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Effect of ginseng and ginsenosides on attention deficit hyperactivity disorder: A systematic review

  • Yunna Kim (College of Korean Medicine, Kyung Hee University) ;
  • Ik-Hyun Cho (College of Korean Medicine, Kyung Hee University) ;
  • Seung-Hun Cho (College of Korean Medicine, Kyung Hee University)
  • Received : 2023.08.25
  • Accepted : 2024.05.23
  • Published : 2024.09.01

Abstract

Attention deficit hyperactivity disorder (ADHD) is a rapidly increasing neurodevelopmental disorder but currently available treatments are associated with abuse risk, side effects, and incomplete symptom relief. There is growing interest in exploring complementary options, and ginseng has gained attention for its therapeutic potential. This systematic review aimed to assess current evidence on the efficacy of ginseng and its active components, ginsenosides, for ADHD. Eligible studies were identified through searches of PubMed, Embase, Cochrane Library, and Web of Science, up to June 2023. The inclusion criteria included both human and animal studies that investigated the effects of ginseng or ginsenosides on ADHD. The risk of bias was assessed according to study type. Six human studies and three animal studies met the inclusion criteria. The results suggest that ginseng and ginsenosides may have beneficial effects on ADHD symptoms, particularly inattention, through dopaminergic/norepinephrinergicmodulation and BDNF/TrkB signaling. Ginseng and ginsenosides have promising potential for ADHD treatment. Due to limitations in evidence quality, such as the risk of bias and variability in study designs, larger controlled studies are essential. Integrating ginseng into ADHD management may have valuable implications for individuals seeking well-tolerated alternatives or adjunctive therapies.

Keywords

Acknowledgement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HF23C0179).

References

  1. Arnold LE, Hodgkins P, Kahle J, Madhoo M, Kewley G. Long-term outcomes of ADHD: academic achievement and performance. J Atten Disord 2020;24(1):73-85. https://doi.org/10.1177/1087054714566076
  2. Fuermaier ABM, Tucha L, Butzbach M, Weisbrod M, Aschenbrenner S, Tucha O. ADHD at the workplace: ADHD symptoms, diagnostic status, and work-related functioning. J Neural Transm 2021;128(7):1021-31. https://doi.org/10.1007/s00702-021-02309-z
  3. Cortese S. The association between ADHD and obesity: intriguing, progressively more investigated, but still puzzling. Brain Sci 2019;9(10):256.
  4. Zahid S, Bodicherla KP, Eskander N, Patel RS. Attention-deficit/hyperactivity disorder and suicidal risk in major depression: analysis of 141,530 adolescent hospitalizations. Cureus 2020;12(5):e7949.
  5. Faraone SV, Banaschewski T, Coghill D, Zheng Y, Biederman J, Bellgrove MA, Newcorn JH, Gignac M, Al Saud NM, Manor I, et al. The world federation of ADHD international Consensus statement: 208 evidence-based conclusions about the disorder. Neurosci Biobehav Rev 2021;128:789-818. https://doi.org/10.1016/j.neubiorev.2021.01.022
  6. National Health Insurance Service. 「Disturbance of activity and attention」, which can make interpersonal relationships difficult if left untreated into adulthood, increased by 92.9% since 2017 [Internet] National Health Insurance Service 2023 [cited 2023 Aug 7]. Available from: http://www.nhis.or.kr/nhis/together/wbhaea01600m01.do?mode=view&articleNo=10832473&title=%EC%84%B1%EC%9D%B8%EA%B9%8C%EC%A7%80+%EB%B0%A9%EC%B9%98%ED%95%98%EB%A9%B4+%EB%8C%80%EC%9D%B8%EA%B4%80%EA%B3%84%EA%B0%80+%ED%9E%98%EB%93%A0+%E3%80%8C%ED%99%9C%EB%8F%99%EC%84%B1+%EB%B0%8F+%EC%A3%BC%EC%9D%98%EB%A0%A5+%EC%9E%A5%EC%95%A0%E3%80%8D%E2%80%9817%EB%85%84+%EB%8C%80%EB%B9%84+92.9%25+%EC%A6%9D%EA%B0%80.
  7. Bitsko RH, Claussen AH, Lichstein J, Black LI, Jones SE, Danielson ML, Hoenig JM, Jack SPD, Brody DJ, Gyawali S. Mental health surveillance among children-United States, 2013-2019. Centers for Disease Control and Prevention 2022;71(2):1.
  8. Chung W, Jiang SF, Paksarian D, Nikolaidis A, Castellanos FX, Merikangas KR, Milham MP. Trends in the prevalence and incidence of attention-deficit/hyperactivity disorder among adults and children of different racial and ethnic groups. JAMA Netw Open 2019;2(11):e1914344.
  9. Sluiter MN, de Vries YA, Koning LG, Hak E, Bos JHJ, Schuiling-Veninga CCM, Batstra L, Doornenbal JM, de Jonge P. A prescription trend analysis of methylphenidate: relation to study reports on efficacy. Adm Policy Ment Health 2020;47(2):291-9. https://doi.org/10.1007/s10488-019-00983-6
  10. Pheils J, Ehret MJ. Update on methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder. Am J Health Syst Pharm 2021;78(10):840-9. https://doi.org/10.1093/ajhp/zxab069
  11. Mechler K, Banaschewski T, Hohmann S, Hage A. Evidence-based pharmacological treatment options for ADHD in children and adolescents. Pharmacol Therapeut 2022;230:107940.
  12. Shellenberg TP, Stoops WW, Lile JA, Rush CR. An update on the clinical pharmacology of methylphenidate: therapeutic efficacy, abuse potential and future considerations. Expet Rev Clin Pharmacol 2020;13(8):825-33. https://doi.org/10.1080/17512433.2020.1796636
  13. Danielson ML. Trends in stimulant prescription fills among commercially insured children and adults - United States, 2016-2021 [Internet] MMWR Morb Mortal Wkly Rep 2023 [cited 2023 Jul 31];72. Available from: https://www.cdc.gov/mmwr/volumes/72/wr/mm7213a1.htm.
  14. Lee SM, Cheong HK, Oh IH, Hong M. Nationwide rate of adult ADHD diagnosis and pharmacotherapy from 2015 to 2018. Int J Environ Res Publ Health 2021;18(21):11322.
  15. Wang Z, Zhang Z, Liu J, Guo M, Li H. Panax Ginseng in the treatment of Alzheimer's disease and vascular dementia. Journal of Ginseng Research 2023;47(4):506-14. https://doi.org/10.1016/j.jgr.2023.03.001
  16. Kim Y, Cho SH. The effect of ginsenosides on depression in preclinical studies: a systematic review and meta-analysis. Journal of Ginseng Research 2021;45(3):420-32. https://doi.org/10.1016/j.jgr.2020.08.006
  17. Hyun SH, Bhilare KD, In G, Park CK, Kim JH. Effects of Panax ginseng and ginsenosides on oxidative stress and cardiovascular diseases: pharmacological and therapeutic roles. Journal of Ginseng Research 2022;46(1):33-8. https://doi.org/10.1016/j.jgr.2021.07.007
  18. Huang Q, Lou T, Lu J, Wang M, Chen X, Xue L, Tang X, Qi W, Zhang Z, Su H, et al. Major ginsenosides from Panax ginseng promote aerobic cellular respiration and SIRT1-mediated mitochondrial biosynthesis in cardiomyocytes and neurons. Journal of Ginseng Research 2022;46(6):759-70. https://doi.org/10.1016/j.jgr.2022.02.002
  19. Jovanovski E, Smircic-Duvnjak L, Komishon A, Au-Yeung F (Rodney, Sievenpiper JL, Zurbau A, Jenkins AL, Sung MK, Josse R, Li D, et al. Effect of coadministration of enriched Korean Red Ginseng (Panax ginseng) and American ginseng (Panax quinquefolius L) on cardiometabolic outcomes in type-2 diabetes: a randomized controlled trial. Journal of Ginseng Research 2021;45(5):546-54. https://doi.org/10.1016/j.jgr.2019.11.005
  20. Yoon SJ, Kim SK, Lee NY, Choi YR, Kim HS, Gupta H, Youn GS, Sung H, Shin MJ, Suk KT. Effect of Korean red ginseng on metabolic syndrome. Journal of Ginseng Research 2021;45(3):380-9. https://doi.org/10.1016/j.jgr.2020.11.002
  21. He S, Lyu F, Lou L, Liu L, Li S, Jakowitsch J, Ma Y. Anti-tumor activities of Panax quinquefolius saponins and potential biomarkers in prostate cancer. Journal of Ginseng Research 2021;45(2):273-86. https://doi.org/10.1016/j.jgr.2019.12.007
  22. Kim H, Choi P, Kim T, Kim Y, Song BG, Park YT, Choi SJ, Yoon CH, Lim WC, Ko H, et al. Ginsenosides Rk1 and Rg5 inhibit transforming growth factor-β1-induced epithelial-mesenchymal transition and suppress migration, invasion, anoikis resistance, and development of stem-like features in lung cancer. Journal of Ginseng Research 2021;45(1):134-48.
  23. Hong JT, Lee MJ, Yoon SJ, Shin SP, Bang CS, Baik GH, Kim DJ, Youn GS, Shin MJ, Ham YL, et al. Effect of Korea red ginseng on nonalcoholic fatty liver disease: an association of gut microbiota with liver function. Journal of Ginseng Research 2021;45(2):316-24. https://doi.org/10.1016/j.jgr.2020.07.004
  24. Han NR, Ko SG, Moon PD, Park HJ. Ginsenoside Rg3 attenuates skin disorders via down-regulation of MDM2/HIF1α signaling pathway. Journal of Ginseng Research 2021;45(5):610-6.
  25. Lee MJ, Choi JH, Kwon TW, Jo HS, Ha Y, Nah SY, Cho IH. Korean Red Ginseng extract ameliorates demyelination by inhibiting infiltration and activation of immune cells in cuprizone-administrated mice. J Ginseng Res 2023;47(5):672-80. https://doi.org/10.1016/j.jgr.2023.05.001
  26. Alam MJ, Hossain MA, Bhilare KD, Kang CW, Kim JH. Korean Red Ginseng modulates immune function by upregulating CD4+CD8+ T cells and NK cell activities on porcine. Journal of Ginseng Research 2023;47(1):155-8. https://doi.org/10.1016/j.jgr.2022.10.002
  27. Ratan ZA, Youn SH, Kwak YS, Han CK, Haidere MF, Kim JK, Min H, Jung YJ, Hosseinzadeh H, Hyun SH, et al. Adaptogenic effects of Panax ginseng on modulation of immune functions. Journal of Ginseng Research 2021;45(1):32-40. https://doi.org/10.1016/j.jgr.2020.09.004
  28. Feng H, Xue M, Deng H, Cheng S, Hu Y, Zhou C. Ginsenoside and its therapeutic potential for cognitive impairment. Biomolecules 2022;12(9):1310.
  29. Geng J, Dong J, Ni H, Lee MS, Wu T, Jiang K, Wang G, Zhou AL, Malouf R. Ginseng for cognition. Cochrane Database Syst Rev 2010;(12):CD007769.
  30. Smith I, Williamson EM, Putnam S, Farrimond J, Whalley BJ. Effects and mechanisms of ginseng and ginsenosides on cognition. Nutr Rev 2014;72(5):319-33. https://doi.org/10.1111/nure.12099
  31. National Institutes of Health. Study Quality Assessment Tools-Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group [Internet]. [cited 2023 Jul 23]. Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.
  32. Ma LL, Wang YY, Yang ZH, Huang D, Weng H, Zeng XT. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Military Medical Research 2020;7(1):7.
  33. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol 2014;14:43.
  34. Macleod MR, O'Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004;35(5):1203-8. https://doi.org/10.1161/01.STR.0000125719.25853.20
  35. McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods 2021;12(1):55-61. https://doi.org/10.1002/jrsm.1411
  36. Lee J, Lee SI. Efficacy of omega-3 and Korean red ginseng in children with subthreshold ADHD: a double-blind, randomized, placebo-controlled trial. J Atten Disord 2021;25(14):1977-87. https://doi.org/10.1177/1087054720951868
  37. Ko HJ, Kim I, Kim JB, Moon Y, Whang MC, Lee KM, Jung SP. Effects of Korean red ginseng extract on behavior in children with symptoms of inattention and hyperactivity/impulsivity: a double-blind randomized placebo-controlled trial. J Child Adolesc Psychopharmacol 2014;24(9):501-8. https://doi.org/10.1089/cap.2014.0013
  38. Lee J, Lee A, Kim JH, Shin YM, Kim SJ, Cho WD, Lee SI. Effect of omega-3 and Korean red ginseng on children with attention deficit hyperactivity disorder: an open-label pilot study. Clinical Psychopharmacology and Neuroscience 2020;18(1):75-80. https://doi.org/10.9758/cpn.2020.18.1.75
  39. Lee SH, Park WS, Lim MH. Clinical effects of Korean red ginseng on attention deficit hyperactivity disorder in children: an observational study. Journal of Ginseng Research 2011;35(2):226-34. https://doi.org/10.5142/jgr.2011.35.2.226
  40. Niederhofer H. Panax ginseng may improve some symptoms of attention-deficit hyperactivity disorder. J Diet Suppl 2009;6(1):22-7. https://doi.org/10.1080/19390210802687221
  41. Lyon MR, Cline JC, Totosy de Zepetnek J, Shan JJ, Pang P, Benishin C. Effect of the herbal extract combination Panax quinquefolium and Ginkgo biloba on attention-deficit hyperactivity disorder: a pilot study. J Psychiatry Neurosci 2001;26(3):221-8.
  42. Nam Y, Shin EJ, Shin SW, Lim YK, Jung JH, Lee JH, Ha JR, Chae JS, Ko SK, Jeong JH, et al. YY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aroclor1254 via interactive signaling between antioxidant potential, BDNF/TrkB, DAT and NET. Food Chem Toxicol 2014;65:280-92. https://doi.org/10.1016/j.fct.2013.12.046
  43. Hu Y, Lin Z, Zheng F, Shi X. Effects of ginsenoside Rg1 on the content of dopamine and norepinephrine in the prefrontal cortex, striatum of SHR rats. Chinese Journal of Traditional Medical Science and Technology 2012;19(1):41-2.
  44. Kim HJ, Joo SH, Choi I, Kim P, Kim MK, Park SH, Cheong JH, Shin CY. Effects of red ginseng on neonatal hypoxia-induced hyperacitivity phenotype in rats. Journal of Ginseng Research 2010;34(1):8-16. https://doi.org/10.5142/JGR.2010.34.1.008
  45. Sarris J. Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytother Res 2018;32(7):1147-62. https://doi.org/10.1002/ptr.6055
  46. Corona JC. Natural compounds for the management of Parkinson's disease and attention-deficit/hyperactivity disorder. BioMed Res Int 2018;2018:4067597.
  47. Ahn J, Ahn HS, Cheong JH, Dela Pena I. Natural product-derived treatments for attention-deficit/hyperactivity disorder: safety, efficacy, and therapeutic potential of combination therapy. Neural Plast 2016;2016:1320423.
  48. Rucklidge JJ, Johnstone J, Kaplan BJ. Nutrient supplementation approaches in the treatment of ADHD. Expert Rev Neurother 2009;9(4):461-76. https://doi.org/10.1586/ern.09.7
  49. Epstein JN, Loren REA. Changes in the definition of ADHD in DSM-5: subtle but important. Neuropsychiatry 2013;3(5):455-8. https://doi.org/10.2217/npy.13.59
  50. Mowlem FD, Rosenqvist MA, Martin J, Lichtenstein P, Asherson P, Larsson H. Sex differences in predicting ADHD clinical diagnosis and pharmacological treatment. Eur Child Adolesc Psychiatr 2019;28(4):481-9. https://doi.org/10.1007/s00787-018-1211-3
  51. Fernandez-Quiros J, Lacasa-Cazcarra M, Alegre-Martin J, Sanmartin-Sentanes R, Almirall M, Launois-Obregon P, Castro-Marrero J, Rodriguez-Urrutia A, Navarro-Sanchis JA, Ramos-Quiroga JA. The Conners Continuous Performance Test CPT3TM: is it a reliable marker to predict neurocognitive dysfunction in Myalgic encephalomyelitis/chronic fatigue syndrome? Front Psychol 2023;14:1127193.
  52. Arrondo G, Mulraney M, Iturmendi-Sabater I, Musullulu H, Gambra L, Niculcea T, Banaschewski T, Simonoff E, Dopfner M, Hinshaw SP, et al. Systematic review and meta-analysis: clinical utility of continuous performance tests for the identification of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2024;63(2):154-71. https://doi.org/10.1016/j.jaac.2023.03.011
  53. Regan SL, Williams MT, Vorhees CV. Review of rodent models of attention deficit hyperactivity disorder. Neurosci Biobehav Rev 2022;132:621-37. https://doi.org/10.1016/j.neubiorev.2021.11.041
  54. Fasmer OB, Johansen EB. Patterns of motor activity in spontaneously hypertensive rats compared to Wistar Kyoto rats. Behav Brain Funct 2016;12(1):32.
  55. Gungor Aydin A, Adiguzel E. The mesocortical dopaminergic system cannot explain hyperactivity in an animal model of attention deficit hyperactivity disorder (ADHD)- Spontaneously hypertensive rats (SHR). Lab Anim Res 2023;39(1):20.
  56. Rahi V, Kumar P. Animal models of attention-deficit hyperactivity disorder (ADHD). Int J Dev Neurosci 2021;81(2):107-24. https://doi.org/10.1002/jdn.10089
  57. Zhou J, Zhang J, Cao L, Liu Y, Liu L, Liu C, Li X. Ginsenoside Rg1 modulates vesicular dopamine storage and release during exocytosis revealed with single-vesicle electrochemistry. Chem Commun 2023;59(21):3087-90. https://doi.org/10.1039/D2CC06950D
  58. Yao Y, Sang W, Yang X shi, Zhai M jing, li Wang L, you Qin P, Wu L, rong Zhou X, jun Wang L, yan Li J, et al. Antidepressant effects of ginsenosides from panax notoginseng. J Integr Agric 2012;11(3):483-8. https://doi.org/10.1016/S2095-3119(12)60034-3
  59. Shi J, Xue W, Zhao W jie, xin Li K. Pharmacokinetics and dopamine/acetylcholine releasing effects of ginsenoside Re in hippocampus and mPFC of freely moving rats. Acta Pharmacol Sin 2013;34(2):214-20. https://doi.org/10.1038/aps.2012.147
  60. Lin WM, Zhang YM, Moldzio R, Rausch WD. Ginsenoside Rd attenuates neuroinflammation of dopaminergic cells in culture. In: Gerlach M, Deckert J, Double K, Koutsilieri E, editors. Neuropsychiatric disorders an integrative Approach. Vienna: Springer; 2007. p. 105-12 [Journal of Neural Transmission. Supplementa)].
  61. Lee SH, Hur JY, Lee EJH, Kim SY. Ginsenoside Rb1 modulates level of monoamine neurotransmitters in mice frontal cortex and cerebellum in response to immobilization stress. Biomolecules & Therapeutics 2012;20(5):482-6. https://doi.org/10.4062/biomolther.2012.20.5.482
  62. Lu G, Yuan WX, Chen XJ. Effects of ginseng root saponins on serum corticosterone and brain neurotransmitters of mice under hypobaric and hypoxic environments. Acta Pharmacologica Sinica 1988;9(6):489-92.
  63. Kim YC, Lee JH, Kim MS, Lee NG. Effect of the saponin fraction of Panax ginseng on catecholamines in mouse brain. Arch Pharm Res (Seoul) 1985;8(1):45-8. https://doi.org/10.1007/BF02897566
  64. Itoh T, Zang YF, Murai S, Saito H. Effects of Panax ginseng root on the vertical and horizontal motor activities and on brain monoamine-related substances in mice. Planta Med 1989;55(5):429-33. https://doi.org/10.1055/s-2006-962058
  65. Xiang H, Liu Y, Zhang B, Huang J, Li Y, Yang B, Huang Z, Xiang F, Zhang H. The antidepressant effects and mechanism of action of total saponins from the caudexes and leaves of Panax notoginseng in animal models of depression. Phytomedicine 2011;18(8-9):731-8. https://doi.org/10.1016/j.phymed.2010.11.014
  66. Dang H, Chen Y, Liu X, Wang Q, Wang L, Jia W, Wang Y. Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression. Prog Neuro Psychopharmacol Biol Psychiatr 2009;33(8):1417-24. https://doi.org/10.1016/j.pnpbp.2009.07.020
  67. Zaafan MA, Abdelhamid AM, Ibrahim SM. The protective effect of Korean red ginseng against rotenone-induced Parkinson's disease in rat model: modulation of nuclear factor-κβ and caspase-3. Curr Pharmaceut Biotechnol 2019;20(7):588-94. https://doi.org/10.2174/1389201020666190611122747
  68. Kim D, Jeon H, Ryu S, Koo S, Ha KT, Kim S. Proteomic analysis of the effect of Korean red ginseng in the striatum of a Parkinson's disease mouse model. PLoS One 2016;11(10):e0164906.
  69. Jun YL, Bae CH, Kim D, Koo S, Kim S. Korean Red Ginseng protects dopaminergic neurons by suppressing the cleavage of p35 to p25 in a Parkinson's disease mouse model. Journal of Ginseng Research 2015;39(2):148-54. https://doi.org/10.1016/j.jgr.2014.10.003
  70. Van Kampen J, Robertson H, Hagg T, Drobitch R. Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson's disease. Exp Neurol 2003;184(1):521-9. https://doi.org/10.1016/j.expneurol.2003.08.002
  71. Van Kampen JM, Baranowski DB, Shaw CA, Kay DG. Panax ginseng is neuroprotective in a novel progressive model of Parkinson's disease. Exp Gerontol 2014;50:95-105. https://doi.org/10.1016/j.exger.2013.11.012
  72. Ge KL, Chen WF, Xie JX, Wong MS. Ginsenoside Rg1 protects against 6-OHDA-induced toxicity in MES23.5 cells via Akt and ERK signaling pathways. J Ethnopharmacol 2010;127(1):118-23. https://doi.org/10.1016/j.jep.2009.09.038
  73. Gao QG, Chen WF, Xie JX, Wong MS. Ginsenoside Rg1 protects against 6-OHDA-induced neurotoxicity in neuroblastoma SK-N-SH cells via IGF-I receptor and estrogen receptor pathways. J Neurochem 2009;109(5):1338-47. https://doi.org/10.1111/j.1471-4159.2009.06051.x
  74. Zhou T, Zu G, Zhang X, Wang X, Li S, Gong X, Liang Z, Zhao J. Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson's disease. Neuropharmacology 2016;101:480-9. https://doi.org/10.1016/j.neuropharm.2015.10.024
  75. Radad K, Gille G, Moldzio R, Saito H, Ishige K, Rausch WD. Ginsenosides Rb1 and Rg1 effects on survival and neurite growth of MPP+-affected mesencephalic dopaminergic cells. J Neural Transm 2004;111(1):37-45. https://doi.org/10.1007/s00702-003-0063-1
  76. Hsieh WT, Chiang BH. A well-refined in vitro model derived from human embryonic stem cell for screening phytochemicals with midbrain dopaminergic differentiation-boosting potential for improving Parkinson's disease. J Agric Food Chem 2014;62(27):6326-36. https://doi.org/10.1021/jf501640a
  77. Luo FC, Wang SD, Qi L, Song JY, Lv T, Bai J. Protective effect of panaxatriol saponins extracted from Panax notoginseng against MPTP-induced neurotoxicity in vivo. J Ethnopharmacol 2011;133(2):448-53. https://doi.org/10.1016/j.jep.2010.10.017
  78. China Association of Chinese Medicine. Clinical diagnosis and treatment guidelines of mental diseases for integrated Chinese and western medicine-attention-deficit hyperactivity disorder. China Association of Chinese Medicine 2022:7.
  79. Jang K, Lee S, Lee J, Cho SH, Min S, Yoo S, Kim K, Chun J, Sung H, Jung M, et al. Clinical practice guideline of Korean medicine-autism spectrum disorder. Seoul: National Institute for Korean Medicine Development; 2021.
  80. Ju J, Seok JH, Moon H. An analysis of factors affecting healthy Food consumption intention and behavior: focusing on ginseng and red ginseng products. J Rural Dev 2022;45(2):41-64.
  81. Lee H, Shim SB, Lee JA, Sung H, Song J, Ahn H, Lee H. Clinical practice guideline of Korean medicine-childhood and adolescent growth disorder. Seoul: National Institute for Korean Medicine Development; 2022.
  82. Yuan B, Bai XH, Chen H, Zhai WS, Jiang YH, Li M, Li YN, Wang LN, Wang MQ, Wang YP, et al. Guideline for the Diagnosis and Treatment of Pediatric Viral Pneumonia in Chinese Medicine (Revision). J Nanjing Univ Tradit Chin Med 2023;39(3):293-300.
  83. Task Force for Evidence Report (ER -TF) Committee for EBM The Japan Society for Oriental Medicine (JSOM). Evidence reports of kampo treatment 2022 : 553 randomized controlled trials (EKAT2022). 2023.
  84. Baeg IH, So SH. The world ginseng market and the ginseng (Korea). J Ginseng Res 2013;37(1):1-7. https://doi.org/10.5142/jgr.2013.37.1
  85. European Medicines Agency. Final community herbal monograph on panax ginseng C.A. Meyer, radix. Amsterdam: committee on herbal medicinal products (HMPC). European Medicines Agency; 2018 Apr. Report No.: EMA/HMPC/321233/2012 Corr.1.
  86. Lee JM, Hah JO, Kim HS. The effect of red ginseng extract on inflammatory cytokines after chemotherapy in children. J Ginseng Res. 2012;36(4):383-90. https://doi.org/10.5142/jgr.2012.36.4.383
  87. Vohra S, Johnston BC, Laycock KL, Midodzi WK, Dhunnoo I, Harris E, Baydala L. Safety and tolerability of North American ginseng extract in the treatment of pediatric upper respiratory tract infection: a phase II randomized, controlled trial of 2 dosing schedules. Pediatrics 2008;122(2):e402-10. https://doi.org/10.1542/peds.2007-2186
  88. Laboratory Animal Center, National Cheng Kung University College of Medicine. Weight to age-in-week table for rat [internet]. 1998 [cited 2024 Jan 9]. Available from: https://animal.ncku.edu.tw/p/412-1130-16363.php?Lang=en.
  89. U.S. Environmental Protection Agency. Recommended use of body weight 3/4 as the default method in derivation of the oral reference dose. Washington, DC: US Environmental Protection Agency; 2011.
  90. Nair A, Morsy M, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res 2018;79:373-82. https://doi.org/10.1002/ddr.21461
  91. Germovsek E, Barker CIS, Sharland M, Standing JF. Scaling clearance in paediatric pharmacokinetics: all models are wrong, which are useful? Br J Clin Pharmacol 2017;83(4):777-90. https://doi.org/10.1111/bcp.13160
  92. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharmaceut Sci 2013;102(9):2941-52. https://doi.org/10.1002/jps.23574
  93. World Health Organization. Growth reference 5-19 years - weight-for-age (5-10 years) [cited 2024 Jan 8]. Available from: https://www.who.int/tools/growth-reference-data-for-5to19-years/indicators/weight-for-age-5to10-years; 2007.
  94. So SH, Lee JW, Kim YS, Hyun SH, Han CK. Red ginseng monograph. Journal of Ginseng Research 2018;42(4):549-61.
  95. National Herbal Medicine Information (NHMI). National herbal medicine information (NHMI): ginseng radix [Internet]. National Herbal Medicine Information (NHMI) 2018 [cited 2024 May 22]. Available from: https://nifds.go.kr/nhmi/hbdc/ofcmhbdc/view.do?selectedDmstcOfcmNo=400&selectedMdntfNo=750.
  96. Ministry of Food and Drug Safety. Dietary supplement ingredient information: red ginseng [Internet]. Ministry of Food and Drug Safety; 2017 [cited 2024 May 22]. Available from: https://www.foodsafetykorea.go.kr/portal/board/boardDetail.do?menu_grp=MENU_NEW01&menu_no=2660&bbs_no=bbs987&nticmatr_yn=N&bbs_type_cd=01&ans_yn=N&ntctxt_no=1062817.
  97. Kim HJ, Oh TK, Kim YH, Lee J, Moon JM, Park YS, Sung CM. Pharmacokinetics of ginsenoside Rb1, Rg3, Rk1, Rg5, F2, and compound K from red ginseng extract in healthy Korean volunteers. Evid Based Complement Alternat Med 2022;2022:8427519.
  98. Shin MB, Kim SA, Lee S, Shim WS, Lee KT, Lee SK, Yim SV, Kim BH. Pharmacokinetic comparison of ginsenosides between fermented and non-fermented red ginseng in healthy volunteers. Pharmaceutics 2022;14(12):2807.
  99. Wolraich ML, Hagan Jr JF, Allan C, Chan E, Davison D, Earls M, Evans SW, Flinn SK, Froehlich T, Frost J, et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics 2019;144(4):e20192528.
  100. Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M. Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with Korean red ginseng. J Ginseng Res. 2011;35(4):457-61. https://doi.org/10.5142/jgr.2011.35.4.457
  101. Lee ST, Chu K, Sim JY, Heo JH, Kim M. Panax ginseng enhances cognitive performance in alzheimer disease. Alzheimer Dis Assoc Disord 2008;22(3):222.
  102. National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management. National Institute for Health and Care Excellence; 2018.
  103. Kawabe K, Horiuchi F, Matsumoto Y, Inoue S, Okazawa M, Hosokawa R, Nakachi K, Soga J, Ueno S. Practical clinical guidelines and pharmacological treatment for attention-deficit hyperactivity disorder in Asia. Neuropsychopharm Rep 2024;44(1):29-33. https://doi.org/10.1002/npr2.12381
  104. Kooij JJS, Bijlenga D, Salerno L, Jaeschke R, Bitter I, Balazs J, Thome J, Dom G, Kasper S, Nunes Filipe C, et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatr 2019;56:14-34. https://doi.org/10.1016/j.eurpsy.2018.11.001
  105. Coghill D, Banaschewski T, Cortese S, Asherson P, Brandeis D, Buitelaar J, Daley D, Danckaerts M, Dittmann RW, Doepfner M, et al. The management of ADHD in children and adolescents: bringing evidence to the clinic: perspective from the European ADHD Guidelines Group (EAGG). Eur Child Adolesc Psychiatr 2021:1-25.
  106. May T, Birch E, Chaves K, Cranswick N, Culnane E, Delaney J, Derrick M, Eapen V, Edlington C, Efron D, et al. The Australian evidence-based clinical practice guideline for attention deficit hyperactivity disorder. Aust N Z J Psychiatr 2023;57(8):1101-16.
  107. Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, Atkinson LZ, Tessari L, Banaschewski T, Coghill D, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatr 2018;5(9):727-38. https://doi.org/10.1016/S2215-0366(18)30269-4
  108. Mariage PA, Hovhannisyan A, Panossian AG. Efficacy of Panax ginseng Meyer herbal preparation HRG80 in preventing and mitigating stress-induced failure of cognitive functions in healthy subjects: a pilot, randomized, double-blind, placebo-controlled crossover trial. Pharmaceuticals 2020;13(4):57.
  109. Wang N, Yang J, Chen R, Liu Y, Liu S, Pan Y, Lei Q, Wang Y, He L, Song Y, et al. Ginsenoside Rg1 ameliorates Alzheimer's disease pathology via restoring mitophagy. Journal of Ginseng Research 2023;47(3):448-57. https://doi.org/10.1016/j.jgr.2022.12.001
  110. Dong X, Kong L, Huang L, Su Y, Li X, Yang L, Ji P, Li W, Li W. Ginsenoside Rg1 treatment protects against cognitive dysfunction via inhibiting PLC-CN-NFAT1 signaling in T2DM mice. Journal of Ginseng Research 2023;47(3):458-68. https://doi.org/10.1016/j.jgr.2022.12.006
  111. Zhang H, Su Y, Sun Z, Chen M, Han Y, Li Y, Dong X, Ding S, Fang Z, Li W, et al. Ginsenoside Rg1 alleviates Aβ deposition by inhibiting NADPH oxidase 2 activation in APP/PS1 mice. Journal of Ginseng Research 2021;45(6):665-75. https://doi.org/10.1016/j.jgr.2021.03.003
  112. Kim M, Mok H, Yeo WS, Ahn JH, Choi YK. Role of ginseng in the neurovascular unit of neuroinflammatory diseases focused on the blood-brain barrier. Journal of Ginseng Research 2021;45(5):599-609. https://doi.org/10.1016/j.jgr.2021.02.003
  113. Sng KS, Li G, yun Zhou L, jia Song Y, Chen X qing, Wang Y jun, Yao M, Cui X jun. Ginseng extract and ginsenosides improve neurological function and promote antioxidant effects in rats with spinal cord injury: a meta-analysis and systematic review. Journal of Ginseng Research 2022;46(1):11-22. https://doi.org/10.1016/j.jgr.2021.05.009
  114. Kim JK, Shin KK, Kim H, Hong YH, Choi W, Kwak YS, Han CK, Hyun SH, Cho JY. Korean Red Ginseng exerts anti-inflammatory and autophagy-promoting activities in aged mice. Journal of Ginseng Research 2021;45(6):717-25. https://doi.org/10.1016/j.jgr.2021.03.009