黑素的正常分泌节律，导致睡眠障碍。值得注意的是，褪黑素受体激动剂（如雷米替隆）在治疗失眠时，也曾有诱发自身免疫性肝炎的案例 20，这提示褪黑素及其受体在肝功能和免疫调节中可能扮演复杂角色，也为肝郁气滞型失眠的“态-靶”研究提供了新的视角。

综上所述，肝郁气滞型失眠的“态”表现为一系列情绪和躯体症状，其“靶”则涉及神经递质、HPA轴、炎症反应、自主神经功能及肠道菌群等多个现代医学靶点，这些靶点相互作用，共同构成了肝郁气滞导致失眠的复杂病理生理机制。

2.2 心脾两虚型：态的表现与靶的定位

心脾两虚型失眠是临床上常见的失眠证型之一，其“态”的特征深刻反映了气血生化不足、心神失养和脾失健运的病理状态。这种证型在失眠患者中的分布广泛，尤其在阴证失眠中占据主导地位，心脾两虚型（31.6%）是所有证型中最常见的一种9。

2.2.1 态的表现：神疲乏力与纳差
心脾两虚型失眠患者的“态”主要体现在以下几个方面：

  • 典型症状： 患者常表现为入睡困难，或多梦易醒，醒后难以再入睡，并伴有心悸健忘、头晕目眩、神疲乏力、面色萎黄或淡白、肢倦神疲、饮食减少、腹胀便溏等症状。女性患者可兼见月经量少色淡，甚至闭经。这些症状反映了心血不足以养心神，脾气虚弱运化失职，气血生化无源的病理机制。
  • 体质特点： 这类患者多为气虚质或血虚质，体质虚弱，易感疲劳，对外界刺激的适应能力较差。舌象多见舌淡苔薄白，脉象细弱。

2.2.2 靶的定位：脑源性神经营养因子减少与肠道菌群紊乱
心脾两虚型失眠的“态”与现代医学研究中的多个“靶点”具有内在联系：

  • 脑源性神经营养因子（BDNF）减少： BDNF是一种重要的神经营养因子，参与神经元的生长、分化、存活和突触可塑性，对认知功能和情绪调节至关重要。研究表明，失眠会显著降低血清中BDNF的水平，这与老年人认知功能下降类似，提示BDNF水平的降低可能与失眠引起的认知障碍有关21。心脾两虚患者常表现出记忆力下降、精力不足等，这可能与BDNF水平的减少有关。BDNF水平的下降，尤其是在睡眠障碍的情况下，可能加剧神经系统的功能失调，从而影响睡眠质量和认知功能21。此外，有研究指出，ghrelin/GHSR系统可以通过激活cAMP/CREB/BDNF等信号通路发挥抗抑郁作用，提示BDNF在情绪和神经保护中的重要性22。
  • 肠道菌群紊乱： 脾主运化，脾虚则运化失职，可能导致肠道功能紊乱。肠道菌群是“脑-肠轴”的重要组成部分，其结构和功能紊乱与多种神经精神疾病包括失眠密切相关。心脾两虚型患者的消化系统症状（如纳差、便溏）提示肠道功能可能存在异常。一项针对脾虚型失眠患者的研究发现，其肠道菌群组成与健康人存在显著差异，并与睡眠质量（PSQI评分）及炎症标志物（如IFN-α）相关联23。例如，在脾气虚伴胃热的失眠患者中，某些细菌丰度较高，而脾气虚单独存在的患者则有不同的菌群特征23。这些发现揭示了肠道菌群失调可能是心脾两虚型失眠的重要“靶点”，通过影响神经递质合成、炎症反应或免疫调节，进而影响睡眠。
  • 代谢组学差异： 肠道菌群紊乱会影响宿主的代谢产物，导致代谢组学的改变。心脾两虚型患者的代谢组学特征可能与脾虚导致的物质转运和代谢异常有关。通过1H NMR代谢组学研究血清中的各种常见代谢物、差异代谢物、潜在代谢生物标志物和代谢途径，可以揭示失眠治疗中脑肠相互作用的潜在机制24。这些代谢组学差异可能包括与能量代谢、神经递质前体或炎症介质相关的代谢产物改变，从而为心脾两虚型失眠的精准诊断和治疗提供客观依据。
  • 神经内分泌免疫网络失衡： 心脾两虚患者往往伴有免疫功能低下，表现为易感冒、抵抗力差等。脾脏在中医中被视为重要的免疫器官。脾气虚可能导致免疫调节异常，进而影响神经内分泌系统，如HPA轴功能，导致皮质醇等应激激素分泌紊乱，进一步干扰睡眠。
  • 神经递质代谢异常： 心脾两虚可能导致神经递质前体物质供应不足或代谢紊乱，例如，色氨酸是5-HT的前体，脾虚可能影响其吸收和代谢，从而影响5-HT的合成，进而影响睡眠。此外，研究发现GABA水平的异常与失眠有关25。
  • PSQI评分及临床研究： 临床研究常采用匹兹堡睡眠质量指数（PSQI）评估失眠患者的睡眠质量。针对心脾两虚型失眠患者的研究显示，其PSQI评分通常较高，提示睡眠障碍较为严重。通过干预治疗，如针灸或中药，可以显著改善这些患者的PSQI评分，并伴随肠道菌群的改变，进一步验证了“肠道-大脑”轴在心脾两虚型失眠中的重要作用2326。

综上所述，心脾两虚型失眠的“态”表现为心脾功能不足导致的气血两虚、心神失养，其“靶”则涉及BDNF减少、肠道菌群紊乱及其导致的代谢组学差异、神经内分泌免疫网络失衡以及神经递质代谢异常等多个现代医学靶点，共同构成了该证型的复杂病理生理基础。

2.3 痰热内扰型：态的表现与靶的定位

痰热内扰型失眠在中医临床中并不少见，其“态”的表现往往与患者的体质、饮食习惯及情志因素密切相关。中医认为，脾失健运，水湿内停，聚湿生痰，郁而化热，痰热上扰心神，则导致心神不宁而发为失眠。

2.3.1 态的表现：胸闷痰多、苔黄腻
痰热内扰型失眠患者的“态”主要包括：

  • 典型症状： 患者表现为入睡困难，或多梦，寐而不酣，胸闷不舒，咽喉多痰，口苦，头重，脘腹胀满，或伴有恶心、食欲不振。这些症状清晰地描绘了痰热阻滞、上扰清窍的病理图景。其中，胸闷痰多是其最具特征性的表现，暗示着湿痰壅滞，气机不畅。
  • 体质特点： 这类患者多为痰湿质或湿热质，体型多肥胖，素有嗜食肥甘厚味或多饮酒的习惯。舌象常可见舌体胖大，舌质暗红，苔黄厚腻；脉象多为滑脉或弦滑。

2.3.2 靶的定位：炎症因子与神经炎症的互作机制
痰热内扰型失眠的“态”与现代医学研究中的多个“靶点”存在密切关联，尤其在炎症反应和肠道代谢方面：

  • 炎症因子（IL-6、TNF-α）升高： 痰热内扰在中医中被认为是体内病理性产物（痰）与热邪交结，类似于现代医学中的炎症反应。研究表明，失眠患者普遍存在全身性炎症反应，表现为促炎细胞因子，如白介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平升高27。这些炎症因子可以穿过血脑屏障，激活大脑中的小胶质细胞和星形胶质细胞，诱发神经炎症。神经炎症会导致神经元损伤、突触功能障碍以及神经递质失衡，从而直接影响睡眠的调节机制。痰热内扰型患者的苔黄腻、口苦等表现，可以被视为身体内部存在热毒和炎症的外部征象，与IL-6、TNF-α等炎症因子的升高高度吻合。
  • 肠道代谢物（如短链脂肪酸）异常： 痰热的形成与脾胃运化功能失调、湿浊内生密切相关。肠道是人体重要的消化吸收器官，脾胃功能失调会导致肠道微生态环境的改变，进而影响肠道菌群的组成和功能。肠道菌群紊乱不仅可以直接产生神经活性物质，也可以通过代谢产物（如短链脂肪酸，SCFAs）间接影响大脑功能2829。例如，丁酸盐等SCFAs可以通过影响血脑屏障的通透性、神经免疫调节以及神经递质合成前体物质的供应，从而对中枢神经系统产生影响。痰热内扰型患者，因其脾胃运化功能障碍，可能导致肠道菌群失调，产生异常的肠道代谢产物，进而影响睡眠。例如，某些有害菌可能产生内毒素，加剧全身炎症反应，而有益菌的减少则可能影响SCFAs的正常生成，削弱其对神经系统的保护作用。
  • 神经炎症的互作机制： 痰热内扰所导致的慢性炎症反应和肠道菌群失调，共同构成了神经炎症的核心驱动因素。痰热内扰促使炎症因子（如IL-6、TNF-α）升高，这些因子直接或间接诱导神经炎症。同时，肠道菌群失调会破坏肠道屏障功能，导致细菌代谢产物或细菌本身进入血液循环，进一步刺激免疫系统，加重全身和脑部的炎症状态。这种“肠道-免疫-大脑”轴的失衡，最终导致神经炎症，干扰大脑对睡眠-觉醒周期的正常调控，加剧失眠症状。
  • 脂质代谢紊乱： 痰湿体质的患者常伴有脂质代谢异常，如血脂升高、脂肪肝等。脂质代谢紊乱本身就是一种低度炎症状态，可进一步加重全身炎症。同时，脂质代谢产物如某些游离脂肪酸，也可能作为信号分子影响中枢神经系统功能，进而影响睡眠。

综上，痰热内扰型失眠的“态”表现为胸闷痰多、苔黄腻等一系列痰热阻滞症状，其“靶”则涉及炎症因子（IL-6、TNF-α）的升高、肠道代谢产物（如短链脂肪酸）的异常以及由此诱发的神经炎症。这些微观靶点相互关联，共同解释了痰热内扰导致失眠的复杂病理生理机制。

3. 中药干预失眠症的态靶关联作用机制

中药治疗失眠症强调辨证论治，其独特的优势在于复方配伍的协同作用和单味药的靶向调控。这种多层次、多维度的干预策略，使得中药能够有效调节患者的“态”（整体功能状态）并作用于具体的“靶”（病理生理靶点），从而实现治疗目的。

3.1 复方中药的多态调节与多靶协同

复方中药在治疗失眠症时，其多成分、多靶点、多通路的协同作用是其核心优势。这些方剂通过综合调节患者的整体“态”，同时作用于多个关键“靶点”，从而发挥治疗效应。

3.1.1 酸枣仁汤的多态调节与多靶协同
酸枣仁汤是中医治疗失眠的经典方剂，由酸枣仁、茯苓、知母、川芎、甘草组成，具有养血安神、清热除烦的功效，常用于治疗肝血不足、虚热内扰所致的失眠。其多态调节与多靶协同机制体现在：

  • 整体“态”的改善： 酸枣仁汤通过其君药酸枣仁的安神作用，以及茯苓的健脾安神、知母的清热除烦、川芎的活血行气、甘草的调和诸药，共同改善患者心烦不寐、头晕目眩、口干咽燥等肝血不足、虚热内扰的整体“态”象。其调节情绪、改善焦虑的作用显著，这在一定程度上是其改善睡眠的“态”的基础 30。
  • 微观“靶”点的干预： 现代药理学和网络药理学研究深入揭示了酸枣仁汤多靶点协同作用的机制：
    • 神经递质调节： 研究表明，酸枣仁汤能够显著改善小鼠脑内5-羟色胺（5-HT）、GABA（γ-氨基丁酸）和去甲肾上腺素（NE）的水平，这些神经递质在睡眠-觉醒周期和情绪调节中扮演关键角色 30。通过调节这些神经递质，酸枣仁汤有助于纠正失眠患者的神经递质失衡状态。
    • HPA轴的调控： 酸枣仁汤能够影响血清皮质酮（CORT）和促肾上腺皮质激素释放激素（CRH）水平，提示其对下丘脑-垂体-肾上腺（HPA）轴的调节作用 30。HPA轴的过度激活是应激相关失眠的重要病理生理基础，酸枣仁汤通过稳定HPA轴功能，减轻应激反应，从而改善睡眠。
    • 炎症通路与神经保护： 网络药理学分析显示，酸枣仁汤的核心靶点涉及炎症反应（如IL-6、TNF-α）、神经系统功能（如神经活性配体-受体相互作用、5-HT能突触）以及代谢过程（如花生四烯酸代谢、色氨酸代谢）31。此外，酸枣仁汤在治疗阿尔茨海默病合并糖尿病时，也被发现与炎症因子IL6、TNF、IL1B等相关32。这些机制有助于减轻神经炎症，保护神经元功能，从而改善睡眠。
    • 肠道菌群与代谢产物： 酸枣仁汤的活性成分，如芒柄花素、阿魏酸等，可通过调节肠道菌群和相关代谢产物（如花生四烯酸、色氨酸、鞘脂和亚油酸代谢）来发挥作用 3033。例如，色氨酸代谢产物的改变可以直接影响中枢神经系统中5-HT的合成，进而影响睡眠。
    • 关键活性成分与靶点： 通过整合代谢组学和网络药理学，研究筛选出酸枣仁汤中进入血液的有效成分，如芒柄花素、替斯佩诺素、阿魏酸、甘草苷、毛蕊异黄酮、木兰花碱和异甘草苷等，这些成分能够与神经活性配体-受体相互作用、cAMP信号通路、5-HT能突触和PI3K-Akt信号通路等关键靶点结合，发挥抗焦虑和改善睡眠的作用 33。

3.1.2 黄连阿胶汤的多态调节与多靶协同
黄连阿胶汤是治疗少阴病心肾不交、阴虚火旺所致失眠的经典方剂。其作用机制同样体现了多态调节与多靶协同：

  • 整体“态”的改善： 黄连阿胶汤以黄连、黄芩清心火，阿胶、芍药滋阴养血，鸡子黄滋养心阴，共同改善患者心烦不寐、口燥咽干、手足心热等阴虚火旺的“态”象。通过滋阴降火，调和阴阳，使心肾交泰，阳气得以下潜入阴。
  • 微观“靶”点的干预：
    • 神经递质与神经炎症： 虽然黄连阿胶汤的直接研究不如酸枣仁汤丰富，但其主要成分如黄连中的小檗碱、黄芩中的黄芩苷等，均具有广谱的药理活性。小檗碱被证实具有抗炎、抗氧化、神经保护以及调节神经递质的作用。这些成分可能通过抑制促炎细胞因子（如IL-6、TNF-α）的释放，减轻神经炎症，从而改善失眠。
    • “肠-脑轴”调节： 黄连等清热燥湿类药物能够调节肠道菌群，改善肠道炎症，这可能通过“肠-脑轴”间接影响中枢神经系统，从而有助于改善因肠道功能紊乱引起的失眠。
    • 细胞凋亡与自噬： 黄连等成分也可能通过调节细胞凋亡和自噬通路，对神经细胞产生保护作用，从而改善睡眠。

3.1.3 网络药理学验证核心靶点
网络药理学在揭示复方中药的多靶点作用机制方面发挥了重要作用。例如，在四逆散（常用于治疗肝郁气滞型失眠）的网络药理学分析中，核心靶蛋白包括AKT1、IL6、TNF、SLC6A4、MAOA和GABRA2等 34。这些靶点涉及炎症、神经退行性变、细胞凋亡以及5-HT能、胆碱能、多巴胺能和GABA能系统，表明四逆散通过多靶点机制缓解焦虑性失眠。其中，核心化合物如β-谷甾醇被预测能够与MAOA结合，提示其可能通过调节单胺类神经递质代谢来发挥作用 34。类似地，对于其他复方如SGML-4，网络药理学分析也揭示了其通过多靶点和多通路机制发挥抗失眠作用，核心活性成分如木犀草素、芹菜素等与AKT1、TNF等核心靶点密切相关，主要通路包括5-HT能突触和钙信号通路 35。

这些研究共同证实了复方中药通过“多成分-多靶点-多通路”的复杂网络协同作用，实现了对失眠症的整体调节，不仅改善了患者的宏观“态”象，也精准干预了微观“靶”点，从而达到标本兼治的效果。

3.2 单味中药的靶向调控与态平衡作用

单味中药在治疗失眠症中同样发挥着重要作用，其独特之处在于通过特定的活性成分，直接靶向调控睡眠相关的分子通路，同时也能对患者的整体“态”产生积极影响，实现局部的精准干预与整体的平衡调节。

3.2.1 酸枣仁的靶向调控与态平衡作用
酸枣仁（Ziziphi Spinosae Semen）是传统中医中常用的安神药物，被广泛用于治疗失眠和焦虑。其“靶向调控”和“态平衡”作用主要通过以下机制实现：

  • 靶向调控GABAergic系统： 酸枣仁及其主要活性成分，如枣仁皂苷A（Jujuboside A），被认为是其发挥镇静安眠作用的关键。研究发现，枣仁皂苷A能显著上调GABA水平，同时抑制谷氨酸（Glu）水平，从而恢复GABA/Glu的平衡 36。GABA是中枢神经系统主要的抑制性神经递质，通过激活GABA受体（包括GABAA和GABAB受体）来降低神经元的兴奋性，促进睡眠。枣仁皂苷A通过增加GABAA和GABAB受体的表达，增强GABA能神经传递，从而缩短入睡潜伏期，延长睡眠时间 3637。一项研究通过电生理分析发现，枣仁皂苷A能够激活GABA能抑制，降低失眠小鼠海马区神经元的兴奋性，从而改善记忆障碍 38。此外，枣仁皂苷A还能通过增加细胞内氯离子内流来模拟GABA受体的激活效果，进一步证实了其对GABAergic系统的调控作用 37。
  • 改善整体状态： 除了直接调节GABAergic系统，酸枣仁还通过多种途径改善失眠患者的整体状态（“态”）。
    • 缓解焦虑： 失眠常伴随焦虑症状，枣仁皂苷A已被证明能减轻小鼠的焦虑样行为 39。通过开放场实验和高架十字迷宫测试，发现枣仁皂苷A能改善由对氯苯丙氨酸（PCPA）诱导的失眠模型小鼠的焦虑水平 39。这提示酸枣仁不仅能改善睡眠质量，还能缓解导致失眠的心理负荷。
    • 神经保护作用： 枣仁皂苷A还能维持前额叶神经元的线粒体稳态，改善线粒体功能障碍，提高ATP含量和细胞色素c（Cyt c）氧化酶的表达，从而减轻神经元损伤，为失眠治疗提供了新的靶点 39。此外，酸枣仁总皂苷（JSS）也被证明具有抗氧化、抗炎和神经保护作用，能够减少海马神经元凋亡，改善神经损伤，这些都有助于稳定患者的神经系统功能，促进“态”的平衡。
    • 调节血脑屏障： 枣仁皂苷A和B的协同作用被发现在下丘脑水平调节睡眠，其作用可能与血脑屏障的改变有关 40。这表明酸枣仁可以通过调节中枢神经系统的微环境，间接影响神经元的正常功能。
    • 多靶点协同： 网络药理学研究也揭示了酸枣仁中的活性成分，如枣仁皂苷A和longikaurin A，与一系列枢纽基因（如AKT1、MAPK3、JUN、IL6、TP53、ALB、ESR1、FOS）具有强大的结合能力，这些基因参与多种生物过程，包括细胞增殖、炎症反应、应激反应和神经递质调节，表明酸枣仁通过多靶点协同作用来治疗失眠 41。

3.2.2 远志的靶向调控与态平衡作用
远志（Radix Polygalae）是另一味常用安神中药，其传统功效为安神益智、祛痰开窍。远志在治疗失眠中的“靶向调控”和“态平衡”作用同样显著：

  • 神经保护与抗炎： 远志提取物及其中所含的活性成分，特别是三萜皂苷类，被发现具有显著的神经保护作用。例如，远志皂苷元（triptoid saponins）被认为具有抗阿尔茨海默病（AD）的潜力，通过抗Aβ聚集、抗Tau蛋白病变、抗炎症、抗氧化、抗神经元凋亡、增强中枢胆碱能系统和促进神经元增殖等多种机制发挥作用 42。这些神经保护作用对于维持大脑功能，改善睡眠质量至关重要。
  • 自噬增强： 有研究从远志中分离出一种新型的自噬增强剂——Onjisaponin B及其活性组分，该组分能有效增强细胞自噬，促进突变亨廷顿蛋白的清除，并减少α-突触核蛋白的水平和聚集 43。自噬是细胞清除受损蛋白和细胞器的一种重要机制，其功能障碍与多种神经退行性疾病和睡眠障碍有关。通过增强自噬，远志有助于清除神经元内的异常蛋白，维持神经细胞的稳态，从而改善失眠等神经精神症状。
  • 缓解焦虑与镇静： 远志在传统上也被用于治疗神经衰弱和健忘症。其活性成分可能通过调节神经递质平衡，如促进GABA能传递或抑制谷氨酸能传递，从而产生镇静、抗焦虑的作用，有助于改善患者的整体情绪状态，使其更容易进入睡眠。

综上所述，酸枣仁和远志等单味中药，通过其特定的活性成分，能够精准地作用于睡眠相关的分子靶点（如GABA受体、线粒体功能），同时通过调节神经递质、缓解焦虑、增强神经保护等途径，全面改善患者的整体状态，体现了中药治疗失眠“局部靶向调控”与“整体态平衡”相结合的独特优势。

3.3 中药对“脑-肠-菌轴”的态靶协同干预

近年来，随着对“脑-肠-菌轴”（Gut-Brain-Microbiota Axis）研究的深入，肠道微生物在失眠发生发展中的关键作用日益凸显，为中药治疗失眠提供了新的“态靶”视角。中药通过调节肠道菌群结构和其代谢产物，进而影响脑内神经递质，实现对“态”（肠道微生态状态）与“靶”（脑肠轴信号）的协同干预。

3.3.1 肠道菌群与失眠的关联
肠道菌群被认为是影响睡眠和精神健康的重要因素。研究表明，失眠患者普遍存在肠道菌群失调，表现为菌群多样性降低、特定菌属丰度改变，以及益生菌数量减少等 2944。这种失调会通过多种途径影响中枢神经系统，例如：

  • 神经递质前体和代谢物： 肠道菌群能够合成或代谢多种神经递质（如GABA、多巴胺、5-HT）及其前体物质（如色氨酸）。例如，色氨酸是5-HT的合成前体，肠道菌群的异常会影响色氨酸的代谢途径，从而影响脑内5-HT的水平，进而干扰睡眠和情绪调节 45。
  • 炎症反应： 肠道菌群失调可导致肠道屏障功能受损，增加肠道通透性，使细菌产物（如脂多糖LPS）进入血液循环，引发全身性炎症反应，甚至神经炎症。这些炎症因子可以穿过血脑屏障，直接影响脑功能，导致失眠 4546。
  • 短链脂肪酸（SCFAs）： 肠道菌群发酵膳食纤维产生的短链脂肪酸（如乙酸、丙酸、丁酸）对宿主健康至关重要。SCFAs不仅是肠道细胞的能量来源，还能通过血脑屏障，影响脑内基因表达、神经递质合成和炎症反应。肠道菌群失调可能导致SCFAs产生不足或比例失衡，进而影响睡眠 46。

3.3.2 中药对“肠道微生态状态”的调节
中药在治疗失眠时，并非仅仅针对脑部靶点，而是通过整体调节，显著改善肠道微生态这一重要的“态”。

  • 黄连温胆汤（HWD）的调节作用： 黄连温胆汤是一种经典的中药复方，常用于治疗痰热内扰型失眠。研究发现，黄连温胆汤能显著改善失眠大鼠的肠道菌群紊乱，恢复菌群的丰富度和多样性，并促进短链脂肪酸（SCFAs）的产生 46。例如，在对氯苯丙氨酸（PCPA）诱导的失眠大鼠模型中，黄连温胆汤不仅能改善睡眠行为，还能显著增加肠道益生菌（如乳酸杆菌）的丰度，降低有害菌的比例 46。这种对肠道菌群组成的调整，直接改善了患者的“肠道微生态状态”。
  • 温胆汤（WDD）的调节作用： 温胆汤在治疗失眠中也显示出对肠道菌群的调节作用。它能通过改善肠道菌群失调，并调节色氨酸代谢来改善睡眠。研究表明，温胆汤能增加结肠和大脑中的紧密连接蛋白（如Occludin, Claudin-1, ZO-1）的表达，从而增强肠道屏障和血脑屏障的完整性，减少炎症物质的渗透 45。此外，温胆汤还被发现能够通过抑制吲哚胺2,3-双加氧酶1和犬尿氨酸-3-单加氧酶的表达，纠正色氨酸代谢中犬尿氨酸通路的异常，进而影响5-HT的合成，改善失眠 45。
  • 复方酸枣颗粒（CZG）的调节作用： 优化后的酸枣仁汤复方——复方酸枣颗粒，在治疗失眠大鼠中也显示出对代谢紊乱的调节作用，提示其可能通过肠道菌群途径影响宿主代谢 47。

3.3.3 “靶”（脑肠轴信号）的联动机制
中药调节肠道微生态的“态”后，通过“脑-肠-菌轴”实现对脑内信号通路的“靶”向干预：

  • BDNF/TrkB信号通路激活： 黄连温胆汤通过维持肠道菌群稳态和促进SCFAs的产生，能够显著降低失眠大鼠脑内的炎症反应和小胶质细胞的激活，并激活脑源性神经营养因子（BDNF）/酪氨酸激酶B受体（TrkB）信号通路 46。BDNF在神经元的生长、分化、存活和突触可塑性中发挥关键作用，其水平的升高有助于改善学习记忆能力，并间接促进睡眠。体外实验也证实，乙酸（一种SCFA）可以激活神经细胞中的BDNF/TrkB信号通路，促进神经细胞生长 46。
  • 神经递质调节： 中药通过调节肠道菌群，影响色氨酸的代谢，进而调节脑内5-HT的合成和释放。5-HT是重要的镇静和睡眠诱导神经递质。例如，温胆汤被发现能够调节神经递质紊乱，增加IL-10水平并降低IL-6、IL-1β、TNF-α和LPS水平，从而改善睡眠 45。
  • 炎症和HPA轴的调控： 肠道菌群的调节有助于减少全身和神经炎症，从而降低炎症因子对中枢神经系统的负面影响。同时，肠道菌群还可以通过影响应激激素（如皮质醇）的分泌来调节下丘脑-垂体-肾上腺（HPA）轴的活性，进而影响睡眠 2947。

综上所述，中药对失眠症的治疗，超越了单一靶点的限制，通过“脑-肠-菌轴”这一复杂的调控网络，实现了对“肠道微生态状态”的整体调节，并进一步影响“脑肠轴信号”的诸多靶点，例如通过增加乳酸杆菌等益生菌、促进SCFA生成、调节色氨酸代谢、激活BDNF/TrkB通路以及抑制神经炎症等，最终改善脑内神经递质平衡和睡眠质量。这种“态靶协同”的干预模式，不仅为中药治疗失眠提供了坚实的科学基础，也为药物研发和临床策略优化指明了方向。

4. 态靶辨证指导下的中药临床应用实践

4.1 基于态靶的个体化处方策略

在“态靶辨证”理论指导下，中药治疗失眠症的核心在于根据患者的个体化“态”（证候类型、体质特征）精准定位其潜在的“靶点”，进而制定相应的治疗策略。这种个体化处方模式，是中医辨证论治精神的体现，也是中药治疗失眠症取得良好临床效果的关键。临床实践中，针对不同证型失眠患者，中医师会遵循特定的处方规律，以期达到最佳的治疗效果。

4.1.1 不同证型的中药处方规律及其作用

  • 肝郁气滞型失眠：

    • 处方规律： 肝郁气滞型失眠患者，其“态”表现为情志不畅、烦躁易怒、胸胁胀痛等，提示其“靶”可能涉及神经递质失衡（如5-HT、NE）、HPA轴功能异常和神经炎症。因此，临床上多选用具有疏肝解郁、清热安神功效的方剂，如柴胡类方（如柴胡加龙骨牡蛎汤、丹栀逍遥散等）。这些方剂以柴胡为君药，配伍其他疏肝、理气、清热、安神的药物。
    • 改善效果： 柴胡类方剂通过调节肝的疏泄功能，平抑肝火，从而间接调节神经递质的平衡，降低交感神经兴奋性。例如，丹栀逍遥散中的柴胡、当归、白芍等能够协同作用，改善情绪，减轻焦虑，从而促进睡眠。尽管缺乏直接针对柴胡类方剂在失眠治疗中对TST、PSQI改善的特异性RCT研究，但其在改善伴随情绪障碍和失眠方面的有效性已被广泛认可。

  • 心脾两虚型失眠：

    • 处方规律： 心脾两虚型失眠患者，其“态”表现为心悸健忘、倦怠乏力、纳差便溏等，提示其“靶”可能涉及BDNF减少、肠道菌群紊乱、以及神经内分泌免疫网络失衡。针对此类患者，临床上常选用益气健脾、养心安神的方剂，如归脾汤、酸枣仁汤等。这些方剂以人参、黄芪等补气药，白术、茯苓等健脾药，以及酸枣仁、远志等安神药为主。
    • 改善效果： 归脾汤通过补益心脾之气血，改善气血生化之源，为心神提供充足的物质基础，从而达到养心安神的目的。酸枣仁汤则直接作用于神经系统，通过调节GABA能神经递质，发挥镇静安眠作用。一项针对原发性失眠的随机安慰剂对照三盲试验显示，基于辨证论治的中医治疗（其中血虚和肝郁是最常见的证型）能显著增加患者的总睡眠时间（TST），平均增加0.6小时，并使34.1%的患者TST增加超过0.5小时，同时匹兹堡睡眠质量指数（PSQI）评分显著下降（改善3.3分），中医症状评分也显著降低2.0分 48。该研究强调了中医辨证论治在改善失眠患者睡眠质量方面的有效性和安全性 48。虽然该研究未细分具体证型处方效果，但其结论支持了中医个体化辨证处方对失眠症的整体疗效。

  • 痰热内扰型失眠：

    • 处方规律： 痰热内扰型失眠患者，其“态”表现为胸闷痰多、苔黄腻、烦躁不寐等，提示其“靶”可能涉及炎症因子升高（如IL-6、TNF-α）、肠道代谢物异常以及神经炎症。临床上多选用清热化痰、和胃安神的方剂，如温胆汤、黄连温胆汤等。
    • 改善效果： 温胆汤通过化痰清热、理气和胃，消除痰热对心神的扰动。黄连温胆汤在此基础上，进一步增强了清热泻火的功效。现代药理研究表明，这些方剂能够调节肠道菌群，减少炎症因子的产生，改善肠道屏障功能，从而减轻神经炎症，调节神经递质平衡，改善睡眠质量。

4.1.2 对睡眠指标（TST、PSQI）及中医症状的改善效果

  • 总睡眠时间（TST）和匹兹堡睡眠质量指数（PSQI）： 多项临床研究表明，基于辨证论治的中药治疗能够显著改善失眠患者的TST和PSQI评分。例如，一项Meta分析结果显示，针灸联合中药治疗围绝经期失眠（PMI）的效果优于单纯西药治疗，在提高疗效（RR: 1.18）、降低PSQI评分（WMD: -2.77）方面具有显著优势 49。虽然该研究是针药联合，但其结果间接支持了中药在改善失眠核心指标上的作用。另一项随机对照试验也明确指出，基于辨证论治的中药治疗能够显著增加原发性失眠患者的TST并改善PSQI评分 48。
  • 中医症状： 个体化中药处方不仅改善了患者的睡眠客观指标，还能有效缓解伴随的中医症状。例如，肝郁气滞型患者的烦躁易怒、胸胁胀痛，心脾两虚型患者的心悸健忘、倦怠乏力，以及痰热内扰型患者的胸闷痰多、口苦等，均能在中药治疗后得到明显改善。上述随机对照试验也表明，中医症状评分在接受中药治疗的患者中显著下降 48。这体现了中药治疗从整体上调节机体功能，达到“态”平衡的优势。

综合来看，态靶辨证指导下的中药个体化处方策略，通过对不同证型患者的精准辨识和针对性治疗，能够有效地改善失眠患者的睡眠质量和伴随症状。这种多靶点、多途径的干预模式，不仅在宏观层面上调整了患者的整体“态”，也在微观层面上作用于与失眠相关的生理“靶点”，从而实现了更好的临床疗效。尽管目前仍需更多高水平的RCT研究来进一步验证不同证型处方的具体疗效和机制，但现有证据已为中医治疗失眠的有效性提供了有力支持。

4.2 中药联合疗法的态靶优化

中药联合疗法，特别是中药与针灸、耳穴等中医外治法的结合，在治疗失眠症方面展现出显著的优势。这种联合应用，不仅仅是治疗手段的简单叠加，更是通过对“态”（整体功能状态）和“靶”（具体病理靶点）的协同干预，实现疗效的优化。针灸、耳穴等外治法通过调节经络气血、脏腑功能等中医“态”层面的因素，为中药作用于分子“靶”点创造有利条件，从而增强疗效，并可能通过不同的作用途径，弥补单一疗法的不足。

4.2.1 针灸与中药的态靶协同作用

针灸作为一种重要的中医外治法，通过刺激特定穴位，调节经络气血运行，平衡阴阳，从而改善患者的整体生理“态”。例如，针刺可以疏通肝气、健脾和胃、养心安神，这些都是从宏观“态”层面进行的调节，与中药的辨证论治思想高度契合。当针灸与中药联合应用时，二者可以形成互补，实现“态”与“靶”的深度协同。

  • 调节经络“态”协同中药作用于“靶”： 针灸通过对经络的调节，能够改善局部和全身的血液循环、神经传导，从而为中药的吸收、分布和作用提供更好的微环境。例如，针刺可以激活神经系统，调节神经递质的释放，如5-HT、GABA等，这与许多安神类中药的分子靶点相吻合。在炎症反应方面，针灸也具有抗炎作用，能够降低促炎因子水平，这与中药清热化痰、解毒消炎的功效异曲同工。
  • SIRT1/Nrf2通路的调节： 近年来研究发现，针灸，特别是电针（EA），在改善中风后失眠（PSI）方面具有显著疗效，其机制可能与调节Sirtuin 1 (Sirt1)和核因子E2相关因子2 (Nrf2)-抗氧化反应元件 (ARE) 通路有关 50。Sirt1是一种重要的去乙酰化酶，参与调节炎症、氧化应激和细胞凋亡。Nrf2-ARE通路则是细胞内主要的抗氧化应激通路。在PSI患者和动物模型中，Sirt1水平降低，Nrf2-ARE通路失活，导致神经炎症、氧化应激和星形胶质细胞损伤。电针治疗能够显著提高Sirt1水平，并激活Nrf2-ARE通路，从而减轻炎症反应，改善氧化应激，并抑制星形胶质细胞凋亡，最终改善睡眠质量 50。虽然这项研究主要针对电针，但它为中药与针灸在分子靶点上的协同作用提供了新的思路。中药，尤其是具有抗炎、抗氧化活性的成分，也可能通过类似或互补的机制调节SIRT1/Nrf2通路，从而实现更强大的协同效应。例如，一些中药成分被发现具有调节Nrf2通路的活性。

4.2.2 耳穴与中药的态靶协同作用

耳穴压豆、耳穴埋籽等耳穴疗法，通过刺激耳廓上的特定穴位，调理脏腑功能，平衡阴阳，具有安神、镇静、止痛等作用。耳穴作为全身经络的缩影，其刺激点可以反映并调节相应的脏腑“态”，从而与中药形成联合作用。

  • 围绝经期失眠（PMI）的Meta分析数据验证： 围绝经期失眠是临床常见且棘手的病症，其发病与女性内分泌变化、情志因素及脏腑功能失调密切相关。一项针对围绝经期失眠的Meta分析发现，针灸联合中药治疗PMI的效果优于单纯西药治疗。该分析结果显示，联合治疗在提高临床有效率（RR: 1.18; 95% CI: 1.08, 1.29; P = .001）、显著降低匹兹堡睡眠质量指数（PSQI）评分（WMD: -2.77; 95% CI: 4.15-1.39; P < .0001），以及改善卵泡刺激素（FSH）水平（WMD: -31.45; 95% CI: 42.7-20.2; P < .001）和汉密尔顿焦虑量表（HAMA）评分（WMD: -2.62, 95% CI: -3.93, -1.32; P < .0001）方面均优于对照组 49。这强有力地证明了中药与针灸（包括耳穴）联合疗法在治疗PMI中的增效机制。这种增效机制可能体现在：
    • 多维度调节激素水平： 中药通过辨证论治，调节女性内分泌，例如滋阴补肾、疏肝解郁，直接或间接影响雌激素、FSH等激素水平。针灸（包括耳穴）通过调节下丘脑-垂体-卵巢轴，进一步协同中药，共同改善激素平衡。
    • 多途径改善睡眠和情绪： 中药通过其活性成分作用于神经递质、HPA轴等靶点，改善睡眠和情绪。针灸通过神经反射和内源性物质释放，调节神经系统功能，缓解焦虑、抑郁，从而促进睡眠。两者的结合，形成了从宏观“态”到微观“靶”的全方位、多层次干预。
    • 改善不良反应和依从性： 中草药和针灸单独或联合使用都能安全地改善脑卒中患者的睡眠 51。

4.2.3 其他非药物疗法的辅助作用

除了针灸和耳穴，刮痧、推拿、艾灸等中医非药物疗法，在失眠治疗中也发挥着重要作用。例如，刮痧疗法在治疗围绝经期综合征时，能够显著改善包括失眠在内的多种临床症状 52。一项系统评价和荟萃分析显示，包括针灸、艾灸、推拿和耳穴压豆在内的中医药非药物疗法能显著提高失眠患者的治疗应答率，改善匹兹堡睡眠质量指数评分，并减轻患者的焦虑和抑郁程度 53。此外，一些研究也探讨了传统中医的外部疗法（如五禽戏结合行为疗法）对失眠患者依从性和疗效的影响 54。

综上所述，中药联合疗法，特别是与针灸、耳穴等外治法的结合，通过对“态”（整体功能状态）和“靶”（分子通路、神经递质等）的协同干预，实现了失眠症治疗效果的显著优化。这种联合策略不仅能够更全面地调节患者机体功能，还能针对性地干预病理靶点，为失眠患者提供了更为有效和安全的治疗方案。

4.3 安全性与长期疗效的态靶考量

中药治疗失眠症在追求疗效的同时，其安全性与长期疗效同样是临床应用中不可忽视的重要方面。态靶辨证理念在安全性评估和长期疗效维持方面提供了独特的视角，强调根据患者的个体“态”差异，合理用药，并关注“态靶”平衡对疗效持续性的影响。

4.3.1 中药治疗失眠的安全性考量与不良反应

尽管中药通常被认为副作用相对较小，但并非完全没有。中药的安全性与患者的体质、证型、药物配伍、剂量以及用药时间等多种因素密切相关。

  • 不良反应监测： 针对中药治疗失眠的安全性研究多聚焦于不良事件的发生率。例如，有研究对舒眠胶囊治疗失眠的有效性和安全性进行了系统评价和Meta分析，结果显示，舒眠胶囊组与西药组在总有效率上无显著差异，但未详细报告具体不良反应发生率 55。另一项针对中药治疗先兆流产的研究中，也提及了口干、便秘和失眠（2-10%）等不良反应，但这并非针对中药治疗失眠的直接研究 56。总体而言，当前关于中药治疗失眠的临床指南普遍质量欠佳，尤其在“适用性”领域得分较低，这表明指南在不良反应、患者偏好和治疗成本等方面的考虑不足，导致许多中药治疗失眠的推荐证据等级较低，主要是基于低或极低确定性的证据 57。
  • 不同证型、体质患者的用药风险： 态靶辨证强调个体差异，不同体质和证型的患者对药物的反应可能不同。
    • 痰湿体质慎用温补药： 例如，痰湿体质的失眠患者，其“态”表现为痰湿内盛，脾失健运。若误用过于温补滋腻的中药，如熟地、阿胶等，可能会加重湿邪内阻，导致脾胃不适，出现消化不良、腹胀、食欲不振等不良反应，甚至加重痰热内扰型失眠。
    • 阴虚火旺体质慎用燥热药： 阴虚火旺型失眠患者，其“态”为阴津亏虚，虚火内扰。若使用过于辛燥或温燥的中药，如干姜、附子等，可能耗伤阴津，加重阴虚火旺，导致口干、心烦、潮热盗汗等症状加剧。
    • 肝郁气滞体质： 肝郁气滞型患者在服用中药时，若方剂中理气药物过重，可能导致耗气伤阴，出现乏力、口干等症状。
    • 气虚体质和阳虚体质： 研究发现，气虚、阳虚、痰湿、气郁和血瘀体质与睡眠质量差显著相关 58。对于这些偏颇体质的患者，用药时需格外谨慎，避免加重其体质偏颇。一项针对老年失眠患者的调查显示，阳虚质和气虚质在不平衡体质中最为常见，且复合体质的比例较高（74.8%） 59。这提示临床医生在用药时需全面考量患者的复合体质特点，进行精细化辨证施治。
  • 与其他药物的相互作用： 中药与西药的联合使用，可能存在药物相互作用的风险，导致药效增强或减弱，甚至产生新的不良反应。因此，在联合用药时，需仔细评估潜在的相互作用。

4.3.2 态靶平衡对长期疗效持续性的影响

中药治疗失眠的优势之一在于其整体调节作用，旨在恢复机体内部的“态靶”平衡，而非仅仅缓解症状。这种平衡的恢复，对于维持长期疗效至关重要。

  • 中药对全身性症状的改善与长期生存率： 一项前瞻性队列研究显示，中药结合西药治疗急性心肌梗死（AMI）患者，在6个月随访期内，不仅能降低中医证候评分（包括失眠症状），还能降低因心绞痛再入院的发生率 60。这提示中药对失眠等全身性症状的改善，可能与患者整体病情的稳定和长期预后相关。
  • 随访数据分析： 现有研究中，部分临床试验会进行短期（如4周治疗后3个月随访）或长期随访，以评估疗效的持续性。例如，有研究表明，中药治疗原发性失眠在改善总睡眠时间（TST）和匹兹堡睡眠质量指数（PSQI）评分方面具有显著效果，且这种改善在治疗结束后仍能维持一段时间，这可能得益于中药对HPA轴、神经递质等“靶点”的稳定调节以及对患者整体“态”的纠正 48。
  • 体质因素在长期疗效中的作用： 中医体质学说认为，体质是人体生命过程中所形成的具有个体特征的结构、功能和代谢活动相对稳定的固有特质。失衡的体质是疾病发生发展的基础。通过中药调理，纠正偏颇体质，使之趋向平和体质，有助于从根本上改善失眠，并维持长期疗效。例如，一项研究发现，平和体质与失眠症呈负相关，而气虚质、阳虚质、痰湿质和气郁质与失眠症呈正相关 61。这提示，通过中药改善这些偏颇体质，能够降低失眠的复发风险，从而维持长期疗效。
  • 态靶平衡的动态维持： 长期疗效的维持并非一劳永逸，而是需要动态的“态靶”平衡。在治疗过程中，患者的“态”会发生变化，其潜在的“靶”点也可能随之改变。因此，在长期随访中，需要根据患者“态”的变化，及时调整中药处方，以维持“态靶”平衡。例如，在老年失眠患者中，气虚质和阴虚质患者在接受新型助眠方剂治疗后，血清中5-HT水平显著增加，IL-6和TNF-α水平显著降低，且总体有效率较高（分别为97.72%和95.34%） 62。这表明针对特定体质（“态”）的治疗能有效调节相关靶点，从而获得更好的长期疗效。

4.3.3 联合疗法对安全性和长期疗效的优化

中药联合其他非药物疗法（如针灸、耳穴）不仅能增强疗效，对安全性和长期疗效的维持也有积极作用。

  • 减少药物依赖性： 中医治疗失眠通常不产生西药常见的药物依赖性或戒断反应。针灸作为一种安全有效的非药物疗法，其不良事件发生率低，且主要为轻中度 6364。与中药联合使用，可以在不增加药物负担的情况下，通过多途径调节，增强疗效并降低单一药物的潜在风险。
  • 整体调节促进自我修复： 联合疗法通过多方位调节机体的整体功能，包括神经、内分泌、免疫系统以及经络气血的平衡，促进机体的自我修复能力。这种从根本上改善生理病理状态的治疗，有助于建立更稳固的“态靶”平衡，从而维持长期疗效。

综上所述，态靶辨证理念为中药治疗失眠的安全性评估和长期疗效维持提供了重要的指导。在临床实践中，医生应充分考虑患者的个体“态”差异，谨慎用药，并通过定期随访和动态调整处方，持续维护“态靶”平衡，以期获得更安全、更持久的治疗效果。然而，当前仍需更多高质量、大样本、长期随访的随机对照试验，以进一步明确中药治疗失眠的长期安全性和疗效。

5. 态靶辨证视角下的中药治疗优化方向

5.1 现有研究的局限性与挑战

尽管“态靶辨证”理论为中药治疗失眠症提供了新的思路和实践框架，并在临床中展现出广阔的应用前景，但现有研究仍存在诸多局限性与挑战，这在一定程度上限制了其临床应用的推广和标准化进程。

5.1.1 证型标准化不足
“态”的辨识是态靶辨证的基础，而中医证型是“态”的集中体现。然而，目前中医失眠证型的诊断标准仍缺乏高度的统一性和客观性。不同研究者、不同医疗机构在证型判断上可能存在差异，导致研究结果难以进行横向比较和推广。例如，尽管辨证论治在中医治疗失眠中广泛应用，但对其具体诊断标准、症状权重和客观指标的界定仍有待进一步细化。这种标准化不足使得“态”的辨识存在一定的主观性，进而影响后续“靶”的定位和“药”的选择的精准度。此外，随着研究深入，失眠患者证型辨识的复杂性也对标准化提出了更高要求。

5.1.2 机制研究深度不够
“靶”的定位是态靶辨证的关键，旨在揭示中药作用的分子机制。当前，虽然网络药理学、代谢组学等技术已在一定程度上揭示了中药复方和单味药的多靶点、多通路作用，但这些研究大多停留在预测和初步验证阶段，缺乏深入的体内外实验和分子生物学验证。例如，许多研究虽然预测了中药成分与某些靶点的结合，但对于这些结合如何具体影响生理病理过程，以及不同成分之间的协同作用机制，仍需更细致的阐明。此外，对中药如何调节“脑-肠-菌轴”的复杂通路，以及其对神经炎症、氧化应激的具体调控机制等，都还需要更深入的探究。现有研究往往侧重于某一或几个靶点的阐释，对于“态”向“靶”转化的完整通路及其在失眠发生发展中的确切作用机制仍需系统性研究。参考文献65通过血清蛋白质组学技术发现失眠患者存在差异表达蛋白，且这些蛋白主要富集在免疫和炎症相关的生物功能和信号通路中，这为中药治疗失眠的机制研究提供了新的方向，但仍需进一步深入验证。

5.1.3 大样本随机对照试验（RCT）缺乏
高质量的临床证据是中药治疗失眠被广泛认可和应用的基础。然而，目前针对中药治疗失眠的临床研究，特别是基于“态靶辨证”指导下的研究，普遍存在样本量小、研究设计不严谨、随访时间短等问题。全球范围内的临床指南对中药治疗失眠的推荐证据等级普遍较低，大部分基于低或极低确定性的证据57。这主要是由于缺乏设计良好、大样本、多中心、随机双盲对照的临床研究。缺乏强有力的临床证据，使得中药治疗失眠在指南推荐中难以获得高等级支持，限制了其在国际上的推广和应用。例如，有研究指出，许多中医护理技术如耳穴、芳香疗法等存在小样本、缺乏客观睡眠质量评估和干预措施异质性高等局限性66。一项多中心、单盲、随机对照试验的方案也强调了需要大样本研究来验证针刺在难治性失眠中的疗效67，这同样适用于中药治疗。

5.1.4 对临床应用的限制
上述局限性对“态靶辨证”指导下的中药临床应用产生了多方面限制：

  • 指南推荐证据等级低： 由于缺乏高质量的临床研究，导致中药治疗失眠在国际和国内临床实践指南中的推荐等级不高。参考文献57指出，中医药治疗失眠的建议主要依赖于低确定性证据，影响了其在临床决策中的地位。
  • 标准化与个性化的矛盾： 态靶辨证强调个体化治疗，但如果证型辨识缺乏统一标准，机制研究深度不够，就难以在个性化治疗的基础上实现一定程度的标准化和规范化。这给中药的质量控制、疗效评价和推广带来了挑战。
  • 安全性与长期疗效评估不足： 虽然中药相对温和，但其潜在的长期安全性和副作用仍需更全面的评估57。缺乏大样本、长期随访的研究，使得中药的长期疗效和安全性数据不足，影响了医生和患者的信心。
  • 跨学科合作待加强： “态靶辨证”本身就是中医与现代医学结合的产物，但目前跨学科团队的深度合作仍有待加强。缺乏生物医学、药理学、临床流行病学等不同领域专家的紧密配合，会阻碍其从理论到实践的全面发展。

综上所述，当前态靶辨证在失眠症中药治疗领域的研究仍处于发展阶段，面临诸多挑战。要实现其临床价值的最大化，亟需在证型标准化、机制深入研究、大样本RCT以及多学科交叉融合等方面取得突破。

5.2 未来研究的重点与技术路径

面对现有研究的局限性与挑战，未来态靶辨证视角下的中药治疗失眠症研究，应聚焦于整合多学科前沿技术，构建动态、精准的“态（表型）-靶（分子）-药（干预）”关联模型，从而推动中药治疗失眠的精准化与标准化。

5.2.1 基于多组学技术的态靶关联研究

多组学技术（如代谢组学、宏基因组学、蛋白质组学等）能够从分子层面全面、系统地解析疾病的发生发展机制和药物作用的分子网络，是实现“靶”精准定位的重要手段。

  • 代谢组学（Metabolomics）： 通过检测生物体内小分子代谢物的种类和含量变化，可以直接反映机体的生理病理状态和中药干预后的效应。例如，利用非靶向代谢组学可以发现失眠患者特有的代谢指纹，揭示其与神经递质、内分泌、能量代谢等相关的潜在靶点。在未来，研究可结合中医证型（“态”）与代谢组学数据，构建证型特异性的代谢谱，并追踪中药干预后这些代谢谱的变化，从而精确捕捉中药作用于失眠的“靶点”（如色氨酸-5-HT通路、短链脂肪酸等）。
  • 宏基因组学（Metagenomics）： 肠道菌群与失眠的“脑-肠-菌轴”密切相关。宏基因组学可全面解析肠道菌群的组成、功能及其基因组信息。未来研究可通过宏基因组测序，深入分析不同证型失眠患者肠道菌群的特征，识别与失眠相关的关键菌种、菌群代谢通路和功能基因。结合中药干预，可进一步阐明中药如何通过调节肠道菌群（“态”）及其代谢产物，进而影响脑内神经递质和炎症反应等“靶点”，实现对失眠的治疗。例如，酸枣仁汤能够调节肠道菌群稳态和促进短链脂肪酸的产生，改善失眠大鼠脑内炎症反应和小胶质细胞激活 68。
  • 蛋白质组学（Proteomics）： 蛋白质是生命活动的主要执行者。通过蛋白质组学技术，可以发现失眠患者或中药干预后的差异表达蛋白，揭示潜在的诊断生物标志物和药物作用靶点。例如，多组学整合分析显示，慢性阻塞性肺疾病和失眠共病患者存在230个共同失调基因，这些基因富集在免疫炎症通路中，其中TNFAIP3是一个关键的中心基因，可作为诊断生物标志物 69。未来可将蛋白质组学与中医证型相结合，构建证型特异性蛋白组学图谱，并在此基础上验证中药作用的核心蛋白靶点。

5.2.2 脑电连接组（Connectomics）与神经影像学研究

脑电连接组学和神经影像技术能够从宏观层面揭示大脑结构和功能网络的改变，为理解失眠症的神经生物学机制提供新的视角。

  • 脑电连接组： 通过分析脑电图（EEG）、功能磁共振成像（fMRI）等数据，构建大脑不同区域之间的连接模式，评估脑功能网络的完整性和活动性。失眠患者常表现出脑功能连接异常，未来研究可利用脑电连接组学，识别不同中医证型失眠患者特有的脑功能连接模式（“态”），并评估中药干预后这些连接模式的变化，从而揭示中药对大脑整体功能网络的调节作用。
  • 神经影像学： 结构磁共振（sMRI）和功能磁共振（fMRI）可以观察大脑结构异常和功能活动模式。未来可利用这些技术，深入研究中药对失眠相关脑区的血流灌注、神经元活性、灰质体积和白质完整性的影响，从而从神经影像学层面验证中药作用于失眠的核心“靶点”。

5.2.3 “态（表型）-靶（分子）-药（干预）”的动态关联模型构建

未来的研究应致力于构建一个整合多层次数据的动态关联模型，实现从宏观表型到微观分子的深度融合。

  • 整合表型数据： 收集标准化、多维度的临床表型数据，包括中医证候、体质类型、PSQI评分、睡眠日记、情绪量表以及患者的遗传背景等。例如，利用机器学习模型预测失眠严重程度时，中医体质分类（如湿热质、阳虚质、气郁质）被证明是重要的预测因子 6170。
  • 连接分子靶点： 将多组学（基因组、转录组、蛋白质组、代谢组、宏基因组）数据与表型数据进行关联分析，识别与不同“态”对应的关键分子靶点。利用系统生物学和网络药理学方法，绘制中药成分与这些靶点之间的相互作用网络。
  • 评估干预效果： 通过严格设计的随机对照试验（RCT），评估中药干预对表型（“态”）和分子靶点（“靶”）的双重影响。并利用时间序列数据，构建动态模型，追踪中药干预下“态”与“靶”之间的相互转化和平衡过程。
  • 人工智能与大数据： 运用人工智能（AI）和大数据分析技术，从海量的临床数据和实验数据中挖掘潜在的“态-靶-药”关联规律，构建智能化的诊断和处方推荐系统，辅助临床决策。

5.2.4 强调跨学科合作与预测模型开发

  • 跨学科合作： 实现上述研究目标，需要中医临床医师、药理学家、分子生物学家、生物信息学家、统计学家和计算机科学家等多学科团队的紧密合作。通过多学科交叉融合，共同解决中药治疗失眠中的复杂科学问题。
  • 预测模型开发： 基于大数据和机器学习算法，开发能够预测失眠风险、证型演变和中药疗效的预测模型。例如，通过患者的体质信息、生活习惯和基因组数据，预测其患失眠的风险和可能所属的证型，并推荐个体化的中药干预方案。这种预测模型将有助于实现中药治疗失眠的精准化和个性化。

通过上述研究重点和技术路径的实施，有望逐步揭示中药治疗失眠症的复杂作用机制，为构建科学、系统、可验证的“态靶辨证”体系提供坚实基础，最终推动中药治疗失眠走向精准化、标准化和国际化。

6. 总结与展望

6.1 中药治疗失眠症的态靶辨证体系

本报告深入探讨了中药治疗失眠症的“态靶辨证”体系，旨在将中医的整体观念、辨证论治与现代医学的精准靶向治疗理念相结合，为临床实践和科学研究提供新的框架。

“态”是患者的宏观整体功能状态，涵盖体质、证候表现、情志等；“靶”是现代医学揭示的微观病理生理靶点，如神经递质、肠道菌群、炎症通路等。失眠症的核心病机“阳不入阴”在“态靶辨证”中得到了重新阐释：不同证型（如肝郁气滞、心脾两虚、痰热内扰）是“阳不入阴”在不同脏腑、病理阶段的宏观“态”表现，而其背后则对应着神经递质失衡、HPA轴异常、肠道菌群紊乱、神经炎症等多种微观“靶点”。本报告构建了“态-靶-药”映射模型，旨在指导临床医生根据患者“态”象推导“靶点”，进而选择具有多靶点协同作用的中药方剂。

中药在干预失眠症时，复方中药展现出“多态调节与多靶协同”的优势。以酸枣仁汤为例，其不仅能改善患者情绪、调整体质等宏观“态”，还能通过调节5-HT、GABA等神经递质、调控HPA轴、抑制炎症因子（IL-6、TNF-α）以及调节肠道菌群与代谢产物等多个微观“靶点”发挥作用 68。单味中药如酸枣仁，其活性成分枣仁皂苷A能够靶向调控GABAergic系统，增强GABA受体表达，同时缓解焦虑，实现“靶向调控与态平衡”的双重效应。

特别值得关注的是，中药对“脑-肠-菌轴”的“态靶协同干预”。失眠患者普遍存在的肠道菌群紊乱被视为一个重要“态”，中药如酸枣仁汤能通过调节肠道菌群结构（如增加普雷沃氏菌科和丁酸梭菌的丰度）、改善代谢物（如短链脂肪酸、色氨酸代谢），进而影响脑内神经递质平衡、抑制神经炎症等“靶点”，实现“肠道微生态状态”与“脑肠轴信号”的联动机制 68。

在临床应用实践中，“态靶辨证”指导下的个体化处方策略，针对不同证型的失眠患者选择相应的方剂（如肝郁型多用柴胡类方，心脾两虚型多用归脾汤），能够显著改善患者的总睡眠时间（TST）、匹兹堡睡眠质量指数（PSQI）评分及中医症状。中药联合疗法，如中药与针灸、耳穴的结合，通过对经络“态”的调节与中药对分子“靶”点的干预，实现了对围绝经期失眠等复杂失眠症的增效作用。同时，态靶辨证也对中药治疗的安全性与长期疗效提供了考量，强调根据体质、证型差异规避用药风险，并通过维持“态靶”平衡以实现长期疗效的持续性。

6.2 未来研究展望

尽管态靶辨证理论已初步应用于中药治疗失眠，但仍面临诸多挑战。例如，证型标准化不足、机制研究深度不够、高质量大样本随机对照试验（RCT）缺乏以及临床应用指南推荐证据等级低等问题，限制了其发展 5771。

未来研究应聚焦以下几个方向，以优化中药治疗失眠的态靶辨证体系：

  1. 证型标准化与客观化： 运用人工智能、生物医学大数据等技术，结合多组学（代谢组学、宏基因组学、蛋白质组学）数据，构建中医证型的客观化诊断标准和量化评估体系，减少主观性误差，提高证型辨识的准确性和可重复性。
  2. 分子机制的深入阐明： 结合多组学、脑电连接组学和神经影像学技术，系统深入地解析中药多成分、多靶点、多通路的复杂作用机制。特别是要聚焦于中药对“脑-肠-菌轴”、神经炎症、氧化应激、神经递质平衡以及HPA轴等核心“靶点”的调控网络，阐明“态”如何转化为“靶”，以及中药如何实现“态靶”平衡的动态过程。
  3. 构建动态“态（表型）-靶（分子）-药（干预）”关联模型： 利用系统生物学和网络药理学方法，整合多层次数据，构建从宏观表型到微观分子、再到中药干预效果的动态关联模型。该模型将有助于精准预测患者对不同中药方剂的反应，实现个体化、精准化治疗。
  4. 高质量临床证据的积累： 开展大样本、多中心、随机双盲、安慰剂对照的临床试验，并引入标准化、客观的疗效评价指标和长期随访，以提供更高级别的证据支持中药治疗失眠的有效性和安全性 72。
  5. 跨学科协同创新： 促进中医、药学、生物医学、信息科学等多学科领域的深度融合，共同研发新型诊断技术、治疗方案和药物，推动中药治疗失眠从经验医学向精准医学的转型。

通过以上研究方向的努力，中药治疗失眠症的“态靶辨证”体系将得到进一步完善和发展，为全球失眠患者提供更安全、有效、个性化的治疗选择，并有望在中医药现代化和国际化进程中发挥引领作用。

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ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi Decoction（SJZD）, as a famous classical prescription for the treatment of colorectal cancer(CRC) in the traditional Chinese medicine (TCM), has achieved good curative effects in clinical practice. However, its specific ingredients and molecular mechanisms is still unclear. AIM OF THE STUDY: To analyze the effective ingredients and molecular mechanisms of SJZD in the treatment of CRC through network pharmacology technology and experimental validation. MATERIALS AND METHODS: First, the TCM Systems Pharmacology database and analysis platform database were searched to screen the effective chemical components of SJZD. Swiss Target Prediction was used to predict corresponding potential target genes of compounds. After that, we constructed a components and corresponding target network by Cytoscape. Simultaneously, 5 disease databases were used to search and filter CRC targets, and then we constructed a drug-disease target protein-protein interaction (PPI) network. Cytoscape 3.7 was used for visualization and cluster analysis, and Metascape database was used for GO and KEGG enrichment analysis. We drew the main pathway-target network diagram. Autodock vina1.5.6 was applied to molecular docking for the main compounds and target proteins. Subsequently, the potential mechanism of SJZD on colon cancer predicted by network pharmacological analysis was experimentally studied and verified in vivo and in vitro. RESULTS: 144 effective active chemical components, 897 potential targets, and 2584 CRC target genes were screened out. The number of common targets between the SJZD and CRC was 414.3250 GO biological process items and 186 KEGG signal pathways were obtained after analysis. The main compounds and the target protein had a good binding ability in molecular docking. The results of cell and animal experiments showed that SJZD could promote apoptosis and autophagy of CRC cells through PI3K/Akt/mTOR pathway. CONCLUSIONS: SJZD can treat CRC through multiple components, multiple targets and multiple pathways. We initially revealed the effective components and molecular mechanisms of SJZD in the treatment of CRC, and we used molecular docking and experiment for preliminary verification.

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Su-Su Huang, Xue-Ru Wang, Jiu-Shu Yuan, et al.
Zhongguo Zhong Yao Za Zhi. 2023 Dec;48(23):6315-6323. doi: 10.19540/j.cnki.cjcmm.20230911.702.
Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.

6Xiaoyao San ameliorates maternal inflammation-induced neurobehavioral deficits by modulating the microbiota-gut-brain axis in offspring.PubMed

Chunqiao Lin, Jiushuang Zhu, Lu Zhang, et al.
Front Pharmacol. 2025 May 19;16:1563496. doi: 10.3389/fphar.2025.1563496. eCollection 2025.
BACKGROUND: XiaoYao San (XYS), a classical Traditional Chinese Medicine (TCM), has demonstrated efficacy in alleviating stress-related neuropsychiatric disorders. However, its therapeutic potential against maternal immune activation (MIA)-induced neurobehavioral impairments remains unexplored. This study aims to investigate the neuroprotective effects of XYS on MIA-related behavioral dysfunctions and elucidate its underlying mechanisms. RESULTS: Using a poly (I:C)-induced MIA mouse model, we demonstrated that XYS effectively ameliorates autism spectrum disorder (ASD) related behavioral phenotypes. Mechanistic investigations revealed that XYS exerts its therapeutic effects through: (1) Attenuation of core behavioral deficits including enhanced social interaction and reduced repetitive behaviors; (2) Downregulation of intestinal amino acid transporters; (3) Restoration of cerebral glutamate-GABA balance via modulation of glutamine pathway; (4) Structural remodeling of gut microbiota with specific enrichment of spp. Notably, was identified as a key microbial mediator capable of recapitulating XYS-mediated neurophysiological improvements through metabolic regulation. CONCLUSION: This study elucidates XYS as a multi-target therapeutic agent that coordinately modulates gut microbial ecosystems, amino acid homeostasis, and neurotransmitter homeostasis. The findings provide novel insights into the gut-brain axis mechanisms of TCM formulations, offering a scientific foundation for developing microbiota-based intervention strategies for neurodevelopmental disorders.

7Structural characteristics of a heteropolysaccharide from Ganoderma lucidum and its protective effect against Alzheimer's disease via modulating the microbiota-gut-metabolomics.PubMed

Li Chen, Xinyan Wang, Jiaxin Sun, et al.
Int J Biol Macromol. 2025 Mar;297:139863. doi: 10.1016/j.ijbiomac.2025.139863. Epub 2025 Jan 13.
Ganoderma lucidum is a traditional Chinese medicine used to treat Alzheimer's disease (AD), whose main active ingredient is polysaccharides. A heteropolysaccharide named GLPZ-1 was isolated from Ganoderma lucidum. GLPZ-1 (6.608 kDa) predominantly consisted of Glc and minor Gal. The results of GC-MS and NMR analyses indicated that the backbone of GLPZ-1 was mainly composed of 1,4-α-D-Glcp, 1,4,6-α-Glcp and a minor amount of 1,3,4-β-D-Glcp, which was substituted with complex side chains at C-6 of 1,4,6-α-D-Glcp and at C-3 of 1,3,4-β-D-Glcp. GLPZ-1 demonstrated a protective effect on AD rats by improving behavioral abnormalities, alleviating pathological damage and ameliorating levels of IL-6, IL-1β, TNF-α and Th17, which were associated with GLPZ-1 modulating the microbiota-gut-metabolomics of AD rats. GLPZ-1 regulated the gut microbiota in AD rats by increasing the abundance of Bacteroides, unclassified_Lachnospiraceae, Lactobacillus, Pediococcus, Oscillibacter, Lachnoclostridium and Bifidobacterium, while simultaneously reducing the abundance of Pseudomonas and Desulfovibrio. GLPZ-1 could regulate fecal metabolites in AD rats tending towards the normal levels. These regulated fecal metabolites belonged to fatty acid metabolism, cholesterol and bile acid metabolism, neurotransmitters and aromatic amino acid metabolism. These findings provide a preliminary research basis for the exploitation of GLPZ-1 as an effective drug to prevent and delay AD.

8Icariside II Ameliorates Depression Induced by High-Fat Diet via the Microbiota-Gut-Brain Axis in Mice.PubMed

Yun-Mei Luo, Lan Dong, Ye-Li Li, et al.
Phytother Res. 2025 Nov;39(11):5159-5173. doi: 10.1002/ptr.70103. Epub 2025 Sep 25.
Obesity can lead to depression via the microbiota-gut-brain axis. Icariside II (ICS II), a flavonoid compound derived from the traditional Chinese medicine Herbal Epimedium, exerts excellent neuroprotective effects. However, the pharmacological effects and underlying mechanisms of ICS II in obesity-induced depression remain unexplored. The present study aims to investigate whether ICS II can mitigate depression induced by a high-fat diet (HFD) in mice through modulating the microbiota-gut-brain axis. Metabolic parameters were reflected through changes in body weight and blood lipids, while depressive phenotypes were evaluated through behavioral tests and neurotransmitter analysis. The microbiota composition was analyzed by 16S ribosomal RNA gene sequencing, and short chain fatty acids (SCFAs) were detected by liquid chromatography-tandem mass spectrometry. The gut barrier and brain blood barrier (BBB) functions were observed by pathological methods. Fecal microbiota transplantation was used to demonstrate the causality of microbiota-mediated effects. The results showed that ICS II alleviated obesity status and depressive-like behaviors. ICS II reshaped gut microbiota and increased SCFAs. Meanwhile, ICS II relieved gut barrier impairment and systemic inflammation. In the brain, ICS II alleviated neuroinflammation and BBB injury. Intriguingly, fecal microbiota from ICS II-treated HFD mice improved depressive-like behaviors, intestinal barrier dysfunction, and BBB damage compared with those receiving microbiota from HFD mice. Our findings reveal for the first time that ICS II improves the obesity-related metabolic dysregulation and alleviates HFD-induced depression via the microbiota-gut-brain axis. Overall, this study indicates that ICS II is a potential candidate compound for treating obesity-related mental diseases.

9Analysis of the distribution of traditional Chinese medicine syndrome types and related factors in insomnia patients.PubMed

Guiqing Zhu, Zelin Yi, Ting Zheng, et al.
Medicine (Baltimore). 2025 May 9;104(19):e42375. doi: 10.1097/MD.0000000000042375.
This study analyzes the distribution characteristics of traditional Chinese medicine (TCM) syndrome types in patients with insomnia and investigate the association between different factors and the distribution of the TCM syndrome types as well as the possible factors affecting this distribution. A retrospective analysis of the data from 468 insomnia patients was conducted. The association between different factors, such as gender, age, occupation, and the distribution of the TCM syndrome types, was evaluated using the Kruskal-Wallis H test, Chi-square test, and Fisher's exact probability method. The potential factors affecting yin-yang syndrome insomnia were analyzed using binary logistic regression. The results of the TCM syndrome type distribution indicated that yin syndrome (69.9%) was significantly more common than yang syndrome (30.1%), among which the heart-spleen deficiency type (31.6%) was the most common. Age, occupation, hypertension, the presence or absence of children, and history of diabetes were significantly different among the different TCM syndrome types. The logistic regression analysis revealed that occupation (odds ratio [OR] = 2.099, 95% confidence interval [CI]: 1.356-3.251), offspring status (OR = 9.034, 95% CI: 1.181-69.085), diabetes status (OR = 2.202, 95% CI: 1.236-3.922), and gender (OR = 1.564, 95% CI: 1.009-2.423) were influencing factors of yang syndrome insomnia. This study revealed the correlation between the distribution of the TCM syndrome types of insomnia patients and age, occupation, hypertension, having offspring, a history of diabetes, especially other occupations, having children, a history of diabetes, and male gender were risk factors for yang syndrome insomnia.

10Insomnia in Elderly Patients: Recommendations for Pharmacological Management.PubMed

Vivien C Abad, Christian Guilleminault
Drugs Aging. 2018 Sep;35(9):791-817. doi: 10.1007/s40266-018-0569-8.
Chronic insomnia affects 57% of the elderly in the United States, with impairment of quality of life, function, and health. Chronic insomnia burdens society with billions of dollars in direct and indirect costs of care. The main modalities in the treatment of insomnia in the elderly are psychological/behavioral therapies, pharmacological treatment, or a combination of both. Various specialty societies view psychological/behavioral therapies as the initial treatment intervention. Pharmacotherapy plays an adjunctive role when insomnia symptoms persist or when patients are unable to pursue cognitive behavioral therapies. Current drugs for insomnia fall into different classes: orexin agonists, histamine receptor antagonists, non-benzodiazepine gamma aminobutyric acid receptor agonists, and benzodiazepines. This review focuses on Food and Drug Administration (FDA)-approved drugs for insomnia, including suvorexant, low-dose doxepin, Z-drugs (eszopiclone, zolpidem, zaleplon), benzodiazepines (triazolam, temazepam), and ramelteon. We review the indications, dosing, efficacy, benefits, and harms of these drugs in the elderly, and discuss data on drugs that are commonly used off-label to treat insomnia, and those that are in clinical development. The choice of a hypnotic agent in the elderly is symptom-based. Ramelteon or short-acting Z-drugs can treat sleep-onset insomnia. Suvorexant or low-dose doxepin can improve sleep maintenance. Eszopiclone or zolpidem extended release can be utilized for both sleep onset and sleep maintenance. Low-dose zolpidem sublingual tablets or zaleplon can alleviate middle-of-the-night awakenings. Benzodiazepines should not be used routinely. Trazodone, a commonly used off-label drug for insomnia, improves sleep quality and sleep continuity but carries significant risks. Tiagabine, sometimes used off-label for insomnia, is not effective and should not be utilized. Non-FDA-approved hypnotic agents that are commonly used include melatonin, diphenhydramine, tryptophan, and valerian, despite limited data on benefits and harms. Melatonin slightly improves sleep onset and sleep duration, but product quality and efficacy may vary. Tryptophan decreases sleep onset in adults, but data in the elderly are not available. Valerian is relatively safe but has equivocal benefits on sleep quality. Phase II studies of dual orexin receptor antagonists (almorexant, lemborexant, and filorexant) have shown some improvement in sleep maintenance and sleep continuity. Piromelatine may improve sleep maintenance. Histamine receptor inverse agonists (APD-125, eplivanserin, and LY2624803) improve slow-wave sleep but, for various reasons, the drug companies withdrew their products.

11Fructus gardeniae ameliorates anxiety-like behaviors induced by sleep deprivation via regulating hippocampal metabolomics and gut microbiota.PubMed

Dong Liu, Qianfei Wang, Ying Li, et al.
Front Cell Infect Microbiol. 2023 Jun 12;13:1167312. doi: 10.3389/fcimb.2023.1167312. eCollection 2023.
Fructus (FG) is a traditional Chinese medicine and health food for thousands of years of application throughout Chinese history and is still widely used in clinical Chinese medicine. FG has a beneficial impact on anxiety, depression, insomnia, and psychiatric disorders; however, its mechanism of action requires further investigation. This study aimed to investigate the effects and mechanisms of FG on sleep deprivation (SD)-induced anxiety-like behavior in rats. A model of SD-induced anxiety-like behavior in rats was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). This was accompanied by neuroinflammation and metabolic abnormalities in the hippocampus and disturbance of intestinal microbiota. However reduced SD-induced anxiety-like behavior and decreased levels of pro-inflammatory cytokines including TNF-α and IL-1β were observed in the hippocampus of rats after 7 days of FG intervention. In addition, metabolomic analysis demonstrated that FG was able to modulate levels of phosphatidylserine 18, Phosphatidylinositol 18, sn-glycero-3-phosphocholine, deoxyguanylic acid, xylose, betaine and other metabolites in the hippocampus. The main metabolic pathways of hippocampal metabolites after FG intervention involve carbon metabolism, glycolysis/gluconeogenesis, pentose phosphate, and glycerophospholipid metabolism. 16S rRNA sequencing illustrated that FG ameliorated the dysbiosis of gut microbiota in anxious rats, mainly increased the abundance of Muribaculaceae and Lactobacillus, and decreased the abundance of Lachnospiraceae_NK4A136_group. In addition, the correlation analysis demonstrated that there was a close relationship between hippocampal metabolites and intestinal microbiota. In conclusion, FG improved the anxiety behavior and inhibited of neuroinflammation in sleep-deprived rats, and the mechanism may be related to the FG regulation of hippocampal metabolites and intestinal microflora composition.

12Insomnia and cardiovascular autonomic control.PubMed

Daniela Grimaldi, Michael R Goldstein, Jason R Carter
Auton Neurosci. 2019 Sep;220:102551. doi: 10.1016/j.autneu.2019.05.003. Epub 2019 May 16.
Insomnia is the most prevalent sleep disorder, particularly among middle and older aged adults, and is associated with a variety of negative health consequences, including higher risk for cardiovascular disease. Unfortunately, the mechanisms linking insomnia with cardiovascular risk remain largely unknown, thus limiting targeted therapeutic interventions. The hyperarousal hypothesis has attracted the most support, positing that insomnia is a result of multisystem over-activation, including sympathetic hyperactivity, which promotes wakefulness and blocks the occurrence of sleep at the desired time. The results from literature in support of this hypothesis are inconclusive and mainly relay on studies that used methods to assess sympathetic activity lacking in specificity and reproducibility. The present review aims at summarizing the primary findings on autonomic nervous system regulation in insomnia while highlighting the advantages and limitations of the methods mainly used to support the increase in sympathetic function in insomnia. Collectively, this review aims to provide novel perspectives on conceptualizing insomnia and suggest innovative approaches to help elucidate the relationship between insomnia and autonomic nervous system activity.

13Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways.PubMed

Kyoko Watanabe, Philip R Jansen, Jeanne E Savage, et al.
Nat Genet. 2022 Aug;54(8):1125-1132. doi: 10.1038/s41588-022-01124-w. Epub 2022 Jul 14.
Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

14[Interpreting the function of Pinellia-Prunella as a sleep aid].PubMed

X Zhang, Y R Wang
Zhonghua Yi Shi Za Zhi. 2025 Sep 28;55(5):283-290. doi: 10.3760/cma.j.cn112155-20250708-00106.
This paper examined the related literature of and , summarised the syndrome and treatment characteristics of refractory insomnia and analysed the clinical cases of refractory insomnia treated by modern well-known doctors. It was found that P and have unique advantages in treating refractory insomnia caused by phlegm and fire stagnation (TanHuo YuJie). In addition, it was found that the interpretation of this medicinal function in terms of sleep aid changed from 'regulating Yin and Yang' to 'treating based on syndrome differentiation'. This elaborated the influence of Chinese traditional culture and current clinical requirements on the functions of herbs. It indicates that the value and meaning of such a change in interpreting the function of and on sleep aid is the in-depth integration of traditional Chinese culture and clinical requirements. This lays the groundwork for empirical research of the efficacy of traditional Chinese medicine.

15Tryptophan Intake in the US Adult Population Is Not Related to Liver or Kidney Function but Is Associated with Depression and Sleep Outcomes.PubMed

Harris R Lieberman, Sanjiv Agarwal, Victor L Fulgoni
J Nutr. 2016 Dec;146(12):2609S-2615S. doi: 10.3945/jn.115.226969. Epub 2016 Nov 9.
BACKGROUND: Tryptophan is an indispensable amino acid and is a precursor of the neurotransmitter serotonin. Tryptophan metabolites, such as serotonin and melatonin, are thought to participate in the regulation of mood and sleep and tryptophan is used to treat insomnia, sleep apnea, and depression. OBJECTIVE: This study examined the intake of tryptophan and its associations with biochemical, behavioral, sleep, and health and safety outcomes in adults in a secondary analysis of a large, publicly available database of the US population. METHODS: Data from the NHANES 2001-2012 (n = 29,687) were used to determine daily intakes of tryptophan and its associations with biochemical markers of health- and safety-related outcomes, self-reported depression, and sleep-related variables. Data were adjusted for demographic factors and protein intake. Linear trends were computed across deciles of intake for each outcome variable, and P-trends were determined. RESULTS: The usual tryptophan intake by US adults was 826 mg/d, severalfold higher than the Estimated Average Requirement for adults of 4 mg/(kg ⋅ d) (∼280 mg/d for a 70-kg adult). Most health- and safety-related biochemical markers of liver function, kidney function, and carbohydrate metabolism were not significantly (P-trend > 0.05) associated with deciles of tryptophan intake and were well within normal ranges, even for individuals in the 99th percentile of intake. Usual intake deciles of tryptophan were inversely associated with self-reported depression measured by the Patient Health Questionnaire raw score (0-27; P-trend < 0.01) and calculated level (1 = no depression, 5 = severe depression; P-trend < 0.01) and were positively associated with self-reported sleep duration (P-trend = 0.02). CONCLUSIONS: Tryptophan intake was not related to most markers of liver function, kidney function or carbohydrate metabolism. Levels of tryptophan intake in the US population appear to be safe as shown by the absence of abnormal laboratory findings. Tryptophan intake was inversely associated with self-reported level of depression and positively associated with sleep duration.

16Insomnia and stress: the mediating roles of frontoparietal network.PubMed

Miao He, Yuan Li, Mengting Chen, et al.
Brain Imaging Behav. 2024 Dec;18(6):1355-1365. doi: 10.1007/s11682-024-00922-6. Epub 2024 Sep 13.
Insomnia is a widespread health problem among adults, and it impairs cognitive control and emotional regulation functions. Stress and insomnia are positively correlated, and their vicious cycle has been widely reported. In this study, we explore the neural biomarkers of insomnia from the perspective of whole-brain functional connectivity and investigate the neural mechanisms underlying the association between stress and insomnia. The current study was conducted on a cross-sectional sample (N = 430). First, we investigated the correlation between perceived stress and insomnia. Second, we applied connectome-based predictive modeling (CPM) to determine the neuromarkers of insomnia. Finally, we explored the neural basis underlying the association between perceived stress and insomnia. A significant positive correlation was found between perceived stress and insomnia in the present research. Results of CPM revealed the following as the neural substrates supporting insomnia: the emotion regulation circuit involving repetitive negative thinking and the cognitive control circuit involving attention control. According to further results from mediation analysis, the frontoparietal network supporting cognitive emotion regulation is an important neural mechanism that maintains the correlation between stress and insomnia. The present study offers a profound insight into the alterations of brain activity related to insomnia, and it further investigates the neural underpinnings of the robust association between stress and insomnia. This study also opens new avenues for neural interventions to alleviate stress-related insomnia.

17A New Ashwagandha Formulation (Zenroot™) Alleviates Stress and Anxiety Symptoms While Improving Mood and Sleep Quality: A Randomized, Double-Blind, Placebo-Controlled Clinical Study.PubMed

Manasvi Mahadevan, Kumarpillai Gopukumar, Ruchi Gupta, et al.
Adv Ther. 2025 Oct;42(10):5238-5254. doi: 10.1007/s12325-025-03327-z. Epub 2025 Aug 28.
INTRODUCTION: Prolonged exposure to stress may lead to low mood, anxiety, depression, insomnia, and metabolic disorders. Ashwagandha, an established adaptogen, is known to combat stress. We studied the safety and efficacy of Ashwagandha formulation, Zenroot™ (ZEN), containing 1.5% total withanolides on stress, anxiety, mood, and sleep quality in human subjects with non-chronic mild to moderate stress. METHODS: This was a prospective, randomized, double-blind, parallel, placebo-controlled, clinical interventional study with supplementation duration of 84 days. Ninety subjects were randomly assigned in a 1:1 ratio to receive 125 mg of ZEN or placebo. We measured stress using the Perceived Stress Scale (PSS) score as a primary endpoint. Various secondary endpoints included Mindfield eSense Skin Response (SCR) and Mindfield eSense PULSE Heart Rate Variability (HRV)-Root Mean Square of Successive Differences (RMSSD), and standard deviation of normal NN interval (SDNN), Beck Anxiety Inventory (BAI), Profile of Mood States (POMS), Pittsburgh Sleep Quality Index (PSQI), stress biomarkers of serum cortisol, and salivary alpha amylase (sAA) levels and safety parameters. The study assessments were performed on days 0, 14, 28, 56, and 84. RESULTS: All 90 randomized subjects completed the study. Mean ± standard error (SE) age of subjects in the ZEN group was 35.5 ± 1.3 years and in the placebo group was 34.5 ± 1.2 years. ZEN 125 mg showed significant (p < 0.05) improvements in PSS, BAI, and PSQI scores on days 28, 56, and 84; SCR on days 14, 28, and 84 and trend (p < 0.1) on day 56; HRV-RMSSD and SDNN on day 14; and POMS on days 56 and 84. No significant differences were observed between the two groups for serum cortisol and sAA. The study product was well tolerated without any safety concerns. CONCLUSION: We observed significant reductions in both subjective and objective measures of stress with improvement in mood, sleep quality, and occasional anxiety symptoms. ZEN was well tolerated without any related adverse events. Future clinical studies are warranted to evaluate the effect of ZEN on chronically stressed adults. CLINICAL TRIAL REGISTRATION NUMBER: http://ctri.nic.in/ Identifier:CTRI/2024/03/063786.

18Sleep and liver function biomarkers in relation to risk of incident liver cancer: a nationwide prospective cohort study.PubMed

Jiahao Song, Lieyang Fan, Da Shi, et al.
BMC Med. 2024 Jun 24;22(1):261. doi: 10.1186/s12916-024-03440-w.
BACKGROUND: To assess the largely undetermined separate and joint effects of sleep and liver function biomarkers on liver cancer. METHODS: Data of 356,894 participants without cancer at baseline in the UK Biobank were analyzed. Sleep score was evaluated using five sleep traits (sleep duration, chronotype, insomnia, snoring, and excessive daytime sleepiness) and dichotomized into healthy or unhealthy sleep. Circulating liver function biomarkers were measured. Cox proportional hazard model was performed to investigate the independent and joint associations of sleep and liver function biomarkers with liver cancer incidence. RESULTS: After a median follow-up time of 13.1 years, 394 cases of incident liver cancer were documented. The multivariable-adjusted hazard ratio (HR) for liver cancer was 1.46 (95% confidence interval: 1.15-1.85) associated with unhealthy sleep (vs. healthy sleep), and was 1.17 (1.15-1.20), 1.20 (1.18-1.22), 1.69 (1.47-1.93), 1.06 (1.06-1.07), 1.08 (1.07-1.09), 1.81 (1.37-2.39), or 0.29 (0.18-0.46) associated with each 10-unit increase in alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total protein (TP), or albumin (ALB), respectively. Individuals with unhealthy sleep and high (≥ median) ALT, AST, TBIL, GGT, ALP, or TP or low (< median) ALB level had the highest HR of 3.65 (2.43-5.48), 4.03 (2.69-6.03), 1.97 (1.40-2.77), 4.69 (2.98-7.37), 2.51 (1.75-3.59), 2.09 (1.51-2.89), or 2.22 (1.55-3.17) for liver cancer, respectively. Significant additive interaction of unhealthy sleep with high TP level on liver cancer was observed with relative excess risk due to an interaction of 0.80 (0.19-1.41). CONCLUSIONS: Unhealthy sleep was associated with an increased risk of liver cancer, especially in participants with lower ALB levels or higher levels of ALT, AST, TBIL, GGT, ALP, or particularly TP.

19Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver Diseases.PubMed

Lan Zhou, Min Yan, Qin Luo, et al.
Cell Mol Gastroenterol Hepatol. 2025;19(3):101439. doi: 10.1016/j.jcmgh.2024.101439. Epub 2024 Dec 10.
BACKGROUND & AIMS: Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study explores the mechanisms underlying CRSDs in CLDs and novel therapies. METHODS: We monitored the sleep of patients with CLD using actigraphic watch and established male mouse cholemia models by feeding with BA or bile duct ligation. Sleep-wake cycle and circadian rhythm were analyzed by electroencephalogram-electromyography and locomotor wheel-running experiments. RESULTS: Patients with CLD showed CRSD-like phenotypes including increased night activity and early awakening, which were strongly correlated with increased BA levels (ie, cholemia). CRSDs, including shortened circadian period, were recapitulated in 2 cholemic mouse models. Mechanistically, elevated BAs in the suprachiasmatic nucleus (SCN) activated BA receptor Takeda G protein-coupled receptor 5 (Tgr5), which, in turn, increased the level and phosphorylation of Period2 (Per2), a master rhythm regulator, through extracellular signal-regulated kinase (Erk) and casein kinase 1ε (CK1ε). Per2 phosphorylation inhibited its nuclear import, which would release its transcriptional inhibition and expedite the circadian cycle. Cholemia also blunted the light entrainment response and light-induced phase change of SCN mediated by the neurons expressing gastrin releasing peptide through Tgr5-Per2 axis. BA sequestrant or CK1 inhibitor reversed the CRSDs in cholemic mice by restoring Per2 distribution. CONCLUSIONS: Cholemia is a major risk factor for CRSDs in CLDs and, hence, a promising target in future clinical study.

20Autoimmune hepatitis in association with ramelteon.PubMed

Lindsay T Fourman, B Robert Meyer
J Clin Gastroenterol. 2013 Aug;47(7):651-4. doi: 10.1097/MCG.0b013e31829174f0.
Ramelteon is a nonscheduled insomnia medication that lacks the abuse potential and residual effects common for other sedative-hypnotics. Distinct in its mechanism, the drug is a melatonin agonist with a high affinity for the membrane receptors MT1 and MT2. Although it therapeutically targets the suprachiasmatic nucleus of the hypothalamus, many organ systems have melatonin receptors and thus may be influenced by ramelteon. A growing body of research on melatonin indicates that it modulates the immune system. Indeed, immune cells have been shown to synthesize and to respond to this compound through receptors including MT1 and MT2. Melatonin's effects are generally immunostimulatory, and there is evidence to suggest that the chemical may potentiate autoimmunty. Here, we describe a case of autoimmune hepatitis that developed in a 50-year-old man after starting ramelteon for insomnia. The temporal association between ramelteon initiation and disease development, as well as the immunomodulatory properties of melatonergic compounds, suggest a role for ramelteon in the etiology of his illness.

21Insomnia Impairs Both the Pro-BDNF and the BDNF Levels Similarly to Older Adults with Cognitive Decline: An Exploratory Study.PubMed

Sergio Sánchez-García, Karla Moreno-Tamayo, Ricardo Ramírez-Aldana, et al.
Int J Mol Sci. 2023 Apr 17;24(8):7387. doi: 10.3390/ijms24087387.
Sleep disorders, including insomnia, are common during aging, and these conditions have been associated with cognitive decline in older adults. Moreover, during the aging process, neurotransmitters, neurohormones, and neurotrophins decrease significantly, leading to the impairment of cognitive functions. In this sense, BDNF, the most abundant neurotrophic factor in the human brain, has been suggested as a potential target for the prevention and improvement of cognitive decline during aging; however, the current evidence demonstrates that the exogenous administration of BDNF does not improve cognitive function. Hence, in the present study, we quantified pro-BDNF (inactive) and BDNF (active) concentrations in serum samples derived from older individuals with insomnia and/or cognitive decline. We used linear regression to analyze whether clinical or sociodemographic variables impacted the levels of BNDF concentration. We observed that insomnia, rather than cognitive decline, is significantly associated with BDNF concentration, and these effects are independent of other variables. To our knowledge, this is the first study that points to the impact of insomnia on improving the levels of BDNF during aging and suggests that opportune treatment of insomnia may be more beneficial to prevent cognitive decline during aging.

22Ghrelin/GHSR System in Depressive Disorder: Pathologic Roles and Therapeutic Implications.PubMed

Xingli Pan, Yuxin Gao, Kaifu Guan, et al.
Curr Issues Mol Biol. 2024 Jul 10;46(7):7324-7338. doi: 10.3390/cimb46070434.
Depression is the most common chronic mental illness and is characterized by low mood, insomnia, and affective disorders. However, its pathologic mechanisms remain unclear. Numerous studies have suggested that the ghrelin/GHSR system may be involved in the pathophysiologic process of depression. Ghrelin plays a dual role in experimental animals, increasing depressed behavior and decreasing anxiety. By combining several neuropeptides and traditional neurotransmitter systems to construct neural networks, this hormone modifies signals connected to depression. The present review focuses on the role of ghrelin in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. Furthermore, ghrelin/GHSR can activate multiple signaling pathways, including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK, to produce antidepressant effects, given which it is expected to become a potential therapeutic target for the treatment of depression.

23Traditional Chinese herbal formulas modulate gut microbiome and improve insomnia in patients with distinct syndrome types: insights from an interventional clinical study.PubMed

Huimei Zeng, Jia Xu, Liming Zheng, et al.
Front Cell Infect Microbiol. 2024 May 16;14:1395267. doi: 10.3389/fcimb.2024.1395267. eCollection 2024.
BACKGROUND: Traditional Chinese medicine (TCM) comprising herbal formulas has been used for millennia to treat various diseases, such as insomnia, based on distinct syndrome types. Although TCM has been proposed to be effective in insomnia through gut microbiota modulation in animal models, human studies remain limited. Therefore, this study employs machine learning and integrative network techniques to elucidate the role of the gut microbiome in the efficacies of two TCM formulas - center-supplementing and qi-boosting decoction (CSQBD) and spleen-tonifying and yin heat-clearing decoction (STYHCD) - in treating insomnia patients diagnosed with spleen qi deficiency and spleen qi deficiency with stomach heat. METHODS: Sixty-three insomnia patients with these two specific TCM syndromes were enrolled and treated with CSQBD or STYHCD for 4 weeks. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) every 2 weeks. In addition, variations in gut microbiota were evaluated through 16S rRNA gene sequencing. Stress and inflammatory markers were measured pre- and post-treatment. RESULTS: At baseline, patients exhibiting only spleen qi deficiency showed slightly lesser severe insomnia, lower IFN-α levels, and higher cortisol levels than those with spleen qi deficiency with stomach heat. Both TCM syndromes displayed distinct gut microbiome profiles despite baseline adjustment of PSQI, ISI, and IFN-α scores. The nested stratified 10-fold cross-validated random forest classifier showed that patients with spleen qi deficiency had a higher abundance of than those with spleen qi deficiency with stomach heat, negatively associated with plasma IFN-α concentration. Both CSQBD and STYHCD treatments significantly improved sleep quality within 2 weeks, which lasted throughout the study. Moreover, the gut microbiome and inflammatory markers were significantly altered post-treatment. The longitudinal integrative network analysis revealed interconnections between sleep quality, gut microbes, such as and Ruminococcaceae, and inflammatory markers. CONCLUSION: This study reveals distinct microbiome profiles associated with different TCM syndrome types and underscores the link between the gut microbiome and efficacies of Chinese herbal formulas in improving insomnia. These findings deepen our understanding of the gut-brain axis in relation to insomnia and pave the way for precision treatment approaches leveraging TCM herbal remedies.

24Study on the mechanism of regulating the hypothalamic cortical hormone releasing hormone/corticotropin releasing hormone type I receptor pathway by vibro-annular abdominal massage under the brain-intestine interaction in the treatment of insomnia.PubMed

Ye Zhang, Deyu Cong, Peng Liu, et al.
Medicine (Baltimore). 2021 May 14;100(19):e25854. doi: 10.1097/MD.0000000000025854.
BACKGROUND: Insomnia is a common disease associated with different nervous system stress response and endocrine disorders. It has been reported previously that abdominal vibration and ring massage therapy can significantly improve the symptoms of insomnia patients, enhance the activity of neurons. In addition, functional MRI (resting state brain functional magnetic resonance imaging [Rs_fMRI]) of the resting state brain test has proved that the functional connection between hypothalamus and parahippocampal gyrus could be significantly enhanced after abdominal massage treatment. It has been confirmed that there is possible involvement of brain-gut interaction effect in the treatment of insomnia, but there is a lack of research to elucidate the possible mechanisms of brain-gut interaction in the treatment of insomnia. The purpose of this study is to investigate the relationship between the hypothalamus and intestinal interaction in the treatment of insomnia by abdominal massage. METHODS AND DESIGN: A single blind randomized controlled trial will be conducted. Sixty chronic insomnia volunteers and 30 healthy volunteers will be recruited for this study. Sixty insomnia volunteers will be randomly divided into a drug group and a massage group, and 30 healthy volunteers will be assigned to the healthy group. The manipulation of the treatment group will be mainly carried out through abdominal rubbing and vibration massage, once a day, 30 min/time, 5 days for a course of treatment, and a total of 4 intervention courses will be carried out. Patients in the drug group will be given orally spleen-invigorating bolus, twice a day, 1 pill in the morning and 1 pill in the evening. The course of treatment will be carried for 5 days, and a total of 4 courses of treatment will be administered.The massage group will be compared with the healthy group and the drug group by Pittsburgh Sleep Index scale (PSQI), Hyperarousal scale (HAS), Hamilton Depression scale (HAMD), Fatigue scale-14 (FS-14), and Wechsler Adult Memory scale (WAIS) scales using to observe the sleep quality. Rs-fMRI will be used to observe various BOLD signals in the brain and compare the values of Reho, fALFF, and FC. MRS technology will be used to observe the contents of GABA and 5-HT in the hypothalamus. Additionally, the contents of cortical hormone releasing hormone (CRH), adrenocorticotropic hormone (ACTH), COR, GABA, NE, PGE2, and 5-HT in the serum will be also detected. The serum of each group will be taken for 1H nuclear magnetic resonance (1HNMR) metabolomics study to analyze the various common metabolites, differential metabolites, potential metabolic biomarkers, and metabolic pathways among the 3 groups. Finally, in combination with the brain functional imaging and brain spectrum, the potential mechanism of abdominal vibration and ring massage will be discussed. DISCUSSION: The results of this study will be used to possibly elaborate the various mechanisms of brain and intestine interaction in the treatment of insomnia by employing abdomen ring rubbing.

25Exploring the mechanism of action of huoermai essential oil for plateau insomnia based on the camp/CREB/BDNF/gabaergic pathway.PubMed

Jianhao Yang, Yuewen Xu, Pengyi Hu, et al.
J Ethnopharmacol. 2025 Feb 10;338(Pt 2):119092. doi: 10.1016/j.jep.2024.119092. Epub 2024 Nov 10.
ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Huoermai therapy is a treatment for insomnia used by the Tibetan people living on the Tibetan plateau in China. This therapy involves the use of Myristica fragrans Houtt. and Carum carvi L., along with fomentation and massage, and has shown significant clinical effects. However, the mechanism of how Huoermai therapy treats plateau insomnia needs further clarification. AIM OF THE STUDY: This study aimed to investigate the mechanism of action of Huoermai essential oil (HEO) in treating plateau insomnia, focusing on the cAMP/CREB/BDNF/GABAergic pathway. METHODS: The major components of Huoermai essential oil were identified by Gas chromatography-mass spectrometry (GC-MS) for subsequent network pharmacology analysis. Proteomics techniques were employed to pinpoint disparities in brain tissue protein expression in a mouse model of plateau insomnia following Huoermai therapy administration, in conjunction with network pharmacology to forecast pathways related to hypoxia and insomnia. Plateau insomnia mouse model was established and the therapeutic impact of Huoermai essential oil was evaluated. Hematoxylin & Eosin staining(HE) was conducted to observe pathological damage to the cortex, hippocampus, thalamus and hypothalamus structures. Changes in serotonin (5-HT), melatonin (MT), adenosine (AD), cyclic adenosine monophosphate (cAMP) and malondialdehyde (MDA) levels in mouse brain tissue were gauged through enzyme-linked immunosorbent assay (ELISA) to assess sleep status and oxidative stress levels in mice. Molecular docking was employed to anticipate the target binding energy of Huoermai essential oil constituents. ELISA and Western Blot (WB) were used to ascertain the expression of cAMP/CREB/BDNF/GABAergic pathway. RESULTS: The results indicated that HEO positively impacted intermittent hypobaric hypoxia-induced plateau insomnia in mice. Histological examination results showed that HEO ameliorated neuronal damage in specific regions of the brain affected by plateau insomnia, such as the cortex, hippocampus, thalamus, and hypothalamus. Through GC-MS analysis, 56 volatile oil components were identified. Subsequently, a combined network pharmacology and proteomics analyses led to selecting the cAMP/CREB/BDNF/GABAergic pathway for further study. ELISA experiments demonstrated that HEO treatment increased GABA and MT levels while significantly reducing 5-HT and adenosine levels in brain tissue of mice with plateau insomnia. WB results revealed that HEO ameliorated plateau insomnia by suppressing the hyperactivation of the cAMP pathway, increasing brain-derived neurotrophic factor (BDNF) levels and B-cell lymphoma-2 (BCL-2) expression, and alleviating hypoxia-induced oxidative stress. Moreover, molecular docking results showed strong binding affinity of all pharmacological components to their targets and proteins in the brain. CONCLUSION: These results indicate that HEO significantly prolongs sleep duration in plateau insomniac mice and treats plateau insomnia by modulating levels of sleep-related regulators, modulating the cAMP pathway, increasing GABA receptor expression, and improving neuronal survival and anti-apoptosis.

26Effects of acupuncture in treating insomnia due to spleen-stomach disharmony syndrome and its influence on intestinal microbiome: Study protocol for a randomized controlled trial.PubMed

Ya-Ru Huangfu, Wei Peng, Bao-Jun Guo, et al.
J Integr Med. 2019 May;17(3):161-166. doi: 10.1016/j.joim.2019.01.007. Epub 2019 Jan 29.
BACKGROUND: Insomnia is a common complaint that is closely related to gastrointestinal symptoms, which is consistent with the traditional Chinese medicine classical theory of "stomach disharmony leading to restless sleep." Acupuncture is an effective complementary and alternative medicine therapy to improve gastrointestinal function and restore the normal sleep-wake cycle. However, studies on the effectiveness of acupuncture for insomnia due to spleen-stomach disharmony syndrome are limited to case reports and few randomized controlled trials; deeper research on its mechanism is still lacking. This randomized controlled trial aims to assess the treatment efficacy of "harmonizing stomach to tranquilize mind" acupuncture for insomnia and its influence on the intestinal microbiome. METHODS/DESIGN: This is a randomized, single-blind, parallel-group study. Sixty eligible patients with insomnia due to spleen-stomach disharmony syndrome will be randomly divided into two groups (1:1 allocation ratio). The intervention group will use "harmonizing stomach to tranquilize mind" acupuncture, and the control group will receive sham acupuncture. Participants will receive 5 acupuncture treatment sessions per week for 4 consecutive weeks. The Pittsburgh Sleep Quality Index will be used to evaluate the clinical efficacy of acupuncture treatment by making assessments at baseline, the end of treatment and the end of the follow-up. High-throughput 16S ribosomal ribonucleic acid gene sequencing will be performed to detect changes in the intestinal microbial composition before and after treatment. DISCUSSION: The results of this trial are expected to confirm that "harmonizing stomach to tranquilize mind" acupuncture can effectively relieve insomnia and alter the intestinal microbiome. TRIAL REGISTRATION: Chinese Clinical Trials Registry: ChiCTR1800017092.

27Research progress in the prevention and treatment of insomnia with classical prescriptions.PubMed

Xiaoyu Shi, Liping Chen, Wenbin Li, et al.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023 Oct 28;48(10):1494-1505. doi: 10.11817/j.issn.1672-7347.2023.230200.
Insomnia is a common disease and its impact on human health cannot be ignored. At present, there are 3 main clinical treatments for insomnia, including traditional Chinese medicine treatment, sedative hypnotic drug therapy, and cognitive behavioral therapy. Traditional Chinese medicine (TCM) treatment for insomnia is widely used due to its advantages of low side effects, good efficacy, and no drug dependence. This paper summarizes the pathogenesis of insomnia in the theories of traditional Chinese and Western medicine. Modern medical research generally believes that sleep-wake disorder is the main pathological mechanism of insomnia, involving many factors such as monoamine neurotransmitter disorder, cytokine imbalance and intestinal flora imbalance. TCM mainly divides the pathogenesis of insomnia into 9 kinds of syndrome types: Liver depression transforming into fire, hyperactivity of fire due to yin deficiency, phlegm-heat attacking internally, disharmony between heart and kidney, deficiency of both heart and spleen, qi deficiency of both heart and gallbaldder, stomach qi disharmony, exuberance of heart fire, and internal blockade of static blood. According to these 9 kinds of pathogenesis of insomnia, the corresponding classical prescriptions such as Longdanxiegan decoction, Suanzaoren decoction, Huanglian-Wendan decoction, Jiaotai pill and Guipi decoction were analyzed and summarized. There is evidence that traditional Chinese medicine could treat insomnia mainly by increasing the level of 5-hydroxytryptamine, reducing the levels of dopamine, noradrenaline, tumor necrosis factor α, and interlukin-6, decreasing the ratio of glutamic acid to γ-aminobutyric acid, and inhibiting the hypothalamic-pituitary-adrenal axis.

28Traditional Chinese medicine treatment of insomnia based on microbial-gut-brain axis theory.PubMed

Xue-Jian Wang
World J Clin Cases. 2024 Dec 26;12(36):6867-6870. doi: 10.12998/wjcc.v12.i36.6867.
In recent years, insomnia has gradually become a common disease in society, which seriously affects people's quality of life. At present, with the deepening of research on intestinal microbiota-gut-brain axis in Western medicine, many studies suggest that regulating the gastrointestinal tract can treat brain-related diseases. It is found that brain-gut-bacteria axis plays an important role in the prevention and treatment of primary insomnia. At present, although the clinical treatment of insomnia with Western medicine can improve the insomnia symptoms of patients to a certain extent, there are still obvious adverse reactions, such as anxiety and depression, drug addiction, , so long-term oral drug therapy cannot be carried out. Traditional Chinese medicine (TCM) and acupuncture techniques have certain therapeutic effects on insomnia. TCM believes that the brain and gastrointestinal system are connected through the meridian, and the pathophysiology is closely related. This paper will discuss the theory and feasibility of TCM for the treatment of insomnia from the pathological relationship between brain-gut axis, intestinal flora and insomnia.

29Insomnia and intestinal microbiota: a narrative review.PubMed

Lu Liu, Ji-Wei Zhu, Jing-Lin Wu, et al.
Sleep Breath. 2024 Nov 26;29(1):10. doi: 10.1007/s11325-024-03206-x.
PURPOSE: The intestinal microbiota and insomnia interact through the microbiota-gut-brain axis. The purpose of this review is to summarize and analyze the changes of intestinal microbiota in insomnia, the interaction mechanisms between intestinal microbiota and insomnia and the treatment methods based on the role of microbiota regulation in insomnia, in order to reveal the feasibility of artificial intervention of intestinal microbiota to improve insomnia. METHODS: Pubmed/ Embase were searched through March 2024 to explore the relevant studies, which included the gut microbiota characteristics of insomnia patients, the mechanisms of interaction between insomnia and gut microbiota, and the relationship between gut microbiota and insomnia treatment. RESULTS: Numerous studies implicated insomnia could induce intestinal microbiota disorder by activating the immune response, the hypothalamic-pituitary-adrenal axis, the neuroendocrine system, and affecting bacterial metabolites, resulting in intestinal ecological imbalance, intestinal barrier destruction and increased permeability. The intestinal microbiota exerted an influence on the central nervous system through its interactions with intestinal neurons, releasing neurotransmitters and inflammatory factors, which in turn, can exacerbate symptoms of insomnia. Artificial interventions of gut microbiota included probiotics, traditional Chinese medicine, fecal microbiota transplantation, diet and exercise, whose main pathway of action is to improve sleep by affecting the release of neurotransmitters and gut microbial metabolites. CONCLUSION: There is an interaction between insomnia and gut microbiota, and it is feasible to diagnose and treat insomnia by focusing on changes in the gut microbiota of patients with insomnia. Large cross-sectional studies and fecal transplant microbiota studies are still needed in the future to validate its safety and efficacy.

30Screening the effective components of Suanzaoren decoction on the treatment of chronic restraint stress induced anxiety-like mice by integrated chinmedomics and network pharmacology.PubMed

Yan Yan, Jiahan Li, Yinjie Zhang, et al.
Phytomedicine. 2023 Jul;115:154853. doi: 10.1016/j.phymed.2023.154853. Epub 2023 May 2.
BACKGROUND: Suanzaoren decoction (SZRD) is a classical traditional Chinese prescription. It is widely used to treat mental disorders, including insomnia, anxiety, and depression, in China and other Asian countries. However, the effective components and mechanisms underlying SZRD remained unclear. PURPOSE: We aimed to develop a new strategy to discover the effects and potential mechanisms of SZRD against anxiety and to further reveal the effective components of SZRD in treating anxiety. STUDY DESIGN AND METHODS: First, the chronic restraint stress (CRS)-induced mouse model of anxiety was orally administered SZRD, and behavioral indicators and biochemical parameters were applied to assess efficacy. A chinmedomics strategy based on UHPLC-Q-TOF-MS technology and network pharmacology were then used to screen and explore potentially effective components and therapeutic mechanisms. Finally, molecular docking was applied to further confirm the effective components of SZRD, and a multivariate network for anxiolytic effects was constructed. RESULTS: SZRD exerted anxiolytic effects by increasing the percentage of entries into open arms and the time spent in open arms; improving hippocampal 5-HT, GABA, and NE levels; and increasing serum corticosterone (CORT) and corticotropin-releasing hormone (CRH) levels caused by CRS challenge. Beside, SZRD exerted a sedative effect by decreasing sleep time and prolonging sleep latency with no muscle relaxation effect in CRS mice. A total of 110 components were identified in SZRD, 20 of which were absorbed in the blood. Twenty-one serum biomarkers involved in arachidonic acid, tryptophan, sphingolipid, and linoleic acid metabolism were identified after SZRD intervention. Finally, a multivariate network including prescription-effective components-targets-pathway of SZRD treating anxiety, including 11 effective components, 4 targets and 2 pathway was constructed. CONCLUSION: The current study demonstrated that integrating chinmedomics and network pharmacology was a powerful approach to investigating the effective components and therapeutic mechanisms of SZRD and provided a solid basis for the quality marker (Q-marker) of SZRD.

31Exploring the mechanism of Suanzaoren decoction in treatment of insomnia based on network pharmacology and molecular docking.PubMed

Shuxiao Wang, Yan Zhao, Xingang Hu
Front Pharmacol. 2023 Aug 21;14:1145532. doi: 10.3389/fphar.2023.1145532. eCollection 2023.
To explore the functional mechanisms of Suanzaoren decoction (SZRD) for treating insomnia using network pharmacology and molecular docking. The active ingredients and corresponding targets of SZRD were obtained from the Traditional Chinese Medicine Systems Pharmacology database, and then, the names of the target proteins were standardized using the UniProt database. The insomnia-related targets were obtained from the GeneCards, DisGeNET, and DrugBank databases. Next, a Venn diagram comprising the drug and disease targets was created, and the intersecting targets were used to draw the active ingredient-target network diagram using Cytoscape software. Next, the STRING database was used to build a protein-protein interaction network, followed by cluster analysis using the MCODE plug-in. The Database for Annotation, Visualization, Integrated Discovery (i.e., DAVID), and the Metascape database were used for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. AutoDock Vina and Pymol software were used for molecular docking. SZRD contained 138 active ingredients, corresponding to 239 targets. We also identified 2,062 insomnia-related targets, among which, 95 drug and disease targets intersected. The GO analysis identified 490, 62, and 114 genes related to biological processes, cellular components, and molecular functions, respectively. Lipid and atherosclerosis, chemical carcinogen-receptor activation, and neuroactive ligand-receptor interaction were the most common pathways in the KEGG analysis. Molecular docking demonstrated that the primary active components of SZRD for insomnia had good binding capabilities with the core proteins in PPI network. Insomnia treatment with SZRD involves multiple targets and signaling pathways, which may improve insomnia by reducing inflammation, regulating neurotransmitters.

32Network pharmacology to unveil the mechanism of suanzaoren decoction in the treatment of alzheimer's with diabetes.PubMed

Tao Chen, Yining Lei, Manqin Li, et al.
Hereditas. 2024 Jan 3;161(1):2. doi: 10.1186/s41065-023-00301-z.
BACKGROUND: Suanzaoren Decoction (SZRD), a well-known formula from traditional Chinese medicine, has been shown to have reasonable cognitive effects while relaxing and alleviating insomnia. Several studies have demonstrated significant therapeutic effects of SZRD on diabetes and Alzheimer's disease (AD). However, the active ingredients and probable processes of SZRD in treating Alzheimer's with diabetes are unknown. This study aims to preliminarily elucidate the potential mechanisms and potential active ingredients of SZRD in the treatment of Alzheimer's with diabetes. METHODS: The main components and corresponding protein targets of SZRD were searched on the TCMSP database. Differential gene expression analysis for diabetes and Alzheimer's disease was conducted using the Gene Expression Omnibus database, with supplementation from OMIM and genecards databases for differentially expressed genes. The drug-compound-target-disease network was constructed using Cytoscape 3.8.0. Disease and SZRD targets were imported into the STRING database to construct a protein-protein interaction network. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on the intersection of genes. Molecular docking and molecular dynamics simulations were conducted on the Hub gene and active compounds. Gene Set Enrichment Analysis was performed to further analyze key genes. RESULTS: Through the Gene Expression Omnibus database, we obtained 1977 diabetes related genes and 622 AD related genes. Among drugs, diabetes and AD, 97 genes were identified. The drug-compound-target-disease network revealed that quercetin, kaempferol, licochalcone a, isorhamnetin, formononetin, and naringenin may be the core components exerting effects. PPI network analysis identified hub genes such as IL6, TNF, IL1B, CXCL8, IL10, CCL2, ICAM1, STAT3, and IL4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that SZRD in the treatment of Alzheimer's with diabetes is mainly involved in biological processes such as response to drug, aging, response to xenobiotic, and enzyme binding; as well as signaling pathways such as Pathways in cancer, Chemical carcinogenesis - receptor activation, and Fluid shear stress and atherosclerosis. Molecular docking results showed that licochalcone a, isorhamnetin, kaempferol, quercetin, and formononetin have high affinity with CXCL8, IL1B, and CCL2. Molecular dynamics simulations also confirmed a strong interaction between CXCL8 and licochalcone a, isorhamnetin, and kaempferol. Gene Set Enrichment Analysis revealed that CXCL8, IL1B, and CCL2 have significant potential in diabetes. CONCLUSION: This study provides, for the first time, insights into the active ingredients and potential molecular mechanisms of SZRD in the treatment of Alzheimer's with diabetes, laying a theoretical foundation for future basic research.

33Screening the components in multi-biological samples and the comparative pharmacokinetic study in healthy and depression model rats of Suan-Zao-Ren decoction combined with a network pharmacology.PubMed

Yiyang Du, Jiahong Wang, Li Jiang, et al.
J Ethnopharmacol. 2024 Jan 30;319(Pt 3):117360. doi: 10.1016/j.jep.2023.117360. Epub 2023 Oct 28.
ETHNOPHARMACOLOGICAL RELEVANCE: Suanzaoren Decoction (SZRD) is a classic traditional Chinese prescription, which has been commonly used for treating insomnia, depression and other nerve system diseases for a long time. AIM OF THIS STUDY: The present study aimed to explore the metabolic profiles in multi-biological samples and pharmacokinetic mechanism between healthy and depression model rats combined with a network pharmacology approach after administration of SZRD. MATERIALS AND METHODS: In our study, an ultra-high performance liquid chromatography (UPLC)-Q-Exactive Orbitrap Mass Spectrometry method was firstly used to study the prototype components and metabolites of SZRD in plasma, brain, urine, and feces between healthy and depressed rats. The possible metabolic pathways were also speculated. Then a network pharmacological study was conducted on the components in the plasma of model rats. According to the above components screened by network pharmacology and the other reported representative active components, the comparative pharmacokinetic study was established for the simultaneous determination of mangiferin, spinosin, ferulic acid, liquiritin, formononetin. magnoflorine and isoliquiritin between healthy and depression model rats. Finally, molecular docking was used to validate the binding affinity between key potential targets and active components in pharmacokinetics. RESULTS: A total of 115 components were identified in healthy rats, and 101 components were identified in model rats. The prototype components and metabolites in plasma, brain, urine, and feces were also distinguished. The main metabolic pathways included phase I and phase II metabolic reactions, such as dehydrogenation, oxidation, hydroxylation, gluconaldehyde conjugation, glutathione conjugation and so on. These results provided a basis for the further study of antidepressive pharmacokinetic and pharmacological action in SZRD. Then, according to the degree value of network pharmacological study, it was predicted that 10 components and 10 core targets, which involved in the critical pathways such as neuroactive ligand-receptor interaction, cyclic adenosine monophosphate (cAMP) signaling pathway, serotonergic synapse, phosphatidylinositol-3 kinase (PI3K)-Akt signaling pathway, etc. Finally, the established pharmacokinetic method was successfully applied to compare the pharmacokinetic behavior of these 7 active components in plasma of healthy and depressed rats after oral administration of SZRD. It showed that except magnoflorine, the pharmacokinetic parameters of each component were different between healthy and depressed rats. Molecular docking analysis also indicated that the active compounds in pharmacokinetics could bind tightly to the key targets of network pharmacological study. CONCLUSION: This study may provide important information for studying the action mechanism of SZRD in treating depression.

34Multi-target Mechanisms of Si-Ni-San on Anxious Insomnia: An Example of Network-pharmacology and Molecular Docking Analysis.PubMed

Chih Ting Lin, Hsin Yi Lin, Wen Huang Peng, et al.
Curr Med Chem. 2025;32(13):2640-2663. doi: 10.2174/0109298673299665240924090617.
BACKGROUND AND OBJECTIVE: Based on comprehensive network-pharmacology and molecular docking analysis, this study was intended to unveil the multiple mechanisms of Si-Ni-San (SNS) in treating anxious insomnia. METHODS: The compounds of SNS were meticulously analyzed, selected and standardized with references to their pharmacological attributes. The components included chaihu (.), baishao (Paeonia lactiflora Pall.), zhishi (.) and gancao ( DC.). We used the Traditional Chinese Medicine System Pharmacology (TCMSP) Database, Traditional Chinese Medicines Integrated Database (TCMID), GeneCards database, therapeutic target database (TTD) and comparative toxicogenomic database (CTD) to construct the components-compounds-targets networks and used Cytoscape 3.9.1 software to visualize the outcome. Afterwards, the STRING database and Cytoscape 3.9.1 software were utilized to construct and visualize the protein-protein interaction (PPI) network analysis. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The molecular docking program was carried out using AutoDock 4.2 software to understand interactions between target receptors and compound ligands selected for study. RESULTS: We thoroughly sorted and filtered 31 pharmacologically active compounds from SNS. Subsequently, several potential target genes were predicted, of which there were 59 target genes distinctly associated with anxious insomnia. The PPI analysis indicated that the core target proteins included AKT1, IL6, TNF, SLC6A4, MAOA and GABRA2. The results of our study indicated that SNS potentially remediates anxious insomnia by reducing inflammation, neurodegeneration, and cell apoptosis of neurons. In addition, GO and KEGG enrichment analysis results indicated that SNS could modulate multiple aspects of anxious insomnia through mechanisms related to pathways of neuroactive ligand-receptor interaction. These pathways include various kinds of synaptic transmission pathways, and anti-inflammatory activity associated with response pathways. When we compared the components-compounds-targets networks and the compounds-targets-synaptic pathways networks, the five active compounds, including beta-Sitosterol, Kaempferol, Tetramethoxyluteolin, Isorhamnetin and Shinpterocarpin, were selected to conduct molecular docking experiments. Eleven target proteins, (AKT1, SLC6A4, ADRB2, MAOA, ACHE, ESR1, CYP3A4, CHRNA7, GABRA2, HTR2A and NOS3), which also play significant roles in regulating serotonergic, cholinergic, dopaminergic and GABAergic systems in the PPI network, were selected to act as receptors in molecular docking trials. The results showed that docking pairs isorhamnetin-AKT1, isorhamnetin-SLC6A4, β-sitosterol-MAOA, β- sitosterol-ACHE, isorhamnetin-CHRNA7 and shinpterocarpin-GABRA2 provided the most stable conformations of ligand-receptor binding between key compounds and core target proteins in the SNS. CONCLUSION: In the study, we offer a computational result, revealing that SNS may alleviate sleep disorders associated with anxiety through a "multi-compounds, multi-targets, and multi-pathways" mechanism. The network-pharmacology and molecular docking outcomes could theoretically confirm the anti-anxiety and anti-insomnia effects of SNS. Although this research is purely statistical and systematic without empirical validation, it serves as a stepping stone and cornerstone for subsequent experimental investigations.

35Prediction of the therapeutic mechanism of Sugemule-4 in insomnia treatment using network pharmacology and molecular docking.PubMed

Rina Su, Jinjing Wang, Dena Su, et al.
Medicine (Baltimore). 2025 Dec 5;104(49):e46489. doi: 10.1097/MD.0000000000046489.
This study aimed to identify the active components and related target pathways as well as examine the potential mechanisms of action of Sugemule-4 (SGML-4) for the treatment of insomnia, based on network pharmacology, molecular docking analysis, and molecular dynamics simulation. The active compounds of SGML-4 were retrieved from the Traditional Chinese Medicine Systems Pharmacology, Herbal Medicine Resource, and Encyclopedia of Traditional Chinese Medicine databases. Their potential targets were predicted using the SwissTargetPrediction platform, while known insomnia-related targets were gathered from GeneCards, Online Mendelian Inheritance in Man, Therapeutic Target Database, Drugbank, and PharmGKB. The intersection of compound-related targets was then determined. Next, a protein-protein interaction network was constructed and visualized using the STRING online platform and Cytoscape 3.10.3 software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted using the DAVID platform. Based on these analyses, key targets and the principal active compounds of Sugemule IV were selected for molecular docking studies using AutoDock software to evaluate their potential interactions. Finally, molecular dynamics simulations were conducted using GROMACS software to assess the stability of the protein-compound complexes. A total of 106 active compounds and 364 overlapping targets were identified. Luteolin, pinocembrin, piplartine, lysicamine, and apigenin showed the highest degree values, and AKT1, glyceraldehyde-3-phosphate dehydrogenase, tumor necrosis factor, albumin, and epidermal growth factor receptor (EGFR) were identified as core targets. Gene Ontology analysis indicated enrichment in chemical synaptic transmission and G protein-coupled receptor signaling. Kyoto Encyclopedia of Genes and Genomes analysis revealed serotonergic synapse and calcium signaling as major pathways. Molecular docking showed strong binding affinities between active compounds and targets, particularly EGFR, which formed stable hydrogen bonds. Molecular dynamics confirmed stable interactions of EGFR with apigenin, luteolin, and piplartine. SGML-4 exerts anti-insomnia effects through multi-target and multi-pathway mechanisms. Apigenin, luteolin, and piplartine are the core active components, and EGFR is identified as the central target, potentially acting through serotonergic synapses and calcium signaling pathways.

36Jujuboside A in ameliorating insomnia in mice via GABAergic modulation of the PVT.PubMed

Mingyu Wang, Gen Wang, Maoyuan Zhao, et al.
J Ethnopharmacol. 2025 Jun 12;349:119939. doi: 10.1016/j.jep.2025.119939. Epub 2025 May 10.
ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphus jujuba var. spinosa (Bunge) Hu ex H. F. Chow (ZSS), a traditional Chinese medicinal herb, has been historically used to treat insomnia and neurological disorders. Jujuboside A, a triterpenoid saponin isolated from ZSS, represents its core bioactive component with purported sedative properties, yet its mechanism of action remains underexplored. AIM OF THE STUDY: To validate the anti-insomnia efficacy of Jujuboside A and elucidate its GABAergic regulatory mechanisms through integrated in vivo and in vitro approaches. MATERIALS AND METHODS: A chronic sleep deprivation mouse model was established using modified multi-platform water environment. Behavioral assessments (open-field test, pentobarbital-induced sleep test) were combined with histopathological analysis (H&E staining), flow cytometry (apoptosis), ELISA (GABA/Glu quantification), and Western blot (GABA A/GABA B, NMDA/AMPA receptors). Pharmacological inhibition of GABA signaling was performed using GABA-IN-1. RESULTS: Jujuboside A significantly shortened sleep latency and prolonged sleep duration vs. model group. Histopathology revealed Jujuboside A-mediated restoration of hippocampal neuronal density and mitigation of nuclear pyknosis. Jujuboside An upregulated GABA levels while suppressing Glu and neuronal apoptosis, with concomitant increases in GABA A and GABA B receptor expression. Crucially, GABA-IN-1 abolished these therapeutic effects, confirming GABA dependency. CONCLUSIONS: Jujuboside A ameliorates insomnia by restoring GABA/Glu homeostasis and enhancing GABA receptor expression, thereby validating ZSS's traditional use through modern pharmacological evidence.

37The Improvement in Sleep Quality by Zizyphi Semen in Rodent Models Through GABAergic Transmission Regulation.PubMed

Mijin Kim, YuJaung Kim, Hyang Woon Lee, et al.
Nutrients. 2024 Dec 11;16(24):4266. doi: 10.3390/nu16244266.
: Sleep, a process physiologically vital for mental health, faces disruptions in various sleep disorders linked to metabolic and neurodegenerative risks. seed (Zizy) has long been recognized for its diverse pharmacological attributes, including analgesic, sedative, insomnia, and anxiety alleviation. : In this study, the sleep-prolonging effects of Zizy extract (100, 200 mg/kg), along with their characterizing compounds jujuboside A (JuA) (5, 10 mg/kg), were evaluated in a mouse model under a pentobarbital-induced sleep. Additionally, the efficacy of Zizy extract was examined on caffeine-induced insomnia in mice. : To confirm the efficacy of Zizy extract on the structure and quality of sleep, an electroencephalogram (EEG) analysis of rats was performed using the MATLAB algorithm. Additionally, Western blot analysis and measurement of intracellular chloride influx were performed to confirm whether these effects acted through the gamma-aminobutyric acid (GABA)ergic system. Administration of Zizy extract showed no effect on the locomotor performance of mice, but the extract and their characteristic compounds significantly prolonged sleep duration in comparison to the pentobarbital alone group in the pentobarbital-induced sleep mouse model. Furthermore, this extract alleviated caffeine-induced insomnia in mice. : The administration of Zizy extract extended non-rapid eye movement sleep (NREMS) duration without inducing significant changes in the brain wave frequency. Zizy extract regulated the expression of GABA receptor subunits and GAD65/67 in specific brain regions (frontal cortex, hippocampus, and hypothalamus). JuA increased intracellular chloride influx in human SH-SY5Y cells, and it was reduced by GABA receptor antagonists. These results suggest that the sleep-maintaining effects of Zizy extract may entail GABAergic regulation. In summary, Zizy extract demonstrated sleep-prolonging properties, improved insomnia, and regulated sleep architecture through GABAergic system modulation. : These findings suggest that Zizy extract has potential as a therapeutic agent for stress-related neuropsychiatric conditions such as insomnia.

38Jujuboside A prevents sleep loss-induced disturbance of hippocampal neuronal excitability and memory impairment in young APP/PS1 mice.PubMed

Sidra Tabassum, Afzal Misrani, Bin-Liang Tang, et al.
Sci Rep. 2019 Mar 14;9(1):4512. doi: 10.1038/s41598-019-41114-3.
Sleep deprivation (SD) is the hallmark of modern society and may increase risk of Alzheimer's disease (AD). However, it is unclear how SD facilitates early cognitive impairments observed in AD models, as the underlying molecular mechanism is largely unknown. Here, we aim to investigate SD-induced cellular and molecular alterations in hippocampus of young APP/PS1 mice and whether jujuboside A (JuA) treatment could negate these alterations. Our results reveal that although SD causes spatial memory impairments in both genotypes, SD decreases frequency and amplitude of mEPSCs and pCREB levels in WT, but increases frequency and amplitude of mEPSCs, NMDAR, GluR1, pCaMKII (β, α) and decreases CREB levels in APP/PS1 mice, implicating that SD may facilitate abnormalities in young APP/PS1 mice via enhancing neuronal excitability. Moreover, JuA suppresses SD-induced enhancement of mEPSCs and prevents memory impairment in APP/PS1 mice. Further, whole-cell puff experiment suggests that JuA may function to activate GABAergic inhibition to reduce SD-induced enhancement of excitatory synaptic transmission in APP/PS1 mice. The present study reveals that sleep loss induces spatial memory impairment in an AD mouse model by disrupting the excitatory signaling pathway, and JuA prevents this via GABAergic mechanism.

39Jujuboside A improves insomnia by maintaining mitochondrial homeostasis in prefrontal neurons.PubMed

Zhen Zhang, Xinyue Che, Tingyu Feng, et al.
Brain Res Bull. 2025 Jun 15;226:111372. doi: 10.1016/j.brainresbull.2025.111372. Epub 2025 May 5.
OBJECTIVE: Jujuboside A (JB-A) is the major component of Semen Ziziphi Spinosae (SZS), a traditional Chinese herbal medicine used to treat sleep with clinical efficacy. This is the first study to investigate the effects of JB-A on mitochondrial structure and function in the prefrontal cortex of the insomnia model mice. METHODS: Young adult C57BL/6 mice were induced to develop insomnia by P-chlorophenylalanine. After 14 d of JB-A treatment via gavage, anxiety level was assessed using the open field and elevated plus maze tests. Next, the mitochondrial metabolic activity and morphological changes in the prefrontal cortex of each group of mice, as well as their effects on mitochondrial membrane potential, oxidative phosphorylation levels, and cytochrome c (Cyt c) content in neurons were measured. RESULTS: In our mouse model, JB-A ameliorated anxiety-like behaviors; up-regulated the membrane potential (Δψm) and had a therapeutic effect on the metabolic activity and damaged microscopic structure of mitochondria in the prefrontal cortex; effectively improved mitochondrial function by increasing the expression of Cyt c oxidase I and IV proteins, ATPase activity, and ATP content; and reduced the accumulation of Cyt c in the neuronal cytoplasm while inhibiting mitochondrial permeability transition pore (mPTP) opening. CONCLUSIONS: JB-A can improve insomnia by restoring mitochondrial intracellular oxidative phosphorylation, regulating mPTP to maintain mitochondrial homeostasis, and alleviating structural damage, providing a scientific basis for finding new targets for insomnia treatment.

40The mechanism of simultaneous intake of Jujuboside A and B in the regulation of sleep at the hypothalamic level.PubMed

Wei Wang, Yi Wang, Hongyan Pei, et al.
Aging (Albany NY). 2023 Sep 5;15(18):9426-9437. doi: 10.18632/aging.204995.
To study the effect of co-administration of Jujuboside A and B (Ju A+B) on sleep, healthy KM mice were given different doses of Ju A+B with a behavioral evaluation of sleep state. Serum levels of key neurotransmitters (5HT, DA, and NE) were measured. The hypothalamus of KM mice was analyzed for differential protein expression using TMT quantitative proteomics, and differential expression protein (DEP) bioinformatics analysis was used to explore potential mechanisms. The result shows that Ju A+B affects sleep by expressing the protein in the hypothalamus. Compared with the control group, the test group showed 10 up-regulated and 139 down-regulated DEPs. The key DEPs were found at the tight junction. Western blot showed reliable alteration of the key DEPs in proteomics. The result of interaction network analysis attributed the potential of Jujuboside to the changes in blood-brain barrier, which provided basic and theoretical data for the efficacy evaluation and mechanism of Jujuboside.

41Mechanism of Sour Jujube Kernel-five-flavour Berry in the Treatment of Insomnia based on Network Pharmacology and Molecular Docking.PubMed

Changlin Zhou, Haozhi Chen, Wen Li, et al.
Curr Pharm Des. 2025;31(36):2934-2945. doi: 10.2174/0113816128356734250322041738.
BACKGROUND: The incidence of insomnia is increasing annually worldwide. Most Western tranquilisers have side effects, such as strong dependence and notable withdrawal reactions. The sour jujube kernel and five-flavour berry can calm the mind and improve sleep, but the underlying mechanism is still unclear. OBJECTIVE: We investigated the active ingredients and mechanism of action of the sour jujube kernel-fiveflavour berry pair in treating insomnia. METHODS: The chemical compositions and targets of sour jujube kernels and five-flavour berries were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, PubChem, and PharmMapper. Insomnia disease targets were screened using the GeneCards, Online Mendelian Inheritance in Man, and Therapeutic Target Database. We constructed shared target data for topological analysis and network construction using the STRING database and the Cytoscape software. Gene Ontology functional and metabolic pathway analyses were performed using the DAVID database and validated through molecular docking using AutoDock and PyMOL software. RESULTS: This study demonstrated that the sour jujube kernel and five-flavour berry combination primarily addresses insomnia through the activity of eight hub genes: , and . Molecular docking simulations showed that jujuboside A exhibited robust docking to these hub genes, whereas longikaurin A showed a strong binding affinity with ALB and ESR1. CONCLUSION: We establish a theoretical foundation for further experimental studies, which may lead to the application of sour jujube kernel and five-flavour berry in clinical practice.

42: a source for anti-Alzheimer's disease drugs.PubMed

Xinxin Deng, Shipeng Zhao, Xinqi Liu, et al.
Pharm Biol. 2020 Dec;58(1):410-416. doi: 10.1080/13880209.2020.1758732.
Alzheimer's disease (AD) is a chronic neurodegenerative disease that originates from central nervous system lesions or recessions. Current estimates suggest that this disease affects over 35 million people worldwide. However, lacking effective drugs is the biggest handicap in treating AD. In traditional Chinese medicine (TCM), Willd. (Polygalaceae) is generally used to treat insomnia, memory dysfunction and neurasthenia. This review article explores the role of and its active components in anti-Alzheimer's disease. Literature for the last ten years was obtained through a search on PubMed, SciFinder, CNKI, Google Scholar, Web of Science, Science Direct and China Knowledge Resource Integrated with the following keywords: Polygala tenuifolia, polygalasaponin XXXII (PGS 32), tenuifolin, polygalacic acid, senegenin, tenuigenin, Alzheimer's disease. and its active components have multiplex neuroprotective potential associated with AD, such as anti-A aggregation, anti-Tau protein, anti-inflammation, antioxidant, anti-neuronal apoptosis, enhancing central cholinergic system and promote neuronal proliferation. and its active components exhibit multiple neuroprotective effects. Hence, is a potential drug against Alzheimer's disease, especially in terms of prevention.

43Identification of novel autophagic Radix Polygalae fraction by cell membrane chromatography and UHPLC-(Q)TOF-MS for degradation of neurodegenerative disease proteins.PubMed

An-Guo Wu, Vincent Kam-Wai Wong, Wu Zeng, et al.
Sci Rep. 2015 Nov 24;5:17199. doi: 10.1038/srep17199.
With its traditional use in relieving insomnia and anxiety, our previous study has identified onjisaponin B from Radix Polygalae (RP), as a novel autophagic enhancer with potential neuroprotective effects. In current study, we have further identified a novel active fraction from RP, contains 17 major triterpenoid saponins including the onjisaponin B, by the combinational use of cell membrane chromatography (CMC) and ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry {UHPLC-(Q)TOF-MS}. By exhibiting more potent autophagic effect in cells, the active fraction enhances the clearance of mutant huntingtin, and reduces protein level and aggregation of α-synuclein in a higher extent when compared with onjisaponin B. Here, we have reported for the first time the new application of cell-based CMC and UHPLC-(Q)TOF-MS analysis in identifying new autophagy inducers with neuroprotective effects from Chinese medicinal herb. This result has provided novel insights into the possible pharmacological actions of the active components present in the newly identified active fraction of RP, which may help to improve the efficacy of the traditional way of prescribing RP, and also provide new standard for the quality control of decoction of RP or its medicinal products in the future.

44Gut microbiota: A new target of traditional Chinese medicine for insomnia.PubMed

Wanying Feng, Zhihua Yang, Yangxi Liu, et al.
Biomed Pharmacother. 2023 Apr;160:114344. doi: 10.1016/j.biopha.2023.114344. Epub 2023 Feb 2.
All species have a physiological need for sleep, and sleep is crucial for the preservation and restoration of many physiological processes in the body. Recent research on the effects of gut microbiota on brain function has produced essential data on the relationship between them. It has been discovered that dysregulation of the gut-brain axis is related to insomnia. Certain metabolites of gut microbiota have been linked to insomnia, and disturbances in gut microbiota can worsen insomnia. Traditional Chinese medicine (TCM) has unique advantages for the treatment of insomnia. Taking the gut microbiota as the target and determining the scientific relevance of TCM to the prevention and treatment of insomnia may lead to new concepts for the treatment of sleep disorders and improve the therapeutic effect of sleep. Taking the gut microbiota as an entry point, this paper reviews the relationship between gut microbiota and TCM, the relationship between gut microbiota and insomnia, the mechanism by which gut microbiota regulate sleep, and the mechanism by which TCM regulates gut microbiota for insomnia prevention and treatment. This review provides new ideas for the prevention and treatment of insomnia through TCM and new ideas for drug development.

45Wendan Decoction exerts therapeutic effects on insomnia by regulating gut microbiota and tryptophan metabolism.PubMed

Yuan Tian, Jianguo Meng, Dezhu Zhang, et al.
Phytomedicine. 2025 Sep;145:157028. doi: 10.1016/j.phymed.2025.157028. Epub 2025 Jun 29.
BACKGROUND: Insomnia has been a public problem threatening human health. Wendan Decoction (WDD) has good therapeutic effects on insomnia. However, its mechanism to improve sleep remains unclear. PURPOSE: To investigate the potential mechanism of WDD in treating insomnia from the perspective of gut microbiota and metabolism. METHODS: The chemical composition of WDD was analyzed by UHPLCOrbitrap Exploris/MS. The efficacy of WDD on PCPA-induced insomnia rats was evaluated through behavioral tests, ELISA, histopathological examination, immunofluorescence and western blotting. 16S rRNA sequencing, untargeted metabolomics, and network pharmacology were integrated to explore the mechanism of WDD in treating insomnia. The role of gut microbiota in WDD treatment was validated by antibiotic treatment and fecal microbiota transplantation (FMT). Targeted metabolomics was used to detect changes in fecal tryptophan metabolites after FMT. Additionally, RT-qPCR and western blotting were used to investigate the potential mechanisms. RESULTS: WDD effectively shortened sleep latency, prolonged sleep duration, alleviated anxiety-like behaviors, attenuated neuronal damage, and modulated neurotransmitter levels in rats with insomnia. Moreover, WDD alleviated intestinal damage, reduced the number of Iba-1 positive cells, increased IL-10 levels and decreased IL-6, IL-1β, TNF-α and LPS levels in the colon, serum and hippocampus. It also increased the expression of Occludin, Claudin-1, and ZO-1 in both the colon and brain. 16S rRNA sequencing suggested that WDD improved gut microbiota disorders. Untargeted metabolomics and network pharmacology jointly suggested that WDD could regulate tryptophan metabolism. Antibiotic treatment and FMT confirmed the involvement of gut microbiota in the therapeutic effects of WDD in alleviating insomnia. Changes of tryptophan metabolites in feces, serum, and hippocampus confirmed the regulatory effect of WDD on tryptophan metabolism. Further mechanistic analysis suggested that WDD may correct the abnormal kynurenine pathway of tryptophan metabolism through inhibition of the expression of indoleamine 2,3-dioxygenase 1 and kynurenine-3-monooxygenase. CONCLUSION: WDD can modulate the neurotransmitter disorders, reduce inflammatory cytokine levels, and strengthen the intestinal barrier and blood-brain barrier by regulating gut microbiota and tryptophan metabolism, thereby improving sleep. This study provides evidence for the potential therapeutic effect of WDD on insomnia via the microbiota-gut-brain axis.

46Huanglian Wendan Decoction Improves Insomnia in Rats by Regulating BDNF/TrkB Signaling Pathway Through Gut Microbiota-Mediated SCFAs and Affecting Microglia Polarization.PubMed

Min Shi, Jie Yang, Ying Liu, et al.
Mol Neurobiol. 2025 Jan;62(1):1047-1066. doi: 10.1007/s12035-024-04330-1. Epub 2024 Jul 2.
Insomnia is a typical type of sleep disorder. Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) with the effects of regulating Qi, drying dampness and resolving phlegm, calming the mind, and relieving irritation. This study aims to investigate the effect of HWD on insomnia in rats and its mechanism. Para-chlorophenylalanine (PCPA)-induced insomnia in rats was used for in vivo experiments and then treated with HWD. Behavioral tests, Western blot, real-time PCR, immunofluorescent staining, 16S rRNA sequencing were conducted. The content of SCFAs was determined by GC-MS. Acetic acid-pretreated rat hippocampal nerve cells were used for in vitro experiments. The results showed that HWD significantly improved the learning memory ability, decreased sleep latency, and prolonged sleep duration in insomniac rats. HWD reduced TNF-α and IL-6 levels and increased IL-10 and Foxp3 levels. HWD also promoted the polarization of macrophages from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. In addition, HWD increased the expression levels of BDNF and TrkB in the hippocampus. Administration of the TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) confirmed the mechanism by which HWD activates BDNF/TrkB signaling to ameliorate insomnia. Furthermore, HWD restored gut microbiota richness and diversity and promoted short-chain fatty acid (SCFA) production in insomniac rats. In vitro experiments confirmed that the acetic acid-treated SCFA group could activate the BDNF/TrkB signaling pathway in neuronal cells, further promoting neuronal cell growth. In conclusion, HWD alleviated insomnia by maintaining gut microbiota homeostasis, promoting SCFA production, reducing neuroinflammatory response and microglia activation, and activating BDNF/TrkB signaling pathway.

47A comprehensive study on the regulation of Compound Zaoren Granules on cAMP/CREB signaling pathway and metabolic disorder in CUMS-PCPA induced insomnia rats.PubMed

Zekun Wang, Danting Li, Min Chen, et al.
J Ethnopharmacol. 2024 Oct 5;332:118401. doi: 10.1016/j.jep.2024.118401. Epub 2024 May 28.
ETHNOPHARMACOLOGICAL RELEVANCE: Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood. AIM OF THE STUDY: The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles. METHODS: The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated. RESULTS: The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted. CONCLUSION: These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.

48Efficacy of Chinese Medicine Treatment Based on Syndrome Differentiation for Primary Insomnia: A Randomized Placebo Controlled Triple-Blinded Trial.PubMed

Zhi-Yi Xiong, Ying Lu, Li-Yun He, et al.
Chin J Integr Med. 2024 Oct;30(10):867-876. doi: 10.1007/s11655-024-3661-4. Epub 2024 May 16.
OBJECTIVE: To assess efficacy of Chinese medicine (CM) on insomnia considering characteristics of treatment based on syndrome differentiation. METHODS: A total of 116 participants aged 18 to 65 years with moderate and severe primary insomnia were randomized to the placebo (n=20) or the CM group (n=96) for a 4-week treatment and a 4-week follow-up. Three CM clinicians independently prescribed treatments for each patient based on syndromes differentiation. The primary outcome was change in total sleep time (TST) from baseline. Secondary endpoints included sleep onset latency (SOL), wake time after sleep onset (WASO), sleep efficiency, Pittsburgh Sleep Quality Index (PSQI) and CM symptoms. RESULTS: The CM group had an average 0.6 h more (95% confidence interval (CI): 0.3-0.9, P<0.001) TST and 34.1% (10.3%-58.0%, P=0.005) more patients beyond 0.5 h TST increment than that of the placebo group. PSQI was changed -3.3 (-3.8 to -2.7) in the CM group, a -2.0 (-3.2 to -0.8, P<0.001) difference from the placebo group. The CM symptom score in the CM group decreased -2.0 (-3.3 to -0.7, P=0.003) more than the placebo group. SOL and WASO changes were not significantly different between groups. The analysis of prescriptions by these clinicians revealed blood deficiency and Liver stagnation as the most common syndromes. Prescriptions for these clinicians displayed relative stability, while the herbs varied. All adverse events were mild and were not related to study treatment. CONCLUSION: CM treatment based on syndrome differentiation can increase TST and improve sleep quality of primary insomnia. It is effective and safe for primary insomnia. In future studies, the long-term efficacy validation and the exploratory of eutherapeutic clinicians' fixed herb formulas should be addressed (Registration No. NCT01613183).

49Acupuncture combined with Chinese herbal medicine in the treatment of perimenopausal insomnia: A systematic review and meta-analysis.PubMed

Zhao Li, Shao Yin, Jie Feng, et al.
Medicine (Baltimore). 2023 Nov 10;102(45):e35942. doi: 10.1097/MD.0000000000035942.
BACKGROUND: Perimenopausal insomnia (PMI) is a relatively common menopausal symptom that can cause serious problems for the women themselves and their families. Today, the world is facing the trend and challenges of an aging population. It is reported that about 1.5 million women worldwide enter menopause every year, with sleep disorder identified as a core symptom. The efficacy of acupuncture combined with traditional Chinese medicine for treating PMI has been recognized by patients and doctors. METHODS: We searched 8 databases to identify 15 randomized controlled trials evaluating the effects of acupuncture combined with traditional Chinese medicine on sleep in patients with PMI compared with Western medicine alone. Subsequently, data extraction and analysis were performed to assess the quality and risk of bias of the study method design, and a meta-analysis of the data was performed. RESULTS: This study included 15 randomized controlled trials involving 1188 patients with PMI. The results show that acupuncture combined with traditional Chinese medicine seems to be more effective than Western medicine in the treatment of PMI: efficiency (RR: 1.18; 95% CI: 1.08, 1.29; P = .001); the Pittsburgh Sleep Quality Index (PSQI) (WMD: -2.77; 95% CI: 4.15-1.39; P < .0001); follicle-stimulating hormone (FSH) (WMD: -31.45; 95% CI: 42.7-20.2; P < .001) and the Hamilton Anxiety Score (HAMA) (WMD: -2.62, 95% CI: -3.93, -1.32; P < .0001). Compared with western medicine, E2 (WMD: 5.07; 95% CI: 5.78-15.92; P = .36) and LH (WMD: -4.86; 95% CI: 11.5-1.78; P = .151) had no difference. CONCLUSION: The current analysis results show that acupuncture combined with Chinese medicine seems to have a more positive effect than western medicine alone in improving sleep and FSHF in PMI patients, but no difference has been found in improving E2 and LH. This study provides a basis for acupuncture combined with Chinese medicine to treat PMI. However, due to the higher risk of evaluation in included studies, more rigorous randomized controlled trials and higher quality studies are needed to validate included studies.

50Electro-Acupuncture Therapy Alleviates Post-Stroke Insomnia by Regulating Sirt1 and the Nrf2-ARE Pathway.PubMed

Yiming Wang, Yifei Chen, Jianbo Yang, et al.
Neuromolecular Med. 2025 May 17;27(1):37. doi: 10.1007/s12017-025-08862-0.
Post-stroke insomnia (PSI) is a common complication following stroke, which seriously affects patients' life quality. Electro-acupuncture (EA) is an innovative form of traditional Chinese acupuncture that combines electricity with needles to achieve the prevention and treatment of diseases. However, there is limited understanding regarding the treatment mechanism of EA in PSI. In our study, we aimed to investigate the role of EA on PSI development. Our study findings indicated that the quality of sleep, levels of neurotransmitters 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (γ-GABA), and antioxidant levels showed significant improvement following EA treatment in PSI clinical samples and rat models, while the levels of pro-inflammatory factor interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and astrocyte damage were notably reduced. Furthermore, it was discovered that the levels of sirtuin 1 (Sirt1) were reduced in PSI, a condition that was significantly ameliorated by EA treatment. Additionally, the inhibition of Sirt1 caused a marked elevation in astrocyte apoptosis, inflammatory response, and oxidative stress. Besides, the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway was deactivated in the PSI rat model and Sirt1-silenced cells. However, the suppressive impact was successfully counteracted by EA or estazolam (ES), and the overexpression of Nrf2 partially alleviated the increase in apoptosis, inflammation, and oxidative stress caused by Sirt1 knockdown. Taken together, these findings indicated that EA improved sleep quality and silenced Sirt1-induced apoptosis, inflammation, and oxidative stress in PSI by activating the Nrf2-ARE pathway.

51Chinese herbal medicine and acupuncture for insomnia in stroke patients: A systematic review and meta-analysis of randomised controlled trials.PubMed

Qing Su, Liyan Wang, Hongshen Yu, et al.
Sleep Med. 2024 Aug;120:65-84. doi: 10.1016/j.sleep.2024.05.006. Epub 2024 May 11.
BACKGROUND: Insomnia is highly prevalent in stroke patients; however, there is no ideal intervention. This systematic review examined the effect and safety of Chinese herbal medicine (CHM) and acupuncture on sleep in adults with stroke. METHODS: Six databases were searched from inception to June 2023 to identify randomised controlled trials (RCTs). The primary outcome was Pittsburgh Sleep Quality Index (PSQI) scores. Risk of bias and evidence quality was assessed. A pairwise random-effect meta-analysis was performed. RESULTS: A total of 54 RCTs published in 55 articles were finally included in the systematic review, including 35 of CHM and 19 of acupuncture therapies. Compared with placebo/sham procedure, CHM and acupuncture were more effective in improving PSQI scores. The evidence of moderate quality suggested that CHM outperformed benzodiazepine drugs (BZDs) while it presented an effect similar to that of non-BZDs in improving sleep quality. CHM and acupuncture also provided additional benefits to the patients treated with pharmacological agents alone. However, the evidence specific to individual CHM prescriptions lay in various factors and methodological quality, and the evidence on the comparative effectiveness between acupuncture and other therapies was conflicting or limited. CONCLUSIONS: Overall, CHM and acupuncture used alone or in combination with pharmacotherapy can safely improve sleep in stroke patients with insomnia. In the future, RCTs on outstanding CHM prescriptions and the comparative effectiveness research between acupuncture and other therapies are needed. REGISTRATION: PROSPERO No. CRD42020194029 and No. CRD42020194030.

52[Observation on the therapeutic effect of scraping therapy on perimenopausal syndrome].PubMed

Rong-Rong Jiang, Gui-Hua Xu, Hong-Li An, et al.
Zhongguo Zhen Jiu. 2012 Dec;32(12):1121-3.
OBJECTIVE: To observe the clinical effects of scraping therapy on perimenopausal syndrome. METHODS: Twenty women with perimenopausal syndrome were treated with scraping therapy and the dorsal course of the Governor Vessell and the Urinary Bladder Meridian of Foot-Taiyang were scraped, especially on the Back-shu points and Ashi points. The clinical symptoms were observed and compared with a modified Kupperman score before and after treatment. RESULTS: In all the 20 patients, 3 cases were cured, 6 cases were markedly effective, 9 cases were effective, 2 cases were ineffective, and the total effective rate was 90.0%. The Kupperman total score after treatment of (10.4 +/- 7.5) was significantly lower than the score before treatment of (25.0 +/- 5.3) (P < 0.001), in which, hot flushes and sweating, insomnia, fatigue, paresthesia, anxiety/irritability, hypaphrodisia, urinary system infection, tinnitus, dizziness, memory deterioration and headache were eased significantly (P < 0.001, P < 0.05). CONCLUSION: The scraping therapy has a good clinical effect on perimenopausal syndrome and can significantly improve the clinical symptoms.

53Observation on the Clinical Efficacy of Traditional Chinese Medicine Non-Drug Therapy in the Treatment of Insomnia: A Systematic Review and Meta-Analysis Based on Computer Artificial Intelligence System.PubMed

Jingqing Zhuang, Jian Wu, Liang Fan, et al.
Comput Intell Neurosci. 2022 Oct 11;2022:1081713. doi: 10.1155/2022/1081713. eCollection 2022.
OBJECTIVE: Insomnia is a common and frequently occurring disease affecting the health of the population, which can seriously affect the work and life of patients. Drug treatment of insomnia has a rapid onset of action but has a large adverse reaction incidence rate. Traditional external treatment of traditional Chinese medicine (TCM) belongs to a type of non-drug therapy, the treatment of insomnia has a long history, but the methods of non-drug treatment of TCM are diverse, and the efficacy is also different. This study investigated the efficacy of TCM non-drug therapy in the treatment of insomnia by means of literature search and meta-analysis. METHODS: We searched Embase, Pubmed, OVid, WOS, CNKI, and CBM for randomized controlled trials (RCTs) on the use of TCM as a non-drug treatment for primary insomnia. After doing a literature search according to the inclusion and exclusion criteria, we used Cochrane rob v2.0 to assess the potential for bias in the studies that were included, and we did a combined analysis and assessment of the effectiveness of the therapy. RESULTS: 16 articles were included in this study for quantitative analysis, and a total of 1285 patients participated in the study, including 643 patients in the intervention group and 642 patients in the control group. Meta-analysis showed that non-drug therapy of TCM could improve the treatment response rate of insomnia patients [ = 6.88, 95%CI (4.40,10.74), = 8.48, < 0.0001], reduce post-treatment total score [ = -3.42, 95%CI (-4.62, -2.22), = -5.60, < 0.0001], and improved patient anxiety [ = -1.25, 95%CI (-2.13, -0.37), = -2.78, =0.01] and degree of depression [ = -1.53, 95%CI (-2.84, -0.21), = -2.28, =0.02]. The heterogeneity survey showed that treatment time was one of the sources of heterogeneity. Meta-regression analysis revealed that publication year, patient age, sample size, and intervention characteristics were not specific factors affecting the combined results. . TCM non-drug therapy (acupuncture, moxibustion, massage, and auricular point pressing beans) can significantly improve the score of patients after treatment and improve the degree of anxiety and depression of patients, with significant effect, which is worthy of clinical promotion.

54Community promotion and application of Wuqinxi combined with brief behavioral therapy for insomnia: A study protocol.PubMed

Yongliang Zheng, Yiyu Qin, Yumeng Lyu, et al.
Medicine (Baltimore). 2021 Dec 10;100(49):e28046. doi: 10.1097/MD.0000000000028046.
BACKGROUND: Brief behavioral therapy for insomnia (BBT-I) has been proven to be a simple and effective alternative to cognitive behavioral therapy. However, low adherence limits the application in Chinese primary medical institutions, resulting in delayed or irregular treatment for many patients. This study aimed to explore the efficacy of traditional Chinese medicine external treatments on the adherence to behavioral therapy for insomnia in Chinese primary healthcare institutions, with a particular focus on patients who live in regions with weak healthcare systems. METHODS: This randomized controlled clinical trial will be conducted in primary medical institutions and will recruit 98 adult participants with insomnia. BBT-I will be used as the base treatment. The participants will be divided into experimental (combined with Wuqinxi and other traditional Chinese medicine [TCM] external treatment n = 49) and control (combined with trazodone treatment, n = 49) groups, and each group will be treated for 4 consecutive weeks. The severity index of insomnia will be used as the main indicator of disease evaluation, with an 8-point reduction in the score considered as effective and a score <8 considered as cured. The secondary indicators of the disease evaluation will include the Pittsburgh sleep quality index, Zung's self-rating anxiety scale, Zung's self-rating depression scale, treatment adherence, and adverse event reports. All participants will be followed up at the time of enrollment, 4 weeks after treatment, and 3 months after the end of treatment. DISCUSSION: This clinical trial will provide evidence for the efficacy of traditional Chinese medicine external treatment on the adherence to behavioral therapy for insomnia in primary medical institutions. This cheap and accessible model may benefit insomnia patients in medically underserved areas. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100042845. Registered on 30 January 2021, dataset: http://www.chictr.org.cn/showproj.aspx?proj=65691. Official scientific title of the research topic: Wuqinxi and other external treatment of Chinese Medicine combined with brief behavior therapy for insomnia.

55Efficacy and safety of Shumian capsules in treating insomnia: A systematic review and meta-analysis.PubMed

Cuiying Wang, Yuying Yang, Xiao Ding, et al.
Medicine (Baltimore). 2021 Dec 17;100(50):e28194. doi: 10.1097/MD.0000000000028194.
BACKGROUND: It is known to all that the incidence of insomnia is becoming higher and higher with the increase of people's life stress. To some extent, it has brought about bad effects on people's life, work, study, and health, such as mental exhaustion, low work efficiency, and mood irritability. Now there are medications and non-medications methods for insomnia. As one of the treatments for insomnia, western medicine is to prolong the sleeping time and improve the anxious mood. However, taking western medicine to treat insomnia can also be accompanied by some adverse reactions at the same time, such as drug dependence, an allergic reaction, and so on. Traditional Chinese medicine therapy is based on syndrome differentiation and holistic concept. Shumian capsules (SM) are a kind of proprietary Chinese medicine for insomnia, which have the effect of relieving depression and calming the mind. But there are no studies on the efficacy and safety of SM in the treatment of insomnia. Therefore, I will provide a systematic review and meta-analysis to evaluate the efficacy and safety of SM for insomnia. METHODS: All the studies searched were from PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and WanFang databases, and the studies types included in the analysis were all randomized controlled trials. All the retrieval contents were completed independently by 2 researchers, and a third reviewer would be involved when there existed any disagreement. The eligible studies were screened out according to the inclusion criteria and exclusion criteria, and some useful information was extracted and made into a feature table, including the year of the included studies, the age, and disease course of the participants in the studies and intervention methods, etc. Cochrane risk-of-bias tool was used to evaluate the quality of literature and meta-analysis was conducted by RevMan 5.4 software. RESULTS: A total of 9 articles including 709 participants were included in the study after screening out. The primary outcomes of statistical analysis were cure rate and total effective rate, while the secondary outcomes included Pittsburgh sleep quality index score and incidence of adverse reactions. The results showed that Pittsburgh sleep quality index score of the SM group and Western medicine group were statistically significant (MD = -0.50, 95% confidence interval [CI] = [-0.78, -0.22], P = .0005). The total effective rate of the SM group was slightly higher than that of the Western medicine group, but there was no statistical significance (relative risk [RR] = 1.03, 95% CI = [0.95,1.13], P = .43). CONCLUSION: This meta-analysis provides evidence for the efficacy and safety of SM in the treatment of insomnia, and provides a new idea for the clinical treatment of insomnia. But more research is needed to support further evidence.

56Adverse outcomes of Chinese medicines used for threatened miscarriage: a systematic review and meta-analysis.PubMed

Lu Li, Li Xia Dou, James P Neilson, et al.
Hum Reprod Update. 2012 Sep-Oct;18(5):504-24. doi: 10.1093/humupd/dms025. Epub 2012 Jun 2.
BACKGROUND: Threatened miscarriage is very common in early pregnancy. Chinese medicines have been widely used to prevent spontaneous pregnancy loss. However, the safety of Chinese medicines is still unknown. A systematic review was performed to identify and describe adverse events of Chinese medicines used for threatened miscarriage. METHODS: Clinical studies of Chinese medicines for threatened miscarriage were selected. Primary outcomes were occurrence of adverse effects or toxicity of Chinese medicines. Secondary outcomes were failure of treatment and adverse pregnancy and perinatal outcomes. RESULTS: Thirty-two relevant articles included 9 randomized controlled trials, 1 quasi-randomized controlled trial and 2 controlled trials comparing Chinese medicines alone or combined medicines with pharmaceuticals and 20 case series with no controls. Sample sizes of each study were generally small. There was variation in Chinese medicine formulation, dosage and duration of treatment. In the pooled randomized controlled trials, dry mouth, constipation and insomnia (2-10%) and intervention failure (3.1-22.3%), diabetic complications (3%), preterm delivery (5%) and neurodevelopmental morbidity (1.8%) were recorded. Meta-analysis demonstrated that intervention failure was significantly lower in the combined Chinese medicines groups than in the Western medicines controls (relative risk = 0.46; 95% confidence interval: 0.30-0.70, I(2)= 0%). No significant differences were found between these groups for adverse effects and toxicity or for adverse pregnancy and perinatal outcomes. CONCLUSIONS: Studies varied considerably in design, interventions and outcome measures, therefore conclusive results remain elusive. In the absence of placebo-controlled trials, the safety of Chinese medicines for the treatment of threatened miscarriage is unknown. Rigorous scientific and clinical studies to assess the possible risks of Chinese medicines are needed.

57Traditional Chinese medicine for insomnia: Recommendation mapping of the global clinical guidelines.PubMed

Ziying Ye, Honghao Lai, Jinling Ning, et al.
J Ethnopharmacol. 2024 Mar 25;322:117601. doi: 10.1016/j.jep.2023.117601. Epub 2023 Dec 18.
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) represents a rich repository of empirically-developed traditional medicines. The findings call for more rigorous study into the efficacy, safety, and mechanisms of action of TCM remedies to strengthen the evidence base. AIM OF THE STUDY: To systematically review the quality of insomnia clinical practice guidelines that involve TCM recommendations and to summarize the certainty of evidence supporting the recommendations, strength, and consistency of recommendations, providing valuable research references for the development of future insomnia guidelines. MATERIALS AND METHODS: We systematically searched PubMed, Web of Science, Embase, CNKI, Wanfang, Chinese Biomedical Literature Database, Chinese Medical Association, Chinese Sleep Research Society, Medsci, Medlive, British National Institute of Health and Clinical Excellence (NICE), and the International Guidelines Collaboration Network (GIN) for clinical practice guidelines on insomnia from inception to March 5, 2023. Four evaluators conducted independent assessments of the quality of the guidelines by employing the AGREE II tool. Subsequently, the guideline recommendations were consolidated and presented as evidence maps. RESULTS: Thirteen clinical practice guidelines addressing insomnia, encompassing 211 recommendations (consisting of 127 evidence-based and 84 expert consensus recommendations), were deemed eligible for inclusion in our analysis. The evaluation results revealed an overall suboptimal quality, with the "scope and purpose" domain achieving the highest score (58.1%), while the "applicability" domain garnered the lowest score (13.0%). Specifically, it was observed that 74.8% (n = 95) of the evidence-based recommendations were supported by evidence of either very low or low certainty, in contrast to the expert consensus recommendations, which accounted for 61.9% (n = 52). We subsequently synthesized 44 recommendations into four evidence maps, focusing on proprietary Chinese medicines, Chinese medicine prescriptions, acupuncture, and massage, respectively. Notably, Chinese herbal remedies and acupuncture exhibited robust support, substantiated by high-certainty evidence, exemplified by interventions such as Xuefu Zhuyu decoction, spleen decoction, body acupuncture, and ear acupuncture, resulting in solid recommendations. Conversely, proprietary Chinese medicines needed more high-certainty evidence, predominantly yielding weak recommendations. As for other therapies, the level of certainty was predominantly categorized as low or very low. Recommendations about magnetic therapy, bathing, and fumigation relied primarily on expert consensus, needing more substantive clinical research evidence, consequently forming weak recommendations. Hot ironing and acupoint injection recommendations were weakly endorsed, primarily based on observational studies. Furthermore, interventions like qigong, gua sha, and moxibustion displayed a relatively limited number of clinical studies, necessitating further exploration to ascertain their efficacy. CONCLUSIONS: Our analysis revealed a need for substantial improvement in the quality of all the included guidelines related to insomnia. Notably, recommendations for Traditional Chinese Medicine (TCM) treatments predominantly rely on low-certainty evidence. This study represents a pioneering effort in the utilization of recommendation mapping to both present and identify existing gaps in the evidence landscape within TCM therapies, thus setting the stage for future research initiatives. The evidence supporting TCM therapy recommendations must be fortified to achieve a more substantial level of recommendation and higher certainty. Consequently, there exists a critical and pressing demand for high-quality clinical investigations dedicated to TCM, with a specific focus on ascertaining its long-term efficacy, safety, and potential side effects in the context of insomnia treatment. These endeavors are poised to establish a robust scientific foundation to inform the development of TCM therapy recommendations within the insomnia guidelines.

58Harmonizing the mind and body: The interrelationship between traditional Chinese medicine body constitution, mental health and sleep quality.PubMed

Juan-Juan Yang, Qian Wang, Wei Jiang
World J Psychiatry. 2025 Mar 19;15(3):103033. doi: 10.5498/wjp.v15.i3.103033.
BACKGROUND: Traditional Chinese medicine (TCM) body constitution is a key factor in determining and influencing the occurrence, development, and variation of diseases. As the mind interact with the body, TCM body constitution is useful in preventing and treating psychiatric disorders and insomnia. AIM: To investigate the interrelationship between TCM body constitution, psychiatric disorders and sleep quality. METHODS: A total of 2441 participants were enrolled in our study. TCM body constitution was measured using the Constitution in Chinese Medicine Questionnaire, sleep quality was assessed using the Chinese version of the Pittsburgh Sleep Quality Index, and psychopathological symptoms were evaluated using Symptom Checklist-90. Logistic regression was used to estimate the interrelationship between TCM body constitution, psychiatric disorders and sleep quality. RESULTS: The Pittsburgh Sleep Quality Index score and the proportions of participants with Qi-deficiency constitution, Qi-stagnation constitution, and blood-stasis constitution were significantly higher in the psychiatric symptoms group. Additionally, psychiatric symptoms were considerably associated with sleep quality, Qi-deficiency constitution, and Qi-stagnation constitution, but were inversely associated with male sex. Obsessive-compulsive symptoms were considerably associated with sleep quality, Qi-deficiency constitution and Qi-stagnation constitution. Depression was considerably associated with sleep quality, hyperuricemia, and Qi-stagnation constitution. Anxiety was considerably associated with sleep quality, diabetes, and Qi-stagnation constitution. Finally, poor sleep quality was considerably associated with Qi-deficiency constitution, Qi-stagnation constitution, dampness-heat constitution, phlegm-dampness constitution, and blood-stasis constitution but was inversely associated with male sex and body mass index > 23.9. CONCLUSION: TCM body constitutions are strongly associated with psychiatric symptoms and sleep quality. Further research is needed to verify whether TCM body constitution can be used to treat and prevent psychiatric conditions as well as enhance sleep quality.

59[Traditional Chinese medicine constitution types in 127 elderly patients with insomnia: an investigation in communities of Yangpu District, Shanghai].PubMed

Chen Xia, Qun-bang Zhu, Feng Huang, et al.
Zhong Xi Yi Jie He Xue Bao. 2012 Aug;10(8):866-73. doi: 10.3736/jcim20120806.
OBJECTIVE: To analyze the distribution of traditional Chinese medicine constitution types in elderly patients with insomnia. METHODS: The epidemiological data were collected from communities in the Yangpu District, Shanghai via a cross-sectional field survey. The elderly participants were enrolled by using the Pittsburgh Sleep Quality Index (PSQI) scale and the TCM Constitution Questionnaire. RESULTS: (1)The distribution of imbalanced constitutions between the elderly with insomnia and normal subjects showed statistical difference (P<0.01) and the elderly with insomnia tend to be of imbalanced constitutions. Among these unbalanced constitutions, deficient constitutions were more frequent than others in the elderly with insomnia, and yang-deficiency and qi-deficiency occurred mostly in unbalanced and simple constitutions. (2) Blood-stasis and qi-stagnation constitutions were more frequent in females than in males among the elderly with insomnia. Frequency of deficiency constitutions in the elderly increased as the age increases. (3) The frequency of composite constitutions was higher than that of simple constitutions in elderly patients with insomnia (74.8%), among which qi-deficiency was more likely to be composite with other constitutions. CONCLUSION: Identification and classification of traditional Chinese medicine constitution types will provide further information for devising projects with systematic intervention for insomnia management.

60Clinical efficacy of traditional chinese medicine on acute myocardial infarction: a prospective cohort study.PubMed

Wen-hui Duan, Fang Lu, Li-zhi Li, et al.
Chin J Integr Med. 2012 Nov;18(11):807-12. doi: 10.1007/s11655-012-1116-9. Epub 2012 Aug 16.
OBJECTIVE: To evaluate the clinical effects of Chinese medicine (CM) on acute myocardial infarction (AMI) with a prospective cohort study. METHODS: A total of 334 AMI patients from January 2007 to March 2009 were consecutively enrolled, and were assigned to a treatment group (169 cases) treated with combined therapy (CM for at least one month and Western medicine) and a control group (165 cases) with Western medicine alone. Clinical data including age, gender, smoking, medical history, infarction area, heart functional classification, CM syndrome scores, blood-stasis syndrome score, primary end-point (death, nonfatal myocardial infarction, and revascularization) and secondary end-point (ischemic stroke, rehospitalization due to angina, heart failure and shock), were collected. CM syndrome scores, blood-stasis syndrome score, primary end-point and secondary end-point were collected during the 6-month follow-up. Kaplan-Meier method was used for the survival analysis. The multifactor analysis was analyzed by Cox proportional hazards regression. RESULTS: At the end of 6-month the CM syndrome score and bloodstasis syndrome score in the treatment group were lower than those in the control group (P<0.01), especially the symptoms of chest pain, spontaneous perspiration and insomnia. Rehospitalization rate due to angina during the 6-month follow-up in the treatment group (2.96%) was lower than that in the control group (7.88%, P<0.05). Kaplan- Meier survival curve showed that event-free cumulated survival of rehospitalization due to angina during the 6-month follow-up in the treatment group was higher than that in the control group (Log rank 4.700, P=0.03). Cox regression analysis showed that heart dysfunction [hazard ratio (HR)=1.601, 95% CI=1.084-2.364, P=0.018] and diabetes mellitus (HR=1.755, 95% CI=1.031-2.989, P=0.038) were hazard factors to end-point, whereas CM (HR 0.405, 95% CI=0.231-0.712, P=0.002), percutaneous coronary intervention (PCI, HR=0.352, 95% CI=0.204-0.607, P<0.001) and angiotensin converting enzyme (ACE) inhibitors (HR=0.541, 95% CI=0.313-0.936, P=0.028) were protective factors. CONCLUSIONS: CM therapy could decrease CM syndrome scores and blood-stasis syndrome score, reduce the rehospitalization rate during 6-month follow-up due to angina. Heart dysfunction and diabetes mellitus were hazard factors to end-point, whereas CM, PCI and ACE inhibitors were protective factors.

61Integrating traditional Chinese medicine constitutions into insomnia management: Findings from a cross-sectional study.PubMed

Yan Han, Yu Wang, Mo-Yi Shi, et al.
J Integr Med. 2025 Jul;23(4):382-389. doi: 10.1016/j.joim.2025.05.004. Epub 2025 May 22.
OBJECTIVE: The concept of constitution in traditional Chinese medicine (TCM) has been increasingly recognized as a crucial factor in both the prevention and treatment of insomnia. However, rigorous statistical evidence on the correlation between TCM constitutions-particularly mixed constitutions-and insomnia disorder remains limited. This study aimed to investigate the association between specific TCM constitutions and insomnia disorder. METHODS: A cross-sectional study was conducted at the Department of Preventive Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, from November 2022 to December 2023. TCM constitutions were assessed using the Constitution in Chinese Medicine Questionnaire. Insomnia disorder was diagnosed by experienced internal medicine physicians according to the criteria of the International Classification of Sleep Disorders, Third Edition. A total of 1065 eligible participants (242 with insomnia disorder and 823 controls) were included in the final analysis. RESULTS: Among the participants, 862 (80.94%) exhibited biased constitutions, with 75.30% of these having mixed constitutions. Logistic regression analysis revealed a negative association between the gentleness constitution and insomnia disorder, whereas qi-deficiency, yang-deficiency, phlegm-dampness and qi-depression constitutions were positively associated with insomnia disorder. These associations remained significant after adjusting for potential confounders and were further validated through sensitivity analysis using propensity score matching. CONCLUSION: Significant associations between TCM constitutions and insomnia disorder were demonstrated. Future research should further investigate these relationships and explore the underlying mechanisms through rigorous longitudinal and interventional studies to improve understanding and clinical applications. Please cite this article as: Han Y, Wang Y, Shi MY, Liu Y, Cheng XD, Zhou Y. Integrating traditional Chinese medicine constitutions into insomnia management: Findings from a cross-sectional study. J Integr Med. 2025; 23(4): 382-389.

62[Research on the anti-inflammatory effects of a novel sleep-aid decoction on elderly insomnia patients across traditional Chinese medicine constitutional types].PubMed

Zhen Wu, Zhuoqiong Bian, Ailin Chen, et al.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Nov;41(11):1007-1012.
Objective To evaluate the clinical efficacy of a novel sleep-aid decoction in treating elderly insomnia patients with different traditional Chinese medicine (TCM) constitutional types, and its effects on neurotransmitter and inflammatory factor levels. Methods A total of 200 patients with four different TCM constitutions-peaceful, Qi-deficient, Yin-deficient, and Yang-deficient-were recruited. Peripheral blood neurotransmitter and inflammatory factor levels were measured for variations among insomnia patients across different constitutions. These patients were treated using the novel sleep-aid decoction, the effects of which were evaluated based on changes in neurotransmitters and inflammatory factors. Results Compared to the peaceful constitution group, insomnia patients with Qi-deficient, Yin-deficient, and Yang-deficient constitutions exhibited significantly elevated baseline levels of neurotransmitters (5-HT, GABA) and inflammatory factors (IL-6, TNF-α, IL-1β, CRP). Following the treatment, the Qi-deficient and Yin-deficient groups showed a marked increase in 5-HT levels, restored balance of Glu, GABA, and melatonin, and significant reductions in IL-6 and TNF-α levels. The overall effective rate was 83.5%, with optimal efficacy observed in the Qi-deficient (97.72%) and Yin-deficient (95.34%) groups. Conclusion The novel sleep-aid decoction is effective in treating insomnia in elderly patients, with the best results observed in the Qi-deficient and Yin-deficient constitution groups.

63Acupuncture for cancer-related insomnia: A systematic review and meta-analysis.PubMed

Jialing Zhang, Zhinan Zhang, Shengtao Huang, et al.
Phytomedicine. 2022 Jul 20;102:154160. doi: 10.1016/j.phymed.2022.154160. Epub 2022 May 14.
BACKGROUND: Cancer-related insomnia is a highly prevalent complaint in cancer patients. However, there is no meta-analytic synthesis explored the efficacy of acupuncture for cancer-related insomnia among cancer patients undergoing active cancer treatments. OBJECTIVE: This systematic review and meta-analysis were performed to explore the efficacy and safety of acupuncture for insomnia in people diagnosed with cancer. STUDY DESIGN: Systematic review and meta-analysis of existing randomized controlled trials on acupuncture in the treatment of cancer-related insomnia. METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, we identified and extracted the trials through November 2021 from ten databases and two trials record platforms (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PUBMED, Web of Science, PsycINFO, Allied and Complementary Medicine, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, Wanfang Digital Journals, ClinicalTrials, World Health Organization International Clinical Trials Registry Platform). The quality of the trials was assessed using Jadad score and Risk of Bias (2.0). A meta-analysis was synthesized using the random-effects model if the included studies were in high methodological quality. RESULTS: A total of 690 studies were identified, with 22 were included in the review, and 6 of them were included in the quantitative synthesis. Studies were highly heterogeneous in terms of participant characteristics and study methodologies. Most studies recruited patients diagnosed with a specific cancer type, and breast cancer patients were the subgroup most represented. The qualitative review of available evidence suggested a beneficial efficacy of acupuncture on sleep without serious adverse events in several studies (55%). The meta-analysis revealed that acupuncture produced a significant improvement in the total Pittsburgh Sleep Quality Index (PSQI) score relative to the wait-list control among breast cancer patients undergoing active cancer treatments (MD -1.92, 95% CI -3.25 to -0.59, p = 0.005). Similar improvement of real and sham acupuncture on PSQI score change post-intervention was found (MD: -0.68, 95% CI: -2.44 to 1.07, p = 0.44). Manual acupuncture had similar effective rate as compared to estazolam immediately post-intervention (RR: 0.94, 95% CI: 0.87 to 1.01, p = 0.09), and had significantly better effective rate than estazolam at 1-week post-intervention follow-up (RR: 1.25, 95% CI: 1.10 to 1.43, p = 0.0009). All reported acupuncture related adverse events were mild or moderate in severity. CONCLUSION: Acupuncture has great potential to be used to manage cancer-related insomnia for cancer patients or survivors. More studies with rigorous designs and larger sample size are warranted to verify the efficacy and safety of acupuncture for insomnia among people diagnosed with cancer, in particular among those with clinically significant insomnia. REGISTRATION: PROSPERO (ID: CRD42021285844).

64Acupuncture for primary insomnia: Effectiveness, safety, mechanisms and recommendations for clinical practice.PubMed

Fei-Yi Zhao, Sarah J Spencer, Gerard A Kennedy, et al.
Sleep Med Rev. 2024 Apr;74:101892. doi: 10.1016/j.smrv.2023.101892. Epub 2023 Dec 11.
Primary insomnia (PI) is an increasing concern in modern society. Cognitive-behavioral therapy for insomnia is the first-line recommendation, yet limited availability and cost impede its widespread use. While hypnotics are frequently used, balancing their benefits against the risk of adverse events poses challenges. This review summarizes the clinical and preclinical evidence of acupuncture as a treatment for PI, discussing its potential mechanisms and role in reliving insomnia. Clinical trials show that acupuncture improves subjective sleep quality, fatigue, cognitive impairments, and emotional symptoms with minimal adverse events. It also positively impacts objective sleep processes, including prolonging total sleep time, improving sleep efficiency, reducing sleep onset latency and wake after sleep onset, and enhancing sleep architecture/structure, including increasing N3% and REM%, and decreasing N1%. However, methodological shortcomings in some trials diminish the overall quality of evidence. Animal studies suggest that acupuncture restores circadian rhythms in sleep-deprived rodents and improves their performance in behavioral tests, possibly mediated by various clinical variables and pathways. These may involve neurotransmitters, brain-derived neurotrophic factors, inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, gut microbiota, and other cellular events. While the existing findings support acupuncture as a promising therapeutic strategy for PI, additional high-quality trials are required to validate its benefits.

65B serum proteome profiles revealed dysregulated proteins and mechanisms associated with insomnia patients: A preliminary study.PubMed

Tao Liu, Guanying Wang, Xingping Zhang, et al.
Front Integr Neurosci. 2022 Jul 26;16:936955. doi: 10.3389/fnint.2022.936955. eCollection 2022.
BACKGROUND: Insomnia is a clinical problem of significant public health importance; however, the underlying pathogenesis of this disorder is not comprehensively understood. METHODS: To identify potential treatment targets and unfold one of the gaps that were involved in insomnia pathological mechanisms, we employed a tandem mass tag-based (TMT) quantitative proteomics technology to detect differentially expressed proteins (DEPs) in serum from patients with insomnia and controls. DEPs were further analyzed by bioinformatics platforms. In addition, parallel reaction monitoring (PRM) was used to verify the TMT results. RESULTS: Patients with insomnia had poorer sleep quality compared with healthy controls. A total of 106 DEPs were identified among patients with insomnia and controls. They were mainly enriched in immune and inflammation-related biological functions and signaling pathways. Using the protein-protein interaction network, we screened the 10 most connected proteins as key DEPs. We predicted that four key DEPs were subject to targeted regulation by natural compounds of herbs. Eight key DEPs were validated using PRM in an additional 15 patients with insomnia and 15 controls, and the results also supported the experimental findings. CONCLUSION: We identified aberrantly expressed proteins in insomnia that may be involved in the immune-inflammatory response. The 10 key DEPs screened may be potential targets for insomnia, especially FN1, EGF, HP, and IGF1. The results of this study will broaden our understanding of the pathological mechanisms of insomnia and provide more possibilities for pharmacotherapy.

66Visualizing Research Trends and Identifying Hotspots of Traditional Chinese Medicine (TCM) Nursing Technology for Insomnia: A 18-Years Bibliometric Analysis of Web of Science Core Collection.PubMed

Junxin Wang, Yufeng Chen, Xing Zhai, et al.
Front Neurol. 2022 Mar 31;13:816031. doi: 10.3389/fneur.2022.816031. eCollection 2022.
OBJECTIVE: To explore the research hotspot and frontier direction of TCM nursing of insomnia and provide reference for the follow-up study of the optimal scheme of TCM nursing of insomnia. BACKGROUND: Insomnia is a common sleep-wake disorder, affects 6-10% of adults and was associated with independent higher risks of cardiovascular disease and diabetes. TCM Nursing Techniques of insomnia has a long history and has shown a definite impact. However, it's still lack of analysis in the field of the most commonly used and effective techniques, as well as the co-morbidities associated with insomnia. Therefore, the database was searched and analyzed to find effective TCM Nursing Techniques for insomnia and related diseases related to insomnia. METHOD: Randomized controlled trials on the intervention of TCM Nursing Techniques in insomnia were retrieved from Web of Science Core Collection and imported into CiteSpace 5.6.R5 visualization software. The works of literature were co-cited by keywords authors and institutions for visual analysis, and the co-morbidities associated with insomnia of TCM Nursing Techniques in literature was extracted manually. The symptoms of co-morbidities associated with insomnia were imported into Cytoscape 3.9.0 software and clustered by CytoHubba. RESULT: As of October 20, 2021, the literature published in the last 20 years from Web of Science Core Collection was screened, and the publication period of the included literature was from 2004 to 2021. From 2016 to now, the total number of articles has been increasing. A total of 146 articles were included, and the highest production year was 2020. There is little cooperation between states, institutions, and authors. China (including Hong Kong and Taiwan) and Hong Kong Polytech University are leading countries and institutions in this area. MYUNGHAENG HUR is the most cited author, and J ALTERN COMPLEM MED is the most cited journal. According to cluster analysis and keyword frequency, auricular therapy, aromatherapy, and acupressure are the three most commonly used techniques. While the top five co-morbidities are fatigue, anxiety, depression, pain and hemodialysis. The three frontier topics and the main research directions are sleep quality, comorbid insomnia and clinical trial design. CONCLUSION: We found that acupressure, aromatherapy, and auricular acupoint therapy are the most commonly used nursing methods of TCM to intervene in insomnia. However, these studies have limitations such as small sample size, lack of objectivity in evaluating sleep quality, and high heterogeneity of intervention measures, which are not conducive to forming TCM clinical nursing guidelines. Therefore, it is necessary to adopt objectified sleep quality evaluation methods, select suitable acupoints according to TCM theories, and design multi-center large-sample clinical trials based on the safety principle of randomized blind control. This study provides an in-depth perspective for insomnia research on TCM Nursing Techniques and includes information for follow-up research on TCM Nursing Techniques of insomnia.

67Clinical efficacy of meridian differentiation acupuncture in the treatment of intractable insomnia based on objective data: a protocol for a multicentre, single-blind, randomised controlled trial.PubMed

Wenming Chu, Ling Gao, Yun Li, et al.
BMJ Open. 2025 Jul 24;15(7):e095833. doi: 10.1136/bmjopen-2024-095833.
INTRODUCTION: Insomnia, a prevalent sleep disorder, significantly impacts individuals' physical and mental well-being. Despite conventional treatments, some patients experience persistent insomnia. Acupuncture, a safe complementary therapy, has been demonstrated to be effective in treating insomnia. Meridian differentiation can enhance acupuncture efficacy by enabling individualised diagnosis. Previous clinical research has indicated that meridian differentiation acupuncture (MA), based on objective data, can notably enhance sleep quality in patients with intractable insomnia. However, small sample sizes and a lack of objective measures necessitate further investigation. Therefore, we plan to conduct a large-scale, multicentre clinical trial to validate its efficacy. METHODS: We propose a multicentre, single-blind, randomised, sham acupuncture (SA)-controlled trial involving 489 participants with intractable insomnia. Patients will be randomly assigned to three groups at a 1:1:1 ratio: the MA group, the conventional acupuncture group and the SA group. We will assess Pittsburgh Sleep Quality Index scores, actigraphy, sleep diary, Insomnia Traditional Chinese Medicine Symptom Scale scores, Hamilton Rating Scale for Anxiety scores and meridian imbalance values at baseline, after 2 weeks and 4 weeks of treatment, and at two follow-up periods (8 weeks and 12 weeks postbaseline). The intention-to-treat principle will be applied to analyse the data, observe differences between meridian differentiation acupuncture, CA and SA in improving outcomes related to intractable insomnia. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine (2024HL-002) and the ethics committees of other participating institutions. Each participant must provide their written informed consent form before enrolling in this study, and consent can be withdrawn at any stage. On completion of the study, the results will be published in a journal or made available by contacting the corresponding author via email. TRIAL REGISTRATION NUMBER: This study protocol was registered in the Chinese Clinical Trial Registry on 22 April 2024 (ChiCTR2400083323).

68Revealing the mechanism of suanzaoren tang against insomnia via integrated metabolomics and gut microbiota analysis.PubMed

Hui Fang, Yan-Huan Wang, Lei Yang, et al.
J Pharm Biomed Anal. 2026 Feb 15;269:117231. doi: 10.1016/j.jpba.2025.117231. Epub 2025 Nov 3.
Suanzaoren Tang (SZRT), a classic prescription from the Jingui Yaolue, is commonly used to treat insomnia associated with liver-blood deficiency. However, the mechanisms underlying SZRT's treatment of insomnia remain poorly understood. Using an integrated multi-omics approach, this research aimed to systematically explore the underlying mechanisms through which SZRT exerted its alleviating efficacy in p-chlorophenylalanine (PCPA)-induced insomnia. UPLC-ESI-MS/MS analysis was performed to identify the compounds in SZRT. Intraperitoneal administration of PCPA was utilized to develop an insomnia model in rats. Behavioral evaluation, ELISA, immunofluorescence, untargeted metabolomics and 16S rRNA sequencing were applied to assess how SZRT affected sleep quality, neurotransmitters, inflammatory markers, gut microbiota composition, and metabolic pathways. 30 compounds were identified in SZRT. PCPA treatment significantly prolonged sleep latency and altered neurochemical profiles, including decreased γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) levels, and increased glutamate (Glu), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and CYP2E1 expression. Immunofluorescence revealed reduced expression of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1(Iba-1), 5-HTA, and 5-HTA receptors, indicating glial cell dysfunction and serotonergic dysregulation in PCPA group. SZRT intervention reversed these changes. Microbiota analysis showed that PCPA disrupted gut microbial composition, with decreased Prevotellaceae and Butyricicoccus abundance, both of which were restored by SZRT. Metabolomics identified key differential metabolites enriched in branched-chain amino acid metabolism, D-amino acid metabolism, α-linolenic acid metabolism, and arachidonic acid pathways. SZRT restored neurotransmitter homeostasis and reduced inflammation via microbiota-metabolite interactions. Suanzaoren Tang may improve insomnia by modulating the gut microbiota-metabolome-brain axis and glial cell activity, thereby restoring neurotransmitter balance, attenuating oxidative stress, and suppressing neuroinflammation. These findings provide experimental support for the clinical application of SZRT in insomnia treatment.

69Berbamine Targets TNFAIP3: A Bioactive Compound Alleviates Oxidative Stress and Inflammation in the Comorbidity of Insomnia and Chronic Obstructive Pulmonary Disease Through Multi-Omics Integration.PubMed

Xinliao Deng, Shuaiyu Jiang, Ziyi Liu, et al.
Int J Mol Sci. 2025 Oct 21;26(20):10227. doi: 10.3390/ijms262010227.
Chronic obstructive pulmonary disease (COPD) and insomnia are highly comorbid, yet their shared pathogenesis and therapeutic targets remain unclear. This study employed multidimensional approaches-including bidirectional Mendelian randomization (MR), transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and computational drug repositioning-to investigate causal relationships, shared pathways, and therapeutic strategies for COPD-insomnia comorbidity. MR analysis indicated that insomnia is a causal risk factor for COPD (OR = 2.04, 95% CI: 1.18-3.51; = 0.011), with no reverse causality. Integrated transcriptomics of COPD (GSE148004) and insomnia (GSE208668) identified 230 co-dysregulated genes enriched in immune-inflammatory pathways (e.g., NF-κB signaling and cytokine response) and oxidative stress. Protein-protein interaction networks highlighted TNFAIP3 as a hub gene, confirmed by LASSO regression as a shared diagnostic biomarker. A co-expression network of 190 overlapping genes linked circadian disruption and airway inflammation. Drug repositioning nominated TNFAIP3-targeting agents, and molecular docking revealed high-affinity binding between berbamine and the TNFAIP3 OTU domain (ΔG = -9.25 kcal/mol). TNFAIP3 emerges as a dual regulator of inflammatory signaling and redox homeostasis. Our systems pharmacology approach bridges epidemiological causality and molecular mechanisms, supporting single-agent polypharmacology for COPD-insomnia comorbidity.

70Application of machine learning models in predicting insomnia severity: an integrative approach with constitution of traditional Chinese medicine.PubMed

Shenguang Li, Po Zhu, Guoying Cai, et al.
Front Med (Lausanne). 2023 Oct 19;10:1292761. doi: 10.3389/fmed.2023.1292761. eCollection 2023.
OBJECTIVE: This study sought to explore the utility of machine learning models in predicting insomnia severity based on Traditional Chinese Medicine (TCM) constitution classifications, with an aim to discuss the potential applications of such models in the treatment and prevention of insomnia. METHODS: We analyzed a dataset of 165 insomnia patients from the Shanghai Minhang District Integrated Traditional Chinese and Western Medicine Hospital. TCM constitution was assessed using a standardized Constitution in Chinese Medicine (CCM) scale. Sleep quality, or insomnia severity, was evaluated using the Spiegel Sleep Questionnaire (SSQ). Machine learning models, including Random Forest Classifier (RFC), Support Vector Classifier (SVC), and K-Nearest Neighbors (KNN), were utilized. These models were optimized using Grid Search algorithm and were trained and tested on stratified patient data, with the TCM constitution classifications serving as primary predictors. RESULTS: The RFC outperformed others, achieving a weighted average accuracy, precision, recall, and F1-score of 0.91, 0.94, 0.92, and 0.92 respectively, it also effectively classified the severity of insomnia with high area under receiver operating characteristic curve (AUC-ROC) values. Feature importance analysis demonstrated the Damp-heat constitution as the most influential predictor, followed by Yang-deficiency, Qi-depression, Qi-deficiency, and Blood-stasis constitutions. CONCLUSION: The results demonstrate the potent utility of machine learning, specifically RFC, coupled with TCM constitution classifications in predicting insomnia severity. Notably, the constitution classifications such as Damp-heat and Yang-deficiency emerged as crucial determinants, emphasizing its potential in guiding targeted insomnia treatments. This approach enables the development of more personalized and efficient interventions, thereby enhancing patient outcomes.

71Treatment of Insomnia With Traditional Chinese Medicine Presents a Promising Prospect.PubMed

Boyi Zhang, Qianqian Wang, Yuhang Zhang, et al.
Phytother Res. 2025 Apr 18. doi: 10.1002/ptr.8495.
Insomnia, a prevalent sleep disorder, significantly impacts global health. While Western medications provide temporary relief, their risks of dependency and cognitive impairment have spurred the search for safer alternatives. Traditional Chinese Medicine (TCM) offers a promising approach to treating insomnia by focusing on harmonizing the balance of Yin and Yang and the functions of internal organs. This review explores recent research advances in TCM for insomnia treatment, integrating classical theories with modern scientific understanding of key pathological mechanisms, including neurotransmitter regulation (GABA, monoamines), immune-inflammatory responses, the HPA axis, and interactions with the gut microbiota. Growing clinical evidence supports the effectiveness of classical TCM prescriptions and treatments like acupuncture in improving sleep quality, particularly when combined with Western medications to enhance efficacy and reduce dependency. However, TCM also has its limitations. Future research directions should focus on modernizing TCM applications, addressing comorbidities associated with insomnia, exploring the role of gut microbiota, and optimizing medicinal and edible homologous products. By integrating traditional knowledge with cutting-edge technologies, TCM holds great potential for advancing personalized and effective insomnia treatments globally.

72Banxia Shumi decoction for the treatment of insomnia: A systematic review and meta-analysis.PubMed

Fang Wang, Lifang Wei
Medicine (Baltimore). 2025 Nov 28;104(48):e46207. doi: 10.1097/MD.0000000000046207.
BACKGROUND: The efficacy of Banxia Shumi decoction (BSD) and its combination with Chinese medicine (acupuncture, formulas, etc) in treating insomnia remains controversial, with varying research conclusions. This study presents a systematic review and meta-analysis of its impact on insomnia. METHODS: We conducted a comprehensive search of databases, including PubMed, Embase, Web of Science, and China National Knowledge Infrastructure. Studies meeting the criteria for the insomnia population, intervention, comparison, and outcome were independently screened and data extracted. Fixed- or random-effects models were used to calculate the standardized mean difference and 95% confidence interval (CI). Publication bias and research quality were evaluated to ensure reliability. RESULTS: BSD was effective in treating method, as shown by improvements in clinical effective rate (risk ratio = 1.16, 95% CI: 1.10-1.23), Pittsburgh Sleep Quality Index (mean standard deviation [MD] = -3.22, 95% CI: -4.41 to - 2.03), Insomnia Severity Index (MD = -5.52, 95% CI: -6.29 to - 4.74), and Athens Insomnia Scale (MD = -1.62, 95% CI: -2.18 to - 1.06) were analyzed. According to the indicators, it has shown good effects in improving the symptoms of patients with insomnia. Compared to Western Medicine, the clinical efficacy of BSD + TCM (MD = 0.16, 95% CI: 0.08-0.24) was more significant than that of BSD alone. For primary insomnia, BSD was more effective (MD=-6.27, 95% CI: -6.43 to - 6.11, P < .0001). CONCLUSION: Based on the clinical efficiency index, BSD can effectively improve sleep and quality of life in patients with insomnia, shorten sleep onset time, increase sleep time and efficiency, and alleviate sleep and daytime dysfunction. However, the results should be considered carefully owing to some methodological weaknesses, including study diversity. Future research should employ standardized methods in large-scale, multicenter, randomized controlled trials to confirm these findings.