Cannabidiol counteracts caffeine-induced sleep inhibition in mice

doi:10.3877/cma.j.issn.1674-0785.2025.08.006

Abstract

Abstract:

Objective

To investigate whether cannabidiol (CBD) has an antagonistic effect on caffeine (CAF)-induced sleep inhibition in mice.

Methods

A pentobarbital sodium synergistic hypnosis test was used to observe the effects of different doses of CAF on sleep duration in normal mice and to evaluate the regulatory effect of CBD on CAF-induced sleep inhibition. A spontaneous activity video analysis system was employed to assess the effects of CAF and CBD on autonomous locomotor behavior in mice. Serum adenosine levels were measured using a mouse adenosine detection kit (Enzyme-Linked Immunosorbent Assay, ELISA), and hypothalamic glutamate content was detected by High Performance Liquid Chromatography (HPLC).

Results

CAF (40 mg/kg) significantly prolonged sleep latency (P＜0.001) and shortened sleep duration (P＜0.01) in mice, whereas CBD (10 mg/kg) significantly shortened sleep latency (P＜0.001) and prolonged sleep duration (P＜0.001). In the CAF (10 mg/kg) group, the total distance traveled by mice increased (P＜0.05), the average speed accelerated (P＜0.05), and the time spent in the central area prolonged (P＜0.05). After CBD (10 mg/kg) intervention, the total distance traveled decreased (P＜0.01), the average speed slowed (P＜0.01), and the time spent in the central area shortened (P＜0.001). The hypothalamic glutamate content increased (P＜0.001) and serum adenosine levels also significantly rose (P＜0.01) in the CAF (40 mg/kg) group. CBD (10 mg/kg) treatment significantly reduced both glutamate (P＜0.001) and adenosine (P＜0.001) levels.

Conclusion

CAF disrupts normal sleep in mice and induces abnormalities in glutamate and adenosine levels; CBD counteracts these CAF-induced sleep disturbances and normalizes the neurochemical alterations.

Key words: Cannabidiol, Caffeine, Sleep inhibition, Glutamate, Adenosine

Xiaopeng Jia, Jingcao Li, Ruiqing Tang, Shuo Li, Rui Xue, Qiongyin Fan, Yang Zhang, Youzhi Zhang, Zhenggang Guo. Cannabidiol counteracts caffeine-induced sleep inhibition in mice[J]. Chinese Journal of Clinicians(Electronic Edition), 2025, 19(08): 594-600.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhlcyszz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-0785.2025.08.006

https://zhlcyszz.cma-cmc.com.cn/EN/Y2025/V19/I08/594

Figures/Tables 6

References 25

1	van Straten A, van der Zweerde T, Kleiboer A, et al. Cognitive and behavioral therapies in the treatment of insomnia: a meta-analysis [J]. Sleep Med Rev, 2018, 38: 3-16.
2	李琼蔚, 苏怡, 卢喆, 等. 内蒙古赤峰地区高中生睡眠问题现状调查 [J/OL]. 中华临床医师杂志(电子版), 2023, 17(2): 117-124.
3	de Zambotti M, Goldstone A, Colrain IM, et al. Insomnia disorder in adolescence: diagnosis, impact, and treatment [J]. Sleep Med Rev, 2018, 39: 12-24.
4	Parvathy S, Luiz A, Varkey JT. Chemical analysis of caffeine content in tea and coffee samples [J]. Asian J Sci Appl Technol, 2014, 3(1): 1-4.
5	Huang ZL, Qu WM, Eguchi N, et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine [J]. Nat Neurosci, 2005, 8(7): 858-859.
6	Garrett BE, Holtzman SG. D1 and D2 dopamine receptor antagonists block caffeine-induced stimulation of locomotor activity in rats [J]. Pharmacol Biochem Behav, 1994, 47(1): 89-94.
7	彭飞, 周璇梓. 社区团体心理干预对社区老年人心理和睡眠健康的影响 [J/OL]. 中华临床医师杂志(电子版), 2020, 14(9): 709-713.
8	吴伟, 邓丽影. 昼夜节律失调性睡眠觉醒障碍的治疗策略 [J]. 中国临床药理学与治疗学, 2021, 26(5): 511-515.
9	Bergamaschi MM, Queiroz RH, Zuardi AW, et al. Safety and side effects of cannabidiol, a Cannabis sativa constituent [J]. Curr Drug Saf, 2011, 6(4): 237-249.
10	Liu YM, Li JC, Gu YF, et al. Cannabidiol exerts sedative and hypnotic effects in normal and insomnia model mice through activation of 5-HT1A receptor [J]. Neurochem Res, 2024, 49(5): 1150-1165.
11	Ko YH, Shim KY, Lee SY, et al. Evodiamine reduces caffeine-induced sleep disturbances and excitation in mice [J]. Biomol Ther (Seoul), 2018, 26(5): 432-438.
12	刘影, 李劲草, 薛瑞, 等. 大麻二酚配伍褪黑素改善大、小鼠失眠和昼夜节律紊乱作用及机制 [J]. 中国药理学与毒理学杂志, 2023, 37(2): 81-90.
13	Chaudhary NS, Grandner MA, Jackson NJ, et al. Caffeine consumption, insomnia, and sleep duration: results from a nationally representative sample [J]. Nutrition, 2016, 32(11-12): 1193-1199.
14	Pisanti S, Malfitano AM, Ciaglia E, et al. Cannabidiol: state of the art and new challenges for therapeutic applications [J]. Pharmacol Ther, 2017, 175: 133-150.
15	Skully J. Oral cbd administration: assessing bioavailability and behavioral outcomes in a rodent model [M]. Wayne State University, 2021.
16	岳小芳, 李帅帅, 刘杰, 等. 坤泰胶囊对初老雌性小鼠的戊巴比妥钠睡眠增强作用及其机制研究 [J]. 现代药物与临床, 2020, 35(3): 433-437.
17	边颖, 周永健, 蔡毅, 等. 酒石酸唑吡坦的主要药效学实验研究 [J]. 天津医科大学学报, 2003, 9(2): 216-218.
18	Kardos J, Blandl T. Inhibition of a gamma aminobutyric acid a receptor by caffeine [J]. Neuroreport, 1994, 5(10): 1249-1252.
19	Lalonde R, Strazielle C. Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents [J]. Fundam Clin Pharmacol, 2010, 24(3): 365-376.
20	Misra AL, Vadlamani NL, Pontani RB. Effect of caffeine on cocaine locomotor stimulant activity in rats [J]. Pharmacol Biochem Behav, 1986, 24(3): 761-764.
21	Sudakov SK, Nazarova GA, Alekseeva EV, et al. Peripheral administration of a μ-opioid receptor agonist DAMGO suppresses the anxiolytic and stimulatory effects of caffeine [J]. Bull Exp Biol Med, 2015, 158(3): 295-297.
22	John J, Ramanathan L, Siegel JM. Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats [J]. Am J Physiol Regul Integr Comp Physiol, 2008, 295(6): R2041-R2049.
23	John J, Kodama T, Siegel JM. Caffeine promotes glutamate and histamine release in the posterior hypothalamus [J]. Am J Physiol Regul Integr Comp Physiol, 2014, 307(6): R704-R710.
24	Reichert CF, Deboer T, Landolt HP. Adenosine, caffeine, and sleep-wake regulation: state of the science and perspectives [J]. J Sleep Res, 2022, 31(4): e13597.
25	Elmenhorst D, Meyer PT, Matusch A, et al. Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET [J]. J Nucl Med, 2012, 53(11): 1723-1729.

[1]	Tingting Liu, Mingyan Ding, Wei Ji, Lijuan Guo, Ying Li, Hanzhang Zhao, Fang Zhu. Correlation between heart rate reserve and microcirculatory dysfunction in female patients with non-coronary obstructive ischemic heart disease [J]. Chinese Journal of Medical Ultrasound (Electronic Edition), 2022, 19(10): 1077-1082.
[2]	Chunhui Chen, Yan Fu, Yuanxiang Zhang, Yinru Qiu, Zhiyao Liang, Wei Xie, Fuxiu Liu. Application of adenosine triphosphate stress contrast-enhanced ultrasound in the diagnosis of coronary artery spasm [J]. Chinese Journal of Medical Ultrasound (Electronic Edition), 2022, 19(02): 161-169.
[3]	Xiangzhu Wang, Yuelin Ma, Xiaoli Xie, Haiye Jiang. Bioinformatics analysis of insulin-like growth factor 2-binding protein 2 in predicting prognosis of oral cancer [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2025, 19(02): 84-95.
[4]	Xin Chen, Xiaochen Zhang, Wen Qin, Zuolin Jin. Overexpression of methyltransferase-like 3 repairs the osteogenic ability of periodontal mesenchymal stem cells in patients with periodontitis [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2023, 17(01): 15-25.
[5]	Xin Chen, Jia Liu, Wen Qin, Zuolin Jin. Research progress on the regulatory role of m⁶A methylation modification of long non-coding RNA in various diseases [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2022, 16(01): 1-6.
[6]	Juncheng Wu, Liguo Zhao. Protective effect of ferulic acid regulating AMPK pathway on H2O2-induced intestinal epithelial barrier injury [J]. Chinese Archives of General Surgery(Electronic Edition), 2021, 15(05): 364-369.
[7]	Nan Zhang, Yu Zhang, Cuixing Zhou, Zhengsheng Li, Nuo Ji, Dong Xue, Yimeng Chen. Dynamic change analysis of N6-methyladenosine methyltransferase-like 3 in renal ischemia-reperfusion injury [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(06): 343-348.
[8]	Zhenyi Xia, Yi Liu, Yucheng Ding, Hongxia Yuan, Xiaoyan Li, Tian Chen. Regulation of 1-methylhistidine and dimethylglycine in lung adenocarcinoma by circUBAP2L via hsalet-7c/GAD1 axis [J]. Chinese Journal of Lung Diseases(Electronic Edition), 2025, 18(02): 273-278.
[9]	Yating Wu, Shenghang Zhang, Shuiliang Wang. Research progress in the role of dysregulated RNA m⁶A modification in breast cancer metastasis [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(01): 45-52.
[10]	Xiaozhou Yang, Huadong Zhao. Research progress of N6-methyladenosine epitranscriptomics in hepatocellular carcinoma [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2023, 12(02): 239-242.
[11]	Shiyao Zhang, Yanyan Xu, Qi Zhang, Chunqiang Li, Zhicheng Zhao, Gang Liu. The m⁶A-binding protein YTHDC2 affects proliferation and apoptosis of colorectal cancer cells by regulating the p38MAPK signaling pathway [J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2023, 12(02): 117-124.
[12]	Xin Cui, Peng Zhang, Tongnan Gu, Yanzhi Zhao. Effect of sulbactam on brain tissue injury in rats with focal cerebral ischemia-reperfusion [J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2023, 09(06): 333-337.
[13]	Zihua Liu, Degui Wang, Xiaojuan Li, Dongrong Tang, Wen Wang, Junyi Chen, Jianlin Wang. Transcriptome sequencing analysis: study on the PI3K, ERK and P38 signaling pathways and metabolic relationship in mice with Parkinson’s disease [J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2021, 07(03): 161-169.
[14]	Fan Yang, Xueli Ding, Xiaoyu Li, Yujun Song, Zibin Tian, Yingjie Guo. Effect of high concentration urate on expression and function of adenosine triphosphate binding box transporter G2 in intestinal cells [J]. Chinese Journal of Clinicians(Electronic Edition), 2024, 18(01): 57-63.
[15]	Juhua Ji, Ming Xu, Fei Hong, Lei Song. Effect of caffeine citrate plus phenobarbital on serum NF-κB and TLR2 in preterm infants with brain injury [J]. Chinese Journal of Clinicians(Electronic Edition), 2022, 16(02): 141-145.

Please choose a citation manager

Content to export