Traditional Chinese medicine for chronic fatigue syndrome: theoretical foundations, mechanisms, and clinical management approaches

Abstract

Chronic fatigue syndrome (CFS), a complex, debilitating disorder that significantly challenges global health systems, is characterized by unrelenting fatigue, cognitive disturbances, and a series of other symptoms that do not improve with rest. While the etiology of CFS remains unclear, emerging research underscores the involvement of neuroendocrine-immune network disruption, metabolic irregularities, and gut microbiota dysbiosis. Current treatments for CFS range from pharmacological interventions, such as anti-depressant and immunosuppressant therapies, to non-pharmacological therapies like cognitive behavioral therapy and graded exercise, but these approaches often fall short in fully alleviating symptoms due to various side effects and limited efficacy. Traditional Chinese medicine (TCM), with its unique therapeutic approach involving herbal medicines, acupuncture, and massage, presents a promising alternative by addressing underlying imbalances, enhancing quality of life, and potentially mitigating fatigue symptoms. This review delves into the efficacy of TCM in managing CFS and the possible underlying mechanisms, highlights recent advancements, and advocates for rigorous clinical trials to help solidify its role in integrative healthcare. By bridging contemporary research with traditional modalities, this paper aims to expand the therapeutic strategies against CFS, offering new hope for comprehensive, effective management.

Keywords

Acupuncture / Complementary therapies / Fatigue / Herbal medicine / TCM

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This work was supported by a Stanford Translational Research and Applied Medicine Pilot Grant (PR1056869), a Stanford School of Medicine Dean’s Postdoctoral Fellowship (1044758-312-KARWY), and the Tianjin Municipal Education Commission Scientific Research Plan Project (2022KJ146).

Author contributions

Bowen Yang, Tianlin Wang, Ke Xiong, Xueqi Ding, Mengrui Zhang, Ming Huang, and Xiaohao Wu conducted the literature review and wrote the draft manuscript. Ming Huang and Xiaohao Wu corrected the draft. All authors agree to be accountable for all aspects of work to ensure integrity and accuracy.

Ethical approval of studies and informed consent

Not applicable.

Acknowledgments

None.

Data availability

All relevant data are within the manuscript.

References

[1] Steiner S, Fehrer A, Hoheisel F, et al. Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome—state of the art:report of the 2nd International Meeting at the Charité Fatigue Center. Autoimmun Rev. 2023; 22(11):103452.

[2] Crawley E. The epidemiology of chronic fatigue syndrome/myalgic encephalitis in children. Arch Dis Child. 2014; 99(2):171-174.

[3] Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994; 121(12):953-959.

[4] Lim EJ, Ahn YC, Jang ES, et al. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020; 18(1):100.

[5] Ruiz-Pablos M, Paiva B, Montero-Mateo R, et al. Epstein-Barr virus and the origin of myalgic encephalomyelitis or chronic fatigue syndrome. Front Immunol. 2021; 12:656797.

[6] Cox BS, Alharshawi K, Mena-Palomo I, et al. EBV/HHV-6A dUTPases contribute to myalgic encephalomyelitis/chronic fatigue syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities. JCI Insight. 2022; 7(11):e158193.

[7] Campos MC, Nery T, Starke AC, et al. Post-viral fatigue in COVID-19: a review of symptom assessment methods, mental, cognitive, and physical impairment. Neurosci Biobehav Rev. 2022; 142:104902.

[8] Tarazi M, Gaffney RG, Pearson D, et al. Fatigue in systemic lupus erythematosus and other autoimmune skin diseases. Br J Dermatol. 2019; 180(6):1468-1472.

[9] Son K, Jamil R, Chowdhury A, et al. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms. Eur Respir J. 2023; 61(1):2200970.

[10] Shoenfeld Y, Ryabkova VA, Scheibenbogen C, et al. Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy. Clin Immunol. 2020; 214:108384.

[11] Patejdl R, Penner IK, Noack TK, et al. Multiple sclerosis and fatigue: a review on the contribution of inflammation and immune-mediated neurodegeneration. Autoimmun Rev. 2016; 15(3):210-220.

[12] Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004; 15(2):55-59.

[13] Tanriverdi F, Karaca Z, Unluhizarci K, et al. The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome. Stress. 2007; 10(1):13-25.

[14] Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013; 2013:784520.

[15] Yang T, Yang Y, Wang D, et al. The clinical value of cytokines in chronic fatigue syndrome. J Transl Med. 2019; 17(1):213.

[16] Roerink ME, Knoop H, Bronkhorst EM, et al. Cytokine signatures in chronic fatigue syndrome patients: a case control study and the effect of anakinra treatment. J Transl Med. 2017; 15(1):267.

[17] Smith ME, Haney E, McDonagh M, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health pathways to prevention workshop. Ann Intern Med. 2015; 162(12):841-850.

[18] Nacul LC, Lacerda EM, Pheby D, et al. Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Med. 2011; 9:91.

[19] Valdez AR, Hancock EE, Adebayo S, et al. Estimating prevalence, demographics, and costs of ME/CFS using large scale medical claims data and machine learning. Front Pediatr. 2018; 6:412.

[20] Orji N, Campbell JA, Wills K, et al. Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in Australian primary care patients: only part of the story? BMC Public Health. 2022; 22(1):1516.

[21] Lim EJ, Lee JS, Lee EJ, et al. Nationwide epidemiological characteristics of chronic fatigue syndrome in South Korea. J Transl Med. 2021; 19(1):501.

[22] Lim EJ, Son CG. Prevalence of chronic fatigue syndrome (CFS) in Korea and Japan: a meta-analysis. J Clin Med. 2021;10(15).

[23] Bierl C, Nisenbaum R, Hoaglin DC, et al. Regional distribution of fatiguing illnesses in the United States: a pilot study. Popul Health Metr. 2004; 2(1):1.

[24] Tang FC, Li RH, Huang SL. The association between job-related psychosocial factors and prolonged fatigue among industrial employees in Taiwan. PLoS One. 2016; 11(3):e0150429.

[25] Bested AC, Marshall LM. Review of myalgic encephalomyelitis/chronic fatigue syndrome: an evidence-based approach to diagnosis and management by clinicians. Rev Environ Health. 2015; 30(4):223-249.

[26] Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007; 17(2):210-218.

[27] Jongen PJ, Ter Horst AT, Brands AM. Cognitive impairment in multiple sclerosis. Minerva Med. 2012; 103(2):73-96.

[28] Yamout BI, Alroughani R. Multiple sclerosis. Semin Neurol. 2018; 38(2):212-225.

[29] Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2):162-173.

[30] Bower JE. Cancer-related fatigue—mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 2014; 11(10):597-609.

[31] Bower JE. The role of neuro-immune interactions in cancer-related fatigue: biobehavioral risk factors and mechanisms. Cancer. 2019; 125(3):353-364.

[32] Bower JE, Lamkin DM. Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immun. 2013 Mar; 30(Suppl 0):S48-57.

[33] Sivan M, Taylor S. NICE guideline on long COVID. BMJ. 2020;371:m4938.

[34] Van der Sluis RM, Holm CK, Jakobsen MR. Plasmacytoid dendritic cells during COVID-19: ally or adversary? Cell Rep. 2022; 40(4):111148.

[35] Saris A, Reijnders TDY, Nossent EJ, et al. Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19. Thorax. 2021; 76(10):1010-1019.

[36] Santopaolo M, Gregorova M, Hamilton F, et al. Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months. Elife. 2023; 12:e85009.

[37] Ramasamy A, Wang C, Brode WM, et al. Immunologic and autoimmune-related sequelae of severe acute respiratory syndrome coronavirus 2 infection: clinical symptoms and mechanisms of disease. Phys Med Rehabil Clin N Am. 2023; 34(3):623-642.

[38] Pan YY, Wang LC, Yang F, et al. New role in intestinal symptoms of COVID-19. World J Gastroenterol. 2023; 29(13):1942-1954.

[39] Gu W, Gan H, Ma Y, et al. The molecular mechanism of SARS-CoV-2 evading host antiviral innate immunity. Virol J. 2022; 19(1):49.

[40] Farzi R, Aghbash PS, Eslami N, et al. The role of antigen-presenting cells in the pathogenesis of COVID-19. Pathol Res Pract. 2022; 233:153848.

[41] Berentschot JC, Drexhage HA, Aynekulu Mersha DG, et al. Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity. Front Immunol. 2023; 14:1254899.

[42] Winslow BT, Vandal C, Dang L. Fibromyalgia: diagnosis and management. Am Fam Physician. 2023; 107(2):137-144.

[43] Bair MJ, Krebs EE. Fibromyalgia. Ann Intern Med. 2020; 172(5):ITC33-ITC48.

[44] Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020; 11:1025.

[45] Chu L, Valencia IJ, Garvert DW, et al. Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: a patient-centered, cross-sectional survey. PLoS One. 2018; 13(6):e0197811.

[46] Moore GE, Keller BA, Stevens J, et al. Recovery from exercise in persons with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Medicina (Kaunas). 2023; 59(3):571.

[47] Shanks L, Jason LA, Evans M, et al. Cognitive impairments associated with CFS and POTS. Front Physiol. 2013; 4:113.

[48] Aoun Sebaiti M, Hainselin M, Gounden Y, et al. Systematic review and meta-analysis of cognitive impairment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Sci Rep. 2022; 12(1):2157.

[49] Cockshell SJ, Mathias JL. Cognitive deficits in chronic fatigue syndrome and their relationship to psychological status, symptomatology, and everyday functioning. Neuropsychology. 2013; 27(2):230-242.

[50] Maksoud R, Eaton-Fitch N, Matula M, et al. Systematic review of sleep characteristics in myalgic encephalomyelitis/chronic fatigue syndrome. Healthcare (Basel). 2021; 9(5):568.

[51] Bazelmans E, Bleijenberg G, Vercoulen JH, et al. The chronic fatigue syndrome and hyperventilation. J Psychosom Res. 1997; 43(4):371-377.

[52] Bogaerts K, Hubin M, Van Diest I, et al. Hyperventilation in patients with chronic fatigue syndrome: the role of coping strategies. Behav Res Ther. 2007; 45(11):2679-2690.

[53] Mancini DM, Brunjes DL, Cook D, et al. Abnormal breathing patterns and hyperventilation are common in patients with chronic fatigue syndrome during exercise. Front Med (Lausanne). 2025; 12:1669036.

[54] Naschitz JE, Mussafia-Priselac R, Kovalev Y, et al. Patterns of hypocapnia on tilt in patients with fibromyalgia, chronic fatigue syndrome, nonspecific dizziness, and neurally mediated syncope. Am J Med Sci. 2006; 331(6):295-303.

[55] Wirth KJ, Scheibenbogen C, Paul F. An attempt to explain the neurological symptoms of myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2021; 19(1):471.

[56] Cao Y, Li Q. The variation of the 5-hydroxytryptamine system between chronic unpredictable mild stress rats and chronic fatigue syndrome rats induced by forced treadmill running. Neuroreport. 2017; 28(11):630-637.

[57] Shungu DC, Weiduschat N, Murrough JW, et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012; 25(9):1073-1087.

[58] Cabanas H, Muraki K, Eaton N, et al. Loss of transient receptor potential melastatin 3 ion channel function in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients. Mol Med. 2018; 24(1):44.

[59] Guenther S, Loebel M, Mooslechner AA, et al. Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome. Hum Immunol. 2015; 76(10):729-735.

[60] Bansal AS, Bradley AS, Bishop KN, et al. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2012; 26(1):24-31.

[61] Maes M, Mihaylova I, De Ruyter M. Lower serum zinc in chronic fatigue syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006; 90(2-3):141-147.

[62] Maes M, Twisk FN, Kubera M, et al. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012; 136(3):909-917.

[63] Armstrong CW, McGregor NR, Sheedy JR, et al. NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Clin Chim Acta. 2012; 413(19-20):1525-1531.

[64] Jerjes WK, Cleare AJ, Wessely S, et al. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J Affect Disord. 2005; 87(2-3):299-304.

[65] Thiagarajah AS, Eades LE, Thomas PR, et al. GILZ: Glitzing up our understanding of the glucocorticoid receptor in psychopathology. Brain Res. 2014; 1574:60-69.

[66] Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009; 22(1):75-83.

[67] Maes M. An intriguing and hitherto unexplained co-occurrence: depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(3):784-794.

[68] Maes M, Kubera M, Kotańska M. Aberrations in the cross-talks among redox, nuclear factor-κB, and Wnt/β-catenin pathway signaling underpin myalgic encephalomyelitis and chronic fatigue syndrome. Front Psychiatry. 2022; 13:822382.

[69] Suárez A, Guillamó E, Roig T, et al. Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt). 2010; 19(6):1073-1077.

[70] Corbitt M, Eaton-Fitch N, Staines D, et al. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol. 2019; 19(1):207.

[71] Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016; 113(37):e5472-e5480.

[72] Saury JM. The role of the hippocampus in the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses. 2016; 86:30-38.

[73] Zeineh MM, Kang J, Atlas SW, et al. Right arcuate fasciculus abnormality in chronic fatigue syndrome. Radiology. 2015; 274(2):517-526.

[74] Finkelmeyer A, He J, Maclachlan L, et al. Grey and white matter differences in chronic fatigue syndrome—a voxel-based morphometry study. Neuroimage Clin. 2018; 17:24-30.

[75] Thapaliya K, Marshall-Gradisnik S, Staines D, et al. Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans. Neuroimage Clin. 2020; 28:102366.

[76] Boissoneault J, Letzen J, Lai S, et al. Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study. Magn Reson Imaging. 2016; 34(4):603-608.

[77] Jones DE, Hollingsworth KG, Jakovljevic DG, et al. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. Eur J Clin Invest. 2012; 42(2):186-194.

[78] Brown AE, Jones DE, Walker M, et al. Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. PLoS One. 2015; 10(4):e0122982.

[79] Flynn JM, Meadows E, Fiorotto M, et al. Myogenin regulates exercise capacity and skeletal muscle metabolism in the adult mouse. PLoS One. 2010; 5(10):e13535.

[80] Kemp BE, Mitchelhill KI, Stapleton D, et al. Dealing with energy demand: the AMP-activated protein kinase. Trends Biochem Sci. 1999; 24(1):22-25.

[81] Yamano E, Sugimoto M, Hirayama A, et al. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. 2016; 6:34990.

[82] Brown AE, Dibnah B, Fisher E, et al. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Biosci Rep. 2018; 38(3):BSR20180242.

[83] Missailidis D, Annesley SJ, Fisher PR. Pathological mechanisms underlying myalgic encephalomyelitis/chronic fatigue syndrome. Diagnostics (Basel). 2019; 9(3):80.

[84] Nourbakhsh B, Azevedo C, Nunan-Saah J, et al. Longitudinal associations between brain structural changes and fatigue in early MS. Mult Scler Relat Disord. 2016; 5:29-33.

[85] Puri BK, Jakeman PM, Agour M, et al. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Br J Radiol. 2012; 85(1015):e270-e273.

[86] Okada T, Tanaka M, Kuratsune H, et al. Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol. 2004; 4(1):14.

[87] van der Schaaf ME, De Lange FP, Schmits IC, et al. Prefrontal structure varies as a function of pain symptoms in chronic fatigue syndrome. Biol Psychiatry. 2017; 81(4):358-365.

[88] Thapaliya K, Marshall-Gradisnik S, Staines D, et al. Diffusion tensor imaging reveals neuronal microstructural changes in myalgic encephalomyelitis/chronic fatigue syndrome. Eur J Neurosci. 2021; 54(6):6214-6228.

[89] Noda M, Ifuku M, Hossain MS, et al. Glial activation and expression of the serotonin transporter in chronic fatigue syndrome. Front Psychiatry. 2018; 9:589.

[90] Vangeel EB, Kempke S, Bakusic J, et al. Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients. J Psychosom Res. 2018; 104:55-60.

[91] Lynn M, Maclachlan L, Finkelmeyer A, et al. Reduction of glucocorticoid receptor function in chronic fatigue syndrome. Mediators Inflamm. 2018; 2018:3972104.

[92] Morris G, Anderson G, Maes M. Hypothalamic-pituitary-adrenal hypofunction in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) as a consequence of activated immune-inflammatory and oxidative and nitrosative pathways. Mol Neurobiol. 2017; 54(9):6806-6819.

[93] Griffith JP, Zarrouf FA. A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Prim Care Companion J Clin Psychiatry. 2008; 10(2):120-128.

[94] Curriu M, Carrillo J, Massanella M, et al. Screening NK-, B- and T-cell phenotype and function in patients suffering from chronic fatigue syndrome. J Transl Med. 2013; 11:68.

[95] Pontrelli P, Rascio F, Castellano G, et al. The role of natural killer cells in the immune response in kidney transplantation. Front Immunol. 2020; 11:1454.

[96] Gianchecchi E, Delfino DV, Fierabracci A. NK cells in autoimmune diseases: linking innate and adaptive immune responses. Autoimmun Rev. 2018; 17(2):142-154.

[97] Marchi S, Patergnani S, Missiroli S, et al. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium. 2018; 69:62-72.

[98] Park YJ, Yoo SA, Kim M, et al. The role of calcium-calcineurin-NFAT signaling pathway in health and autoimmune diseases. Front Immunol. 2020; 11:195.

[99] Cabanas H, Muraki K, Balinas C, et al. Validation of impaired transient receptor potential melastatin 3 ion channel activity in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients. Mol Med. 2019; 25(1):14.

[100] Loebel M, Strohschein K, Giannini C, et al. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS One. 2014; 9(1):e85387.

[101] Newberry F, Hsieh SY, Wileman T, et al. Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome? Clin Sci (Lond). 2018; 132(5):523-542.

[102] Roman P, Carrillo-Trabalón F, Sánchez-Labraca N, et al. Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review. Benef Microbes. 2018; 9(4):603-611.

[103] Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006; 333(7568):575.

[104] Fagundes CP, Glaser R, Alfano CM, et al. Fatigue and herpesvirus latency in women newly diagnosed with breast cancer. Brain Behav Immun. 2012; 26(3):394-400.

[105] Mantovani E, Mariotto S, Gabbiani D, et al. Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors? J Neurovirol. 2021; 27(4):631-637.

[106] Fluge O, Mella O, Bruland O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376.

[107] Wu Y, Wang Q, He Y. Study on administration law of HE Ying Chun’s differentiation and treatment of chronic fatigue syndrome. New Chin Med. 2020; 52(18):190-192.

[108] Conroy KE, Islam MF, Jason LA. Evaluating case diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): toward an empirical case definition. Disabil Rehabil. 2023; 45(5):840-847.

[109] Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011; 270(4):327-338.

[110] National Institute for Health and Care Excellence (NICE). Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. NICE guideline NG206. Published 29 October 2021. Available from: https://www.nice.org.uk/guidance/ng206 [Accessed December 2024].

[111] Kim DY, Lee JS, Park SY, et al. Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020; 18(1):7.

[112] Bureau NTS. Terminology of Traditional Chinese Medicine Clinical Diagnosis and Treatment: Syndrome Part. Beijing; 1997.

[113] Collatz A, Johnston SC, Staines DR, et al. A systematic review of drug therapies for chronic fatigue syndrome/myalgic encephalomyelitis. Clin Ther. 2016; 38(6):1263-1271.e9.

[114] Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev. 2000; 5(2):93-108.

[115] Vercoulen JH, Swanink CM, Zitman FG, et al. Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet. 1996; 347(9005):858-861.

[116] Cleare AJ, Heap E, Malhi GS, et al. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999; 353(9151):455-458.

[117] Stulemeijer M, de Jong LW, Fiselier TJ, et al. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ. 2005; 330(7481):14.

[118] Gotaas ME, Stiles TC, Bjørngaard JH, et al. Cognitive behavioral therapy improves physical function and fatigue in mild and moderate chronic fatigue syndrome: a consecutive randomized controlled trial of standard and short interventions. Front Psychiatry. 2021; 12:580924.

[119] Haines C, Loades M, Davis C. Illness perceptions in adolescents with chronic fatigue syndrome and other physical health conditions: application of the common sense model. Clin Child Psychol Psychiatry. 2019; 24(3):546-563.

[120] Gilbody S, Littlewood E, Hewitt C, et al. Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial. BMJ. 2015 Nov 11;351:h5627.

[121] Daniels J, Brigden A, Kacorova A. Anxiety and depression in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): examining the incidence of health anxiety in CFS/ME. Psychol Psychother. 2017; 90(3):502-509.

[122] Malouff JM, Thorsteinsson EB, Rooke SE, et al. Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: a meta-analysis. Clin Psychol Rev. 2008; 28(5):736-745.

[123] White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377(9768):823-836.

[124] Moss-Morris R, Sharon C, Tobin R, et al. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol. 2005; 10(2):245-259.

[125] Seo TB, Kim TW, Shin MS, et al. Aerobic exercise alleviates ischemia-induced memory impairment by enhancing cell proliferation and suppressing neuronal apoptosis in hippocampus. Int Neurourol J. 2014; 18(4):187-197.

[126] Vink M, Vink-Niese F. Graded exercise therapy does not restore the ability to work in ME/CFS—rethinking of a Cochrane review. Work. 2020; 66(2):283-308.

[127] Seton KA, Espejo-Oltra JA, Giménez-Orenga K, et al. Advancing research and treatment: an overview of clinical trials in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and future perspectives. J Clin Med. 2024; 13(2):325.

[128] Dai L, Liu Z, Zhou W, et al. Sijunzi decoction, a classical Chinese herbal formula, improves fatigue symptoms with changes in gut microbiota in chronic fatigue syndrome: a randomized, double-blind, placebo-controlled, multi-center clinical trial. Phytomedicine. 2024; 129:155636.

[129] Wang C, Tang X, Li C, et al. A multicenter randomized controlled clinical trial of Astragalus injection combined with Buzhong Yiqi acupuncture in the treatment of chronic fatigue syndrome with Qi deficiency syndrome. Chin J Exper Tradit Med Formulae. 2024(7):163-169.

[130] Yu XT, Yang WJ, Zhao N, et al. Acupuncture for delayed sleep-wake phase disorder: a randomized controlled trial. Zhongguo Zhen Jiu. 2023; 43(3):245-251.

[131] Sun D, Mingxia W, Xiaocheng N, et al. Curative effect of the combined therapy of acupuncture at back-shu-point of five organs and massage for chronic fatigue syndrome of liver stagnation spleen deficiency and the regulatory effect on immunity and dyslipidemia. Hebei J Tradit Chin Med. 2022; 44(2):275-279.

[132] Han L, Yan ZL, Hu MF. GSH-Px, Effects of Yishenqianggankangpi recipe on SOD, IFN-γ and immune function in patients with chronic fatigue syndrome(liver and kidney deficiency). Chin J Immunol. 2022; 38(7):853-858.

[133] Feng L, Zhenqin Z, Ling G, et al. Clinical observation of thunder and fire moxibustion on five zang shu in treating chronic fatigue syndrome. China’s Naturopathy. 2020; 28(11):52-55.

[134] Wang C.Clinical Observation on the Treatment of Spleen Deficiency and Dampness Obstruction Type CFS with Modifications of San Ren Tang and Si Jun Zi Tang. Gangdong: Guangzhou University of Traditional Chinese Medicine;. 2020.

[135] Liu J, Hu Y, Ying R, et al. Clinical efficacy of Chaihu Guizhi Decoction in the treatment of chronic fatigue syndrome of liver depression and spleen deficiency type and its influence on immune function of patients. Lishizhen Med Materia Med Res. 2019(6):1414-1416.

[136] Shi J. Clinical efficacy of Xiaoyao powder in the treatment of chronic fatigue syndrome of liver depression and spleen deficiency. Syst Med. 2019; 4(1):135-137.

[137] Tan Y.Observation on the Immune Function and Clinical Efficacy of Fuyang Fire Moxibustion in Yang Deficiency Chronic Fatigue Syndrome. Gangdong: Guangzhou University of Traditional Chinese Medicine;. 2019.

[138] MS S, QW T. Analysis of the treatment of chronic fatigue syndrome based on the idea of supporting Yang using moxibustion. J External Ther Tradit Chin Med. 2021; 30(2):94-95.

[139] XS X, W M, CL D, et al. Research progress on different moxibustion therapies for the treatment of chronic fatigue syndrome. J World Tradit Chin West Med. 2022; 17(1):209-212.

[140] Tian L, Wang J, Luo C, et al. Moxibustion at Gaohuang (BL 43) for chronic fatigue syndrome: a randomized controlled trial. Zhongguo Zhen Jiu. 2015; 35(11):1127-1130.

[141] Chen, Xu K, Zhou J, et al. Clinical observation on treating chronic fatigue syndrome by Moxibustion at Guanyuan and Qihai points. New Chin Med. 2011; 43(2):109-110.

[142] You J, Ye J, Li H, et al. Moxibustion for chronic fatigue syndrome: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2021; 2021:6418217.

[143] Xu X, Luojle X, Wei M, et al. Effect of medicinal cake moxibustion on immune proteins and T cell regulatory factors tim-3 and LAG-3 in rats with chronic fatigue syndrome. J Basic Chin Med. 2023; 29(10):1666-1671.

[144] Tingting MA, Jie WU, Lijie Y, et al. Ginger-indirect moxibustion plus acupuncture versus acupuncture alone for chronic fatigue syndrome: a randomized controlled trial. J Tradit Chin Med. 2022; 42(2):242-249.

[145] Xu J, Deng H, Shen X. Safety of moxibustion: a systematic review of case reports. Evid Based Complement Alternat Med. 2014; 2014:783704.

[146] Yin ZH, Wang LJ, Cheng Y, et al. Acupuncture for chronic fatigue syndrome: an overview of systematic reviews. Chin J Integr Med. 2021; 27(12):940-946.

[147] Pei-fang C, De-peng X, Ting-ting R, et al. Clinical study on acupuncture and moxibustion for chronic fatigue syndrome in middle-aged women. Shanghai J Acupunct Moxibustion. 2021; 40(10):1208-1211.

[148] Wang T, Xu C, Pan K, et al. Acupuncture and moxibustion for chronic fatigue syndrome in traditional Chinese medicine: a systematic review and meta-analysis. BMC Complement Altern Med. 2017; 17(1):163.

[149] Lin W, Chen XL, Chen Q, et al. Jin’s three-needle acupuncture technique for chronic fatigue syndrome: a study protocol for a multicentre, randomized, controlled trial. Trials. 2019; 20(1):155.

[150] Fang Y, Yue BW, Ma HB, et al. Acupuncture and moxibustion for chronic fatigue syndrome: a systematic review and network meta-analysis. Medicine (Baltim). 2022; 101(31):e29310.

[151] Wei F. Curative effect observation on abdominal massage for chronic fatigue syndrome with deficiency of heart and spleen. Chin J Urban Rural Enterprise Hyg. 2022; 37(5):166-168.

[152] Xia T, Lu DM, Tang HL, et al. Clinical observation of pivot meridian massage in the treatment of chronic fatigue syndrome. Liaoning J Tradit Chin Med. 2018; 45(6):1266-1268.

[153] Yuxin X. Back Shu points combined with head acupoint massage in the treatment of chronic fatigue syndrome. J Zhejiang Chin Med Univ. 2018; 42(6):491-493.

[154] Ren J, He T, Zhou X, et al. The effects of traditional Chinese manual therapy (Tuina) for chronic fatigue syndrome: a protocol for systematic review and meta-analysis. Medicine (Baltim). 2021; 100(44):e27700.

[155] Ma G, Zhao W, Wang H, et al. Clinical observation of modified Erxian decoction in the treatment of chronic fatigue syndrome. Chin Med Mod Distance Educ China. 2019; 17(2):72-74.

[156] Yang Y, Sun Z-R, Li C-R, et al. Effect of electroacupuncture on expression of protein phosphorylation in hippocampus tissues of rats with chronic fatigue syndrome. Zhen Ci Yan Jiu. 2024; 49(6):594-603.

[157] Wei X, Xin J, Chen W, et al. Astragalus polysaccharide ameliorated complex factor-induced chronic fatigue syndrome by modulating the gut microbiota and metabolites in mice. Biomed Pharmacother. 2023; 163:114862.

[158] Zhong XL, Tong BY, Yang YH, et al. Effect of transcutaneous electrical acupoint stimulation on learning and memory ability of chronic fatigue syndrome rats and its mechanisms. Zhen Ci Yan Jiu. 2023; 48(4):317-324.

[159] Lei C, Chen J, Huang Z, et al. Ginsenoside Rg1 can reverse fatigue behavior in CFS rats by regulating EGFR and affecting taurine and mannose 6-phosphate metabolism. Front Pharmacol. 2023; 14:1163638.

[160] Li T, Li X, Zhang J, et al. Chemical component analysis of the traditional Chinese medicine Guipi Tang and its effects on major depressive disorder at molecular level. Heliyon. 2022; 8(12):e12182.

[161] Miao X, Li S, Xiao B, et al. Metabolomics study of the effect of Danggui Buxue Tang on rats with chronic fatigue syndrome. Biomed Chromatogr. 2022; 36(7):e5379.

[162] Huang WY, Pan JH, Jeong I, et al. Antifatigue and anti-inflammatory effects of cervus elaphus L., Angelica gigas Nakai, and astragalus membranaceus bunge complex extracts in physically fatigued mice. J Med Food. 2022; 25(12):1126-1132.

[163] Araki R, Tachioka H, Kita A, et al. Kihito prevents corticosterone-induced brain dysfunctions in mice. J Tradit Complement Med. 2021; 11(6):513-519.

[164] Feng CW, Qu YY, Sun ZR, et al. Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome. Zhen Ci Yan Jiu. 2021; 46(9):775-781.

[165] Li X, Qin X-M, Tian J-S, et al. Integrated network pharmacology and metabolomics to dissect the combination mechanisms of Bupleurum chinense DC-Paeonia lactiflora Pall herb pair for treating depression. J Ethnopharmacol. 2021; 264:113281.

[166] Mu DZ, Xue M, Xu JJ, et al. Antidepression and prokinetic effects of paeoniflorin on rats in the forced swimming test via polypharmacology. Evid Based Complement Alternat Med. 2020; 2020:2153571.

[167] Li H, Sang L, Xia X, et al. Therapeutic duration and extent affect the effect of moxibustion on depression-like behaviour in rats via regulating the brain tryptophan transport and metabolism. Evid Based Complement Alternat Med. 2019; 2019:7592124.

[168] Li HN, Han YH, Liu Y, et al. Effect of abdominal massage on behavior and expression of BDNF and CREB in hippocampus of rats with chronic fatigue syndrome. J Basic Chin Med. 2019; 25(6):750-753.

[169] Li HN, Han YH, Liu Y, et al. Effects of abdominal massage on Ca^²⁺ concentration in the hippocampus and expression of MAPK and ERK proteins in a rat model of chronic fatigue syndrome. Liaoning J Tradit Chin Med. 2019; 46(9):1817-20.

[170] Yang Y, Delong W, Jing G, et al. Effect of electroacupuncture on behavior and pathomorphology of brain tissue in rats with chronic fatigue syndrome. China Med Her. 2018; 15(26):9-12.

[171] Wang YH, Wei XL, Song SL, et al. Effects of mechanical massage on behavior and serum IL-1 β IL-6 in rats with chronic fatigue syndrome of kidney deficiency type. Lishizhen Med Materia Med Res. 2018; 29(5):1235-1237.

[172] Chen XQ, Chen SJ, Liang WN, et al. Saikosaponin a attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress. Neurosci Lett. 2018; 662:283-289.

[173] Zhao D, Zhang J, Wang S, et al. Effect of Xiaoyao Pill on peripheral blood picture and hypothalamus pituitary adrenal axis in rats with blood deficiency and liver depression syndrome. Chin Tradit Herbal Drugs. 2017(16):3384-3389.

[174] Yu L, Zhengzheng X, Shengwei W, et al. Modified Xiaoyao San can improve ethology behave and inhabite inflammatory factor expression in hippocampus of depression rats. New Chin Med. 2017; 49(7):9-13.

[175] Cao G-P, Gui D, Fu L-D, et al. Anxiolytic and neuroprotective effects of the traditional Chinese Medicinal formulation Dan-zhi-xiao-yao-san in a rat model of chronic stress. Mol Med Rep. 2016; 14(2):1247-1254.

[176] Merzoug S, Toumi ML, Tahraoui A. Quercetin mitigates adriamycin-induced anxiety- and depression-like behaviors, immune dysfunction, and brain oxidative stress in rats. Naunyn Schmiedebergs Arch Pharmacol. 2014; 387(10):921-933.

[177] Lin H, Xu R, Tian M, et al. Effects of ginseng stem and leaf polysaccharides on serum free radical scavenging ability and anti fatigue ability in rats. J Liaoning Normal Univ (Nat Sci Ed). 2015(4):555-560.

[178] Qi B, Liu L, Zhang H, et al. Anti-fatigue effects of proteins isolated from Panax quinquefolium. J Ethnopharmacol. 2014; 153(2):430-434.

[179] Li Q, Wang L, Fang X, et al. Highly efficient biotransformation of notoginsenoside R1 into ginsenoside Rg 1 by dictyoglomus thermophilum β-xylosidase Xln-DT. J Microbiol Biotechnol. 2022; 32(4):447-457.

[180] Oh MS, Huh Y, Bae H, et al. The multi-herbal formula Guibi-tang enhances memory and increases cell proliferation in the rat hippocampus. Neurosci Lett. 2005; 379(3):205-208.

[181] Yu Y, Nie J, Zhao B, et al. Structure characterization and anti-fatigue activity of an acidic polysaccharide from Panax ginseng C. A. Meyer. J Ethnopharmacol. 2023; 301:115831.

[182] Zhang G, Lu B, Wang E, et al. Panax ginseng improves physical recovery and energy utilization on chronic fatigue in rats through the PI3K/AKT/mTOR signalling pathway. Pharm Biol. 2023; 61(1):316-323.

[183] Li X, Yang M, Zhang YL, et al. Ginseng and ginseng herbal formulas for symptomatic management of fatigue: a systematic review and meta-analysis. J Integr Complement Med. 2023; 29(8):468-482.

[184] Chen XY, Shao R, Wang Y. Multi-layered effects of Codonopsis Radix on the immune system. Acupunct and Herb Med. 2024; 4(3):405-419.

[185] Pan H, Zhao Z, Wen X. Effects of ginsenoside Rb1 and total ginsenosides on biochemical indexes of skeletal muscle in exercise-induced fatigue rats. J Nanjing Inst Phys Educ (Nat Sci Ed). 2010; 44(1):24-25.

[186] Zhang C, Guo W, Yao X, et al. Database mining and animal experiment-based validation of the efficacy and mechanism of radix astragali (Huangqi) and rhizoma atractylodis macrocephalae (Baizhu) as core drugs of traditional Chinese medicine in cancer-related fatigue. J Ethnopharmacol. 2022; 285:114892.

[187] He J, Yu Q, Wu C, et al. Acupuncture of the Beishu acupoint participates in regulatory effects of ginsenoside Rg1 on T cell subsets of rats with chronic fatigue syndrome. Ann Palliat Med. 2020; 9(5):3436-3446.

[188] Li J, Zhai X, Liu J, et al. Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome. Acupunct Herbal Med. 2024; 4(1):122-133.

[189] Jiao Y, Chen J, Hao F, et al. Ginseng pectin WGPA alleviates exercise-induced fatigue by enhancing gluconeogenesis. Evid Based Complement Altern Med. 2022; 2022:7973380.

[190] Chen J-B, Li M-J, Chen L-X, et al. Corrigendum to “Effects of Raphani Semen on anti-fatigue and pharmacokinetics of Panax ginseng “ Chinese herbal medicines 11 2019 308-313. Chin Herb Med. 2021; 13(2):290.

[191] Wang C-H, Lin C-Y, Chen J-S, et al. Karnofsky performance status as a predictive factor for cancer-related fatigue treatment with astragalus polysaccharides (PG2) injection-a double blind, multi-center, randomized phase IV study. Cancers (Basel). 2019; 11(2):128.

[192] Zhang G, Zhou S-M, Zheng S-J, et al. Astragalus on the anti-fatigue effect in hypoxic mice. Int J Clin Exp Med. 2015; 8(8):14030-14035.

[193] Yumel Z, Yang C, Xiaochao L, et al. A meta-analysis of effects of moxibustion on pro-inflammatory cytokines in animal model with rheumatoid arthritis. J Basic Chin Med. 2022; 28(7):1134-1139.

[194] Xu L, Xu X-Y, Hou X-Q, et al. Adjuvant therapy with Astragalus membranaceus for post-stroke fatigue: a systematic review. Metab Brain Dis. 2020; 35(1):83-93.

[195] Ahn S, Jamrasi P, Lim B, et al. Herbal extract (Cervus elaphus Linnaeus, Angelica gigas Nakai, and Astragalus membranaceus Bunge) ameliorates chronic fatigue: a randomized, placebo-controlled, double-blind trial. Integr Med Res. 2024; 13(4):101085.

[196] Joung J-Y, Lee J-S, Choi Y, et al. Evaluating myelophil, a 30% ethanol extract of Astragalus membranaceus and Salvia miltiorrhiza, for alleviating fatigue in long COVID: a real-world observational study. Front Pharmacol. 2024; 15:1394810.

[197] Yeh T-S, Chuang H-L, Huang W-C, et al. Astragalus membranaceus improves exercise performance and ameliorates exercise-induced fatigue in trained mice. Molecules. 2014; 19(3):2793-2807.

[198] Yu L, Zhen Z, Wu S, et al. Effects of Jiawei Xiaoyao powder on behavior and expression of inflammatory factors in hippocampus of depression rats. J New Chin Med. 2017(7):9-13.

[199] Jiang P, Ji X, Xia J, et al. Structure and potential anti-fatigue mechanism of polysaccharides from Bupleurum Chinense DC. Carbohydr Polym. 2023; 306:120608.

[200] Ishaque S, Shamseer L, Bukutu C, et al. Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complement Altern Med. 2012; 12:70

[201] Olsson EM, Schéele B von, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009; 75(2):105-112.

[202] Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine. 2010; 17(7):481-493.

[203] Wang J, Zhang G, Wang D, et al. Effects of nano-Rhodiola rosea combined with treadmill exercise on anti-exercise fatigue in rats. Front Nutr. 2024; 11:1446944.

[204] Jk M, We M. Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea. J Neural Transm (Vienna). 2024; 131(3):203-212.

[205] Luo C, Xu X, Wei X, et al. Natural medicines for the treatment of fatigue: bioactive components, pharmacology, and mechanisms. Pharmacol Res. 2019;148.

[206] Ivanova Stojcheva E, Quintela JC. The effectiveness of rhodiola rosea L. Preparations in alleviating various aspects of life-stress symptoms and stress-induced conditions-encouraging clinical evidence. Molecules. 2022; 27(12):3902.

[207] Yu-min L, Gang-hui J. Clinical efficacy of moxibustion at Qihai and Guanyuan acupoints for treatment of chronic fatigue syndromes and its influence on immune function of rats. Guangxi Med J. 2017; 39(10):1546-1549.

[208] Wu Y, Wang YJ, Li M, et al. Advances in research on immune mechanism of moxibustion for treating tumor. Zhen Ci Yan Jiu. 2020; 45(1):83-86.

[209] You-hong R, Lan Z, Jing H. Influence of moxibustion at Shenque on senile symptoms and melatonin. World J Acupunct Moxibustion. 2013; 23(2):6-10.

[210] Wang XY, Liu CZ, Lei B. Effect of acupuncture on the expression of transcription factor T-bet/GATA-3 in plasma of rats with chronic fatigue syndrome. Zhen Ci Yan Jiu. 2017; 42(3):246-248.