Cannabidiol Combats Depression Through Isgs-Mediated Inflammation in Zebrafish Model
DOI:
https://doi.org/10.54097/8rz7q762Keywords:
Zebrafish; Cannabidiol (CBD); Depression; Immune response; Reward system.Abstract
Major depressive disorder (MDD) is chronic and disabling. Current monoaminergic drugs act slowly and fail to achieve remission in many patients. The endocannabinoid system (ECS), which regulates mood, reward processing, and synaptic plasticity, has emerged as a promising target, yet clinical results are inconsistent, and key determinants such as dose, cellular context, and individual variability remain unresolved. We addressed these gaps by coupling a systematic review of placebo-controlled trials of exogenous cannabinoids with an experimental zebrafish model of reserpine-induced depression. In zebrafish larvae, behavior was quantified in the light-dark box, and whole-organism RNA sequencing was used to map the mechanism. The result showed largely non-significant antidepressant outcomes, with efficacy appearing formulation-dependent. In zebrafish, cannabidiol (CBD) at the maximum tolerated concentration (0.312 μg/mL) partially rescued depression-like behavior. Transcriptomics analysis revealed selective upregulation of interferon-stimulated genes (ISGs), including IFIT15 and RSAD2, with enrichment of immune, synaptic, and metabolic pathways. These cross-species findings indicate that CBD can ameliorate depressive phenotypes through endocannabinoid-linked modulation of neuroimmune pathways. They highlight dose sensitivity and microglial state as likely drivers of heterogeneity and motivate species-appropriate dosing and stratification by inflammatory status. Interferon-stimulated gene networks emerge as tractable entry points for developing safer, more effective, and personalized antidepressant strategies targeting the ECS.
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[1] Alizadeh, S., Djafarian, K., Nejad, M. M., Yekaninejad, M. S., & Javanbakht, M. H. (2022). The effect of β-caryophyllene on food addiction and its related behaviors: A randomized, double-blind, placebo-controlled trial. Appetite, 178, 106160. https://doi.org/10.1016/j.appet.2022.106160 DOI: https://doi.org/10.1016/j.appet.2022.106160
[2] American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. https://doi.org/10.1176/appi.books.9780890425596 DOI: https://doi.org/10.1176/appi.books.9780890425596
[3] Bailone, R. L., Fukushima, H. C. S., De Aguiar, L. K., & Borra, R. C. (2022). The endocannabinoid system in zebrafish and its potential to study the effects of Cannabis in humans. Laboratory Animal Research, 38(1). https://doi.org/10.1186/s42826-022-00116-5 DOI: https://doi.org/10.1186/s42826-022-00116-5
[4] Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., Amit, I., & Schwartz, M. (2014). Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science, 346(6205), 89–93. https://doi.org/10.1126/science.1252945 DOI: https://doi.org/10.1126/science.1252945
[5] Beurel, E., Toups, M., & Nemeroff, C. B. (2020). The bidirectional relationship of depression and inflammation: double trouble. Neuron, 107(2), 234–256. https://doi.org/10.1016/j.neuron.2020.06.002 DOI: https://doi.org/10.1016/j.neuron.2020.06.002
[6] Blank, T., & Prinz, M. (2017). Type I interferon pathway in CNS homeostasis and neurological disorders. Glia, 65(9), 1397–1406. https://doi.org/10.1002/glia.23154 DOI: https://doi.org/10.1002/glia.23154
[7] Chaves, C., Bittencourt, P. C. T., & Pelegrini, A. (2020). Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Pain Medicine, 21(10), 2212–2218. https://doi.org/10.1093/pm/pnaa303 DOI: https://doi.org/10.1093/pm/pnaa303
[8] Chin, J. S., Albert, L. T., Loomis, C. L., Keene, A. C., & Duboué, E. R. (2019). Behavioral approaches to studying innate stress in zebrafish. Journal of Visualized Experiments, 147. https://doi.org/10.3791/59092 DOI: https://doi.org/10.3791/59092-v
[9] Chu, A., & Wadhwa, R. (2023, May 1). Selective serotonin reuptake inhibitors. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK554406/
[10] Dong, B., Shilpa, B. M., Shah, R., Goyal, A., Xie, S., Bakalian, M. J., Suckow, R. F., Cooper, T. B., Mann, J. J., Arango, V., & Vinod, K. Y. (2019). Dual pharmacological inhibitor of endocannabinoid degrading enzymes reduces depressive-like behavior in female rats. Journal of Psychiatric Research, 120, 103–112. https://doi.org/10.1016/j.jpsychires.2019.10.010 DOI: https://doi.org/10.1016/j.jpsychires.2019.10.010
[11] Fairhurst, C., Kumar, R., Checketts, D., Tayo, B., & Turner, S. (2020). Efficacy and safety of nabiximols cannabinoid medicine for paediatric spasticity in cerebral palsy or traumatic brain injury: a randomized controlled trial. Developmental Medicine & Child Neurology, 62(9), 1031–1039. https://doi.org/10.1111/dmcn.14548 DOI: https://doi.org/10.1111/dmcn.14548
[12] Fattore, L., Melis, M., Fadda, P., Pistis, M., & Fratta, W. (2010). The endocannabinoid system and nondrug rewarding behaviours. Experimental Neurology, 224(1), 23–36. https://doi.org/10.1016/j.expneurol.2010.03.020 DOI: https://doi.org/10.1016/j.expneurol.2010.03.020
[13] Fernezelian, D., Rondeau, P., Gence, L., & Diotel, N. (2024). Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish: unveiling the role of vascular endothelial growth factor signaling and microglia. Neural Regeneration Research. https://doi.org/10.4103/nrr.nrr-d-23-01881 DOI: https://doi.org/10.4103/NRR.NRR-D-23-01881
[14] Ferretti, M. L., Stanley, T. B., Peters, E. N., Bonn-Miller, M. O., & Irons, J. G. (2024). Examination of the effects of cannabidiol on menstrual-related symptoms. Experimental and Clinical Psychopharmacology. https://doi.org/10.1037/pha0000709 DOI: https://doi.org/10.1037/pha0000709
[15] Gerritsen, L., Staufenbiel, S. M., Penninx, B. W., Van Hemert, A. M., Noppe, G., De Rijke, Y. B., & Van Rossum, E. F. (2018). Long-term glucocorticoid levels measured in hair in patients with depressive and anxiety disorders. Psychoneuroendocrinology, 101, 246–252. https://doi.org/10.1016/j.psyneuen.2018.11.019 DOI: https://doi.org/10.1016/j.psyneuen.2018.11.019
[16] Gonçalves, S. F., Gonzalez, N., Merranko, J., Raytselis, J., Diler, R. S., & Ladouceur, C. D. (2025). Differences in Reward and Punishment Sensitivity among Adolescents with Depression Varying in Manic Symptoms. Research on Child and Adolescent Psychopathology. https://doi.org/10.1007/s10802-025-01331-z DOI: https://doi.org/10.1007/s10802-025-01331-z
[17] Gundugurti, P. R., Banda, N., Yadlapalli, S. S. R., Narala, A., Thatikonda, R., Kocherlakota, C., & Kothapalli, K. S. (2024). Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150mg/ml) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial. Asian Journal of Psychiatry, 97, 104073. https://doi.org/10.1016/j.ajp.2024.104073 DOI: https://doi.org/10.1016/j.ajp.2024.104073
[18] Hardy, J., Greer, R., Huggett, G., Kearney, A., Gurgenci, T., & Good, P. (2022). Phase IIB Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind study of cannabidiol oil for the Relief of Symptoms in Advanced Cancer (MeDCaN1-CBD). Journal of Clinical Oncology, 41(7), 1444–1452. https://doi.org/10.1200/jco.22.01632 DOI: https://doi.org/10.1200/JCO.22.01632
[19] Helbig, K., & Beard, M. (2014). The role of Viperin in the innate antiviral response. Journal of Molecular Biology, 426(6), 1210–1219. DOI: https://doi.org/10.1016/j.jmb.2013.10.019
[20] Hill, M. N., & Gorzalka, B B. (2009). The endocannabinoid system and the treatment of mood and anxiety disorders. CNS & Neurological Disorders - Drug Targets, 8(6), 451–458. https://doi.org/10.2174/187152709789824624 DOI: https://doi.org/10.2174/187152709789824624
[21] Hill, M. N., & Gorzalka, B. B. (2005). Pharmacological enhancement of cannabinoid CB1 receptor activity elicits an antidepressant-like response in the rat forced swim test. European Neuropsychopharmacology, 15(6), 593–599. https://doi.org/10.1016/j.euroneuro.2005.03.003 DOI: https://doi.org/10.1016/j.euroneuro.2005.03.003
[22] Höflich, A., Michenthaler, P., Kasper, S., & Lanzenberger, R. (2018). Circuit mechanisms of reward, anhedonia, and depression. The International Journal of Neuropsychopharmacology, 22(2), 105–118. https://doi.org/10.1093/ijnp/pyy081 DOI: https://doi.org/10.1093/ijnp/pyy081
[23] Licitra, R., Marchese, M., Naef, V., Ogi, A., Martinelli, M., Kiferle, C., Fronte, B., & Santorelli, F. M. (2022). A review on the bioactivity of cannabinoids on zebrafish models: Emphasis on Neurodevelopment. Biomedicines, 10(8), 1820. https://doi.org/10.3390/biomedicines10081820 DOI: https://doi.org/10.3390/biomedicines10081820
[24] Malik, Z., Bayman, L., Valestin, J., Rizvi-Toner, A., Hashmi, S., & Schey, R. (2016). Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. Diseases of the Esophagus, n/a. https://doi.org/10.1111/dote.12455 DOI: https://doi.org/10.1111/dote.12455
[25] McInnes, L. A., & Marton, T. F. (2024). Considering new and emerging treatment strategies for depression: beyond STAR*D and the monoamines. Current Psychiatry Research and Reviews, 21(3), 215–228. https://doi.org/10.2174/0126660822284575240130053259 DOI: https://doi.org/10.2174/0126660822284575240130053259
[26] Mecha, M., Carrillo-Salinas, F., Feliú, A., Mestre, L., & Guaza, C. (2016). Microglia activation states and cannabinoid system: Therapeutic implications. Pharmacology & Therapeutics, 166, 40–55. https://doi.org/10.1016/j.pharmthera.2016.06.011 DOI: https://doi.org/10.1016/j.pharmthera.2016.06.011
[27] Mecha, M., Feliú, A., Carrillo-Salinas, F., Rueda-Zubiaurre, A., Ortega-Gutiérrez, S., De Sola, R. G., & Guaza, C. (2015). Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behavior and Immunity, 49, 233–245. https://doi.org/10.1016/j.bbi.2015.06.002 DOI: https://doi.org/10.1016/j.bbi.2015.06.002
[28] Mecha, M., Feliú, A., Iñigo, P., Mestre, L., Carrillo-Salinas, F., & Guaza, C. (2013). Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: A role for A2A receptors. Neurobiology of Disease, 59, 141–150. https://doi.org/10.1016/j.nbd.2013.06.016 DOI: https://doi.org/10.1016/j.nbd.2013.06.016
[29] Mechoulam, R., & Parker, L. A. (2012). The endocannabinoid system and the brain. Annual Review of Psychology, 64(1), 21–47. https://doi.org/10.1146/annurev-psych-113011-143739 DOI: https://doi.org/10.1146/annurev-psych-113011-143739
[30] Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major Depression. Biological Psychiatry, 65(9), 732–741. https://doi.org/10.1016/j.biopsych.2008.11.029 DOI: https://doi.org/10.1016/j.biopsych.2008.11.029
[31] Miller, A. H., & Raison, C. L. (2015). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews. Immunology, 16(1), 22–34. https://doi.org/10.1038/nri.2015.5 DOI: https://doi.org/10.1038/nri.2015.5
[32] Mitarnun, W., Kanjanarangsichai, A., Junlaor, P., Kongngern, L., Mitarnun, W., Pangwong, W., & Nonghan, P. (2025). Cannabidiol and Cognitive Functions/Inflammatory Markers in Parkinson’s Disease: A Double-Blind Randomized Controlled Trial at Buriram Hospital (CBD-PD-BRH trial). Parkinsonism & Related Disorders, 135, 107841. https://doi.org/10.1016/j.parkreldis.2025.107841 DOI: https://doi.org/10.1016/j.parkreldis.2025.107841
[33] Moreira, F. A., Grieb, M., & Lutz, B. (2009). Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Practice & Research Clinical Endocrinology & Metabolism, 23(1), 133–144. https://doi.org/10.1016/j.beem.2008.09.003 DOI: https://doi.org/10.1016/j.beem.2008.09.003
[34] Mosley, P. E., Webb, L., Suraev, A., Hingston, L., Turnbull, T., Foster, K., Ballard, E., Gomes, L., Mohan, A., Sachdev, P. S., Kevin, R., Gordon, R., Benson, M., & McGregor, I. S. (2023). Tetrahydrocannabinol and cannabidiol in Tourette syndrome. NEJM Evidence, 2(9). https://doi.org/10.1056/evidoa2300012 DOI: https://doi.org/10.1056/EVIDoa2300012
[35] Müller-Vahl, K. R., Pisarenko, A., Szejko, N., Haas, M., Fremer, C., Jakubovski, E., Musil, R., Münchau, A., Neuner, I., Huys, D., Van Elst, L. T., Schröder, C., Ringlstetter, R., Koch, A., Jenz, E. B., & Großhennig, A. (2023). CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders – Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study. Psychiatry Research, 323, 115135. https://doi.org/10.1016/j.psychres.2023.115135 DOI: https://doi.org/10.1016/j.psychres.2023.115135
Notcutt, W., Price, M., Miller, R., Newport, S., Phillips, C., Simmons, S., & Sansom, C. (2004). Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 ‘N of 1’ studies. Anaesthesia, 59(5), 440–452. https://doi.org/10.1111/j.1365-2044.2004.03674.x DOI: https://doi.org/10.1111/j.1365-2044.2004.03674.x
[36] Pandey, R., Mousawy, K., Nagarkatti, M., & Nagarkatti, P. (2009). Endocannabinoids and immune regulation☆. Pharmacological Research, 60(2), 85–92. https://doi.org/10.1016/j.phrs.2009.03.019 DOI: https://doi.org/10.1016/j.phrs.2009.03.019
[37] Pinto, J. V., Crippa, J. a. S., Ceresér, K. M., Vianna-Sulzbach, M. F., De Moura Silveira Júnior, É., Da Rosa, G. S., Da Silva, M. G. T., Hizo, G. H., Medeiros, L. S., De Oliveira, C. E. S., Bristot, G., Campos, A. C., Guimarães, F. S., Hallak, J. E. C., Zuardi, A. W., Yatham, L. N., Kapczinski, F., & Kauer-Sant’Anna, M. (2023). Cannabidiol as an Adjunctive Treatment for Acute Bipolar Depression: A Pilot Study: Le cannabidiol comme traitement d’appoint de la dépression bipolaire aiguë: une étude pilote. The Canadian Journal of Psychiatry, 69(4), 242–251. https://doi.org/10.1177/07067437231209650 DOI: https://doi.org/10.1177/07067437231209650
[38] Poleszak, E., Wośko, S., Sławińska, K., Wyska, E., Szopa, A., Doboszewska, U., Wlaź, P., Wlaź, A., Dudka, J., Szponar, J., & Serefko, A. (2019). Influence of the CB1 cannabinoid receptors on the activity of the monoaminergic system in the behavioural tests in mice. Brain Research Bulletin, 150, 179–185. https://doi.org/10.1016/j.brainresbull.2019.05.021 DOI: https://doi.org/10.1016/j.brainresbull.2019.05.021
[39] Raft, D., Gregg, J., Ghia, J., & Harris, L. (1977). Effects of intravenous tetrahydrocannabinol on experimental and surgical pain; Psychological correlates of the analgesic response. Clinical Pharmacology & Therapeutics, 21(1), 26–33. https://doi.org/10.1002/cpt197721126 DOI: https://doi.org/10.1002/cpt197721126
[40] Rahaman, O., & Ganguly, D. (2021). Endocannabinoids in immune regulation and immunopathologies. Immunology, 164(2), 242–252. https://doi.org/10.1111/imm.13378 DOI: https://doi.org/10.1111/imm.13378
[41] Sălcudean, A., Popovici, R., Pitic, D. E., Sârbu, D., Boroghina, A., Jomaa, M., Salehi, M. A., Kher, A. a. M., Lica, M. M., Bodo, C. R., & Enatescu, V. R. (2025). Unraveling the complex interplay between neuroinflammation and Depression: A Comprehensive review. International Journal of Molecular Sciences, 26(4), 1645. https://doi.org/10.3390/ijms26041645 DOI: https://doi.org/10.3390/ijms26041645
[42] Silva, N. R., Arjmand, S., Domingos, L. B., Chaves-Filho, A. M., Mottin, M., Real, C. C., Waszkiewicz, A. L., Gobira, P. H., Ferraro, A. N., Landau, A. M., Andrade, C. H., Müller, H. K., Wegener, G., & Joca, S. R. L. (2024). Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression. Pharmacological Research, 107545. https://doi.org/10.1016/j.phrs.2024.107545 DOI: https://doi.org/10.1016/j.phrs.2024.107545
[43] Toth, C., Mawani, S., Brady, S., Chan, C., Liu, C., Mehina, E., Garven, A., Bestard, J., & Korngut, L. (2012). An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain, 153(10), 2073–2082. https://doi.org/10.1016/j.pain.2012.06.024 DOI: https://doi.org/10.1016/j.pain.2012.06.024
[44] Vela, J., Dreyer, L., Petersen, K. K., Arendt-Nielsen, L., Duch, K. S., & Kristensen, S. (2021). Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind, placebo-controlled trial. Pain, 163(6), 1206–1214. https://doi.org/10.1097/j.pain.0000000000002466 DOI: https://doi.org/10.1097/j.pain.0000000000002466
[45] Wang, H., He, Y., Sun, Z., Ren, S., Liu, M., Wang, G., & Yang, J. (2022). Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. Journal of Neuroinflammation, 19(1). https://doi.org/10.1186/s12974-022-02492-0 DOI: https://doi.org/10.1186/s12974-022-02492-0
[46] Weber, M., Goldman, B., & Truniger, S. (2010). Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial. Journal of Neurology Neurosurgery & Psychiatry, 81(10), 1135–1140. https://doi.org/10.1136/jnnp.2009.200642 DOI: https://doi.org/10.1136/jnnp.2009.200642
[47] Wilson, E. H., Weninger, W., & Hunter, C. A. (2010). Trafficking of immune cells in the central nervous system. Journal of Clinical Investigation, 120(5), 1368–1379. https://doi.org/10.1172/jci41911 DOI: https://doi.org/10.1172/JCI41911
[48] World Health Organization. (2023, March 31). Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression
[49] Yirmiya, R., Rimmerman, N., & Reshef, R. (2015). Depression as a microglial disease. Trends in Neurosciences, 38(10), 637–658. https://doi.org/10.1016/j.tins.2015.08.001 DOI: https://doi.org/10.1016/j.tins.2015.08.001
[50] Zhan, Y., Zhou, Y., Zheng, W., Liu, W., Wang, C., Lan, X., Deng, X., Xu, Y., Zhang, B., & Ning, Y. (2020). Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder. Translational Psychiatry, 10(1). https://doi.org/10.1038/s41398-020-00933-z DOI: https://doi.org/10.1038/s41398-020-00933-z
[51] Zimmermann, T., Maroso, M., Beer, A., Baddenhausen, S., Ludewig, S., Fan, W., Vennin, C., Loch, S., Berninger, B., Hofmann, C., Korte, M., Soltesz, I., Lutz, B., & Leschik, J. (2018). Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. Cerebral Cortex, 28(12), 4454–4471. https://doi.org/10.1093/cercor/bhy258 DOI: https://doi.org/10.1093/cercor/bhy258
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