Influência do uso de canabinoides na concentração de citocinas inflamatórias na esclerose múltipla: uma revisão sistemática e meta-análise

Influence of cannabinoids use on inflammatory cytokine concentrations in multiple sclerosis: a systematic review and meta-analysis

Authors

  • Rodrigo Gentil Miquilino de Oliveira Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil. https://orcid.org/0009-0002-5187-9484
  • Isabela Camporioni Stacanelli Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.
  • Daniel Ferreira Fagundes Departamento de Clínica Médica, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.
  • Mariléia Chaves Andrade Andrade Departamento de Fisiopatologia, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil. https://orcid.org/0000-0002-4496-7331
  • Waldemar de Paula Júnior de Paula Departamento de Fisiopatologia, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.

Keywords:

Cannabis, Cannabis Medicinal, Citocinas, Esclerose Múltipla, Doenças Autoimunes

Abstract

Introdução: A Cannabis sativa contém diversos canabinoides, especialmente THC e CBD, que apresentam potencial farmacológico. A esclerose múltipla caracteriza-se por desmielinização associada à ativação anômala de linfócitos T CD4⁺/CD8⁺, produção de autoanticorpos por linfócitos B e falhas na regulação das células T reguladoras, resultando em inflamação e dano neuronal. Apesar dos avanços terapêuticos, persistem limitações, tornando os canabinoides uma alternativa promissora. Objetivo: Avaliar os efeitos do uso de canabinoides no perfil secretório de citocinas na esclerose múltipla. Material e Métodos: Revisão sistemática e meta-análise conduzida segundo PRISMA, abrangendo ensaios clínicos, coortes e caso-controle publicados até setembro de 2025, nas bases de dados PubMed, Cochrane e Scielo. A seleção e avaliação dos artigos foram realizadas por pesquisadores independentes, utilizando ferramentas para avaliação de risco de viés. A meta-análise utilizou RevMan 4.2.2 e o pacote meta. Calculou-se diferenças com IC 95% e a heterogeneidade foi avaliada pelo teste I². Resultados: A revisão sistemática incluiu sete artigos. Desses, três estavam aptos à meta-análise. Nos grupos de indivíduos portadores de esclerose múltipla que faziam uso de canabinoides, houve uma elevação significativa da IL-17 (-1,09; IC 0,88–1,29), aumento global do TNF-α (22,61; IC 21,09–24,13), elevação dos níveis de IL-12 (41,36; IC 38,24–44,49) e pouco efeito estatístico para o IFN-γ (−0,01; IC −0,04–0,01). Conclusão: Embora o uso de canabinoides tenha alterado o padrão secretório de citocinas inflamatórias, os resultados devem ser interpretados com cautela devido à elevada heterogeneidade entre os estudos e a escassez de padronização dos compostos e das doses. Apesar do benefício clínico descrito para dor e espasticidade, os seus efeitos imunomoduladores da cannabis medicinal na autoimunidade permanecem inconclusivos.

Downloads

Download data is not yet available.

Author Biographies

Rodrigo Gentil Miquilino de Oliveira, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.

He completed high school in 2021 at the Federal University of Viçosa's College of Application (CAP-COLUNI - UFV). He is currently a seventh-semester medical student at the State University of Montes Claros (Unimontes). He has been a scolarship researcher since 2023, specializing in Immunology, Metabolism, and Public Health. He is a student representative on the Medical School Board at the Mário Ribeiro Academic Center (CAMR), a Semiology tutor for the Medical School, an extension worker, and secretary of Sensibilizarte. He is also the scientific director of the Academic League of Palliative Care (LACP). He is participating in a research project on food and nutritional security in Montes Claros, funded by FAPEMIG. He is the general coordinator of CLEV-Unimontes (Local Coordination of Internships and Experiences). He was a member (2023) and treasurer (2024) of Sensibilizarte, president of LACP (2024) and member of PET-Saúde Equidade (2024-2025).

Isabela Camporioni Stacanelli, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.

Medical student at the State University of Montes Claros (Unimontes). Undergraduate teaching assistant in Biochemistry and Metabolism (2021) and a research volunteer (2021-2022), in the area of ​​Immunology. She is currently director and member of the Academic League of Psychiatry of Montes Claros (LAPMOC).

Daniel Ferreira Fagundes, Departamento de Clínica Médica, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.

Master in Neurology from the Fluminense Federal University - UFF (2020). Neurologist graduated from Santa Casa de Belo Horizonte (2015). Specialist in Headaches and Epilepsies from Santa Casa de Belo Horizonte (2016). Graduated in Medicine from the State University of Montes Claros (2011). Preceptor of the Internal Medicine Residency, Geriatrics Residency and Psychiatry Residency at the Clemente de Faria University Hospital. Preceptor of the Neurology Outpatient Clinic of the Medical School at the State University of Montes Claros (UNIMONTES). Professor of the Medical School at the State University of Montes Claros (UNIMONTES). Preceptor of the Neurology Outpatient Clinic of the Medical School at UniFIPMOC. Professor of the Medical School at UniFIPMOC. Coordinator of the Neurology Service and the Stroke Unit at Santa Casa de Montes Claros. Neurologist at the Clemente de Faria University Hospital. Vice-President of the Minas Gerais Chapter of the Brazilian Academy of Neurology - ABN (2020-2022). Member of the Board of Directors of the Minas Gerais Society of Neurology - SMN. Full Member of the Brazilian Academy of Neurology - ABN.

Mariléia Chaves Andrade Andrade, Departamento de Fisiopatologia, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.

She holds a degree in Biological Sciences from the Federal University of Minas Gerais (1995), a master's degree in Immunology from the Federal University of Minas Gerais (1999), a PhD in Immunology from the Federal University of Minas Gerais (2003), and a post-doctorate from the René Rachou Research Center-FIOCRUZ-MG (2006). She is currently a professor at the State University of Montes Claros-UNIMONTES, part of the faculty of the Postgraduate Program in Health Sciences strictu sensu, a professor at the Itajubá School of Medicine-FMIT, and a collaborating researcher at the René Rachou Research Center-FIOCRUZ-MG. She has experience in basic Immunology, working mainly on the following topics: Mucosal Immunology, Oral Tolerance, Food Allergy; and in the area of ​​Immunoparasitology, with an emphasis on Chagas disease and Leishmaniasis. In September 2015, she completed her postdoctoral studies at the University of Santiago de Compostela-USC, Spain, under the supervision of Dr. Arturo Gonzalez Quintela. In 2020, she participated in the Technical Committee on Health of Minas Gerais Health of the Regional Council of Biology of the 4th Region-CRBio-04, and as a member in 2021 and 2022.

Waldemar de Paula Júnior de Paula, Departamento de Fisiopatologia, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brasil.

He holds a degree in Pharmacy-Biochemistry from the University of Ribeirão Preto (1997), a Master's degree in Pharmaceutical Sciences from the Federal University of Paraná (2004) and a Master's degree in Pharmaceutical Sciences from the Federal University of Ouro Preto (2022). He was coordinator of the Pharmacy Course at Faculdades Santo Agostinho (Montes Claros) from 2006 to 2017. He was coordinator of the League of Immunology of Infectious and Autoimmune Diseases at Unimontes from 2018 to 2023. He served as Regional Counselor of the Regional Pharmacy Council of Minas Gerais from 2016 to 2019 and as Director of the Secretariat and Treasury of CRFMG in 2019. Coordinator of the Extension Project in Scientific Research for the Biological and Health Areas since 2023. Professor of Higher Education at the State University of Montes Claros since 1998, Department of Pathophysiology acting as Immunology disciplines for the Nursing course and as Tutor of the Mechanisms of Aggression and Defense module of the Medical Course. He is a member of the construction team of the second period of the Medical Course at Unimontes and advises numerous scientific initiation students. He has experience in pharmaceutical education, active methodologies, immunology, project development, management and scientific writing.

References

Hoch E, Volkow ND, Friemel CM, Lorenzetti V, Freeman TP, Hall W. Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits. Eur Arch Psychiatry Clin Neurosci. 2024 Sep 19; 275. DOI: 10.1007/s00406-024-01880-2.

Petzke F, Tölle T, Fitzcharles MA, Häuser W. Cannabis-based medicines and medical cannabis for chronic neuropathic pain. CNS Drugs. 2021 Nov 21; 36(1) DOI: 10.1007/s40263-021-00879-w.

Nachnani R, Raup-Konsavage WM, Vrana KE. The pharmacological case for cannabigerol. J Pharmacol Exp Ther. 2021 Feb 1; 376(2):204-12. DOI: 10.1124/jpet.120.000340.

Bautista JL, Yu S, Tian L. Flavonoids in Cannabis sativa: biosynthesis, bioactivities, and biotechnology. ACS Omega. 2021 Feb 18; 6(8):5119-23. DOI: 10.1021/acsomega.1c00318.

Mujahid K, Rasheed MS, Sabir A, Nam J, Ramzan T, Ashraf W, et al. Cannabidiol as an immune modulator: A comprehensive review. Saudi Pharmaceutical Journal. 2025 May 23; 33(3). DOI: 10.1007/s44446-025-00005-7.

Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The endocannabinoid system: a potential target for the treatment of various diseases. Int J Mol Sci. 2021 Aug 31; 22(17):9472. DOI: 10.3390/ijms22179472.

Lu HC, Mackie K. Review of the endocannabinoid system. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Aug; 6(6). DOI: 10.1016/j.bpsc.2020.07.016.

Rezende B, Alencar AKN, Bem GF, Fontes-Dantas FL, Montes GC. Endocannabinoid system: chemical characteristics and biological activity. Pharmaceuticals (Basel). 2023 Jan 19; 16(2):148. DOI: 10.3390/ph16020148.

Finn DP, Haroutounian S, Hohmann AG, Krane E, Soliman N, Rice ASC. Cannabinoids, the endocannabinoid system, and pain. Pain. 2021 Mar 15; 162(Suppl 1):S5-S25. DOI: 10.1097/j.pain.0000000000002268.

Peters KZ, Cheer JF, Tonini R. Modulating the neuromodulators: dopamine, serotonin, and the endocannabinoid system. Trends Neurosci. 2021 Jun 1; 44(6):464-77. DOI: 10.1016/j.tins.2021.02.001.

Maccarrone M, Di Marzo V, Gertsch J, Grether U, Howlett AC, Hua T, et al. Goods and bads of endocannabinoid system as a therapeutic target: lessons learned after 30 years. Pharmacol Rev. 2023 May 10;75(3):000600. DOI: 10.1124/pharmrev.122.000600.

Khayat W, Lehmann C. The endocannabinoid system: a potential therapeutic target for coagulopathies. Metabolites. 2022 Jun 14; 12(6):541. DOI: 10.3390/metabo12060541.

Amin M, Hersh CM. Updates and advances in multiple sclerosis neurotherapeutics. Neurodegener Dis Manag. 2022 Oct 31; 13(1). DOI: 10.2217/nmt-2021-0058.

Ghosh R, Roy D, Dubey S, Das S, Benito-León J. Movement disorders in multiple sclerosis: an update. Tremor Other Hyperkinet Mov (N Y). 2022 May 4; 12(1):14. DOI: 10.5334/tohm.671.

Liu R, Du S, Zhao L, Jain S, Sahay K, Rizvanov A, et al. Autoreactive lymphocytes in multiple sclerosis: pathogenesis and treatment target. Front Immunol. 2022 Sep 23; 13:000000. DOI: 10.3389/fimmu.2022.996469.

Yong VW. Microglia in multiple sclerosis: protectors turn destroyers. Neuron. 2022 Jul; 110(21). DOI: 10.1016/j.neuron.2022.06.023.

Montague T, Drummond J, Ng K, Parratt J. Advancements in multiple sclerosis. Intern Med J. 2025 Apr 2. DOI: 10.1111/imj.70023.

Sampaio MFS Paiva YB, Sampaio TB, Pereira MG, Coimbra NC. Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease and in comorbidity with psychiatric disorders. Basic Clin Pharmacol Toxicol. 2024 Mar 13. DOI: 10.1111/bcpt.13997.

Furgiuele A, Cosentino M, Ferrari M, Marino F. Immunomodulatory potential of cannabidiol in multiple sclerosis: a systematic review. J Neuroimmune Pharmacol. 2021 Jan 25. DOI: 10.1007/s11481-021-09982-7.

Almuntashiri N, El Sharazly BM, Carter WG. Are Cannabis-Based Medicines a Useful Treatment for Neuropathic Pain? A Systematic Review. Biomolecules. 2025 Apr;15(6):816. DOI: 10.3390/biom15060816.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guide-line for reporting systematic reviews. BMJ. 2021; 372:n71. DOI: 10.1136/bmj.n71.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898. DOI: 10.1136/bmj.l4898.

Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology. 2010 Jul 22; 25(9):603–5. DOI: 10.1007/s10654-010-9491-z.

Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355(355):i4919. DOI: 10.1136/bmj.i4919.

RStudio Team. RStudio Integrated Development for R. RStudio, PBC, Boston [Internet]. 2020 Aug 4. Disponível em: https://www.scirp.org/reference/referencespapers?referenceid=3542223.

Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evidence Based Mental Health. 2019 Sep 28; 22(4):153–60. DOI: 10.1136/ebmental-2019-300117.

Roever L. Compreendendo os estudos de metanálise na pesquisa clínica [Internet]. 2016 Dec 1; 14(4). 2025 Aug 4. Disponível em: https://www.researchgate.net/publication/311271419_Compreendendo_os_estudos_de_metanalise_na_pesquisa_clinica.

Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis [Internet]. 2009 Mar 13. 2025 Aug 7. Disponível em: https://onlinelibrary.wiley.com/doi/book/10.1002/9780470743386.

Rodrigues CL, Ziegelmann PK. Metanálise: um guia prático. Rev HCPA & Fac Med Univ Fed Rio Gd do Sul [Internet]. 2024;436–47. 2025 Aug 7. Disponível em: https://pesquisa.bvsalud.org/portal/resource/pt/biblio-834369.

Katona S, Kaminski E, Sanders H, Zajicek J. Cannabinoid influence on cytokine profile in multiple sclerosis. Clinical and Experimental Immunology. 2005 May 3; 140(3):580–5. DOI: 10.1111/j.1365-2249.2005.02803.x.

Killestein J, Hoogervorst ELJ, Reif M, Blauw B, Smits M, Uitdehaag BMJ, et al. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. Journal of Neuroimmunology. 2003 Apr; 137(1-2):140–3. DOI: 10.1016/s0165-5728(03)00045-6.

Meuth SG, Henze T, Essner U, Trompke C, Vila Silván C. Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial. International Journal of Neuroscience. 2020 Mar 1; 1–7. DOI: 10.1080/00207454.2020.1730832.

Rezapour-Firouzi S, Arefhosseini SR, Mehdi F, Mehrangiz EM, Baradaran B, Sadeghihokmabad E, et al. Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients. Complementary Therapies in Medicine. 2013 Oct; 21(5):473–80. DOI: 10.1016/j.ctim.2013.06.006.

Centonze D, Mori F, Koch G, Buttari F, Codecà C, Rossi S, et al. Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurological Sciences. 2009 Sep 19; 30(6):531–4. DOI: 10.1007/s10072-009-0136-5.

Mustafa W, Elgendy N, Salama S, Jawad M, Eltoukhy K. The Effect of Cannabis on the Clinical and Cytokine Profiles in Patients with Multiple Sclerosis. Fernandez O. Multiple Sclerosis International. 2021 Feb 5; 2021:1–10. DOI: 10.1155/2021/6611897.

Sexton M, Cudaback E, Abdullah RA, Finnell J, Mischley LK, Rozga M, et al. Cannabis use by individuals with multiple sclerosis: effects on specific immune parameters. Inflammopharmacology. 2014 Aug 19; 22(5):295–303. DOI: 10.1007/s10787-014-0214-z.

Kozela E, Juknat A, Kaushansky N, Rimmerman N, Ben-Nun A, Vogel Z. Cannabinoids decrease the th17 inflammatory autoimmune phenotype. J Neuroimmune Pharmacol. 2013 Dec; 8(5):1265-76. DOI: 10.1007/s11481-013-9493-1.

Kozela E, Juknat A, Kaushansky N, Ben-Nun A, Coppola G, Vogel Z. Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells. J Neuroinflammation. 2015 Mar 15;12:52. DOI: 10.1186/s12974-015-0273-0.

Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB, et al. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int J Mol Sci. 2021 Mar 8; 22(5):2719. DOI: 10.3390/ijms22052719.

Yu L, Zeng L, Zhang Z, Zhu G, Xu Z, Xia J, et al. Cannabidiol Rescues TNF-α-Inhibited Proliferation, Migration, and Osteogenic/Odontogenic Differentiation of Dental Pulp Stem Cells. Biomolecules. 2023 Jan 6; 13(1):118. DOI: 10.3390/biom13010118.

Haj CG, Sumariwalla PF, Hanuš L, Kogan NM, Yektin Z, Mechoulam R, et al. HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid. J Pharmacol Exp Ther. 2015 Oct; 355(1):66-75. DOI: 10.1124/jpet.115.226100.

Onwumeh J, Okwundu CI, Kredo T. Interleukin-2 as an adjunct to antiretroviral therapy for HIV-positive adults. Cochrane Database Syst Rev. 2017 May 25; 5(5):CD009818. DOI: 10.1002/14651858.CD009818.pub2.

Mahmoudpour SH, Jankowski M, Valerio L, Becker C, Espinola-Klein C, Konstantinides S, Quitzau K, Barco S. Safety of low-dose subcutaneous recombinant interleukin-2: systematic review and meta-analysis of randomized controlled trials. Sci Rep. 2019 May 9; 9(1):7145. DOI: 10.1038/s41598-019-43530-x.

Kaplan BLF, Springs AEB, Kaminski NE. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem Pharmacol. 2008 Sep 15; 76(6):726-37. DOI: 10.1016/j.bcp.2008.06.022.

Faouzi M, Wakano C, Monteilh-Zoller MK, Neupane RP, Starkus JG, Neupane JB, et al. Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry. Function (Oxf). 2022 Jul 8; 3(4):zqac033. DOI: 10.1093/function/zqac033.

Nguyen KG, Vrabel MR, Mantooth SM, Hopkins JJ, Wagner ES, Gabaldon TA, et al. Localized Interleukin-12 for Cancer Immunotherapy. Front Immunol. 2020 Oct 15;11:575597. DOI: d10.3389/fimmu.2020.575597.

Sun L, He C, Nair L, Yeung J, Egwuagu CE. Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine. 2015; 75(2):249-55. DOI: 10.1016/j.cyto.2015.01.030.

He H, Jiang Y, Qiu J, Shen F, Qian D, Meng L. Role of interleukin 17 and T helper cells 17 cells as a new immune target and signalling in the pathogenesis and treatment of autoimmune thyroid diseases. Annals of medicine. 2025 Dec; 57(1):2586216. DOI: d10.1080/07853890.2025.2586216.

Bruno M, Kröger C, Ferreira AV, Zhang B, Röring RJ, Liu R, et al. Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring. Blood advances [Internet]. 2025; 9(20):5306–22. DOI: 10.1182/bloodadvances.2025016213.

Downloads

Published

2026-03-27

How to Cite

1.
de Oliveira RGM, Stacanelli IC, Fagundes DF, Andrade MCA, de Paula W de PJ. Influência do uso de canabinoides na concentração de citocinas inflamatórias na esclerose múltipla: uma revisão sistemática e meta-análise: Influence of cannabinoids use on inflammatory cytokine concentrations in multiple sclerosis: a systematic review and meta-analysis. HU Rev [Internet]. 2026Mar.27 [cited 2026Mar.29];51:1-12. Available from: https://periodicos.ufjf.br/index.php/hurevista/article/view/50387

Issue

Vol. 51 (2025)

Section

Artigos de Revisão Sistemática

License

Copyright (c) 2026 Rodrigo Gentil Miquilino de Oliveira, Isabela Camporioni Stacanelli, Daniel Ferreira Fagundes, Mariléia Chaves Andrade Andrade, Waldemar de Paula Júnior de Paula

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Cessão de Primeira Publicação à HU Revista

Os autores mantém todos os direitos autorais sobre a publicação, sem restrições, e concedem à HU Revista o direito de primeira publicação, com o trabalho licenciado sob a Licença Creative Commons Attribution que permite o compartilhamento irrestrito do trabalho, com reconhecimento da autoria e crédito pela citação de publicação inicial nesta revista, referenciando inclusive seu DOI.