Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin
Open accessAbstract
We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.
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Preclinical studies in disease models sharing features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition.
“Preclinical studies in disease models that share numerous features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition (Ayoub et al., 2020; Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003; Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Ayoub et al., 2020
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Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair
Gilbert, E. A. B., Lakshman, N., Lau, K. S. K., & Morshead, C. M. (2022) · Cells · doi:10.3390/cells11050846 · Cited by 80 · see citing works
“Following brain injury, metformin leads to improved functional outcomes in preclinical animal models (stroke, traumatic brain injury and cranial radiation) and has led to promising results in children with acquired brain injury [98,99,240,247,248].”
BackgroundZhu, L., Yang, K., Ren, Z., Yin, D., & Zhou, Y. (2024) · Translational Oncology · doi:10.1016/j.tranon.2024.101945 · Cited by 75 · see citing works
Froldi, G. (2024) · Pharmaceuticals · doi:10.3390/ph17040478 · Cited by 68 · see citing works
“With the idea that metformin can increase NPCs and repair brain damage, the authors administered metformin (1000 mg/m 2 orally, twice daily for 12 weeks), showing enhanced performance in declarative and working memory tests [144].”
BackgroundProwse, N. A., & Hayley, S. P. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.018 · Cited by 67 · see citing works
Metformin, Cognitive Function, and Changes in the Gut Microbiome
Rosell-Díaz, M., & Fernández‐Real, J. M. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad029 · Cited by 68 · see citing works
Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas
Panwalkar, P., Tamrazi, B., Dang, D., Chung, C., Sweha, S. R., Natarajan, S. K., Pun, M. J., Bayliss, J. M., Ogrodzinski, M. P., Pratt, D. W., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc0497 · Cited by 58 · see citing works
Promising use of metformin in treating neurological disorders: biomarker-guided therapies
Loan, A., Syal, C., Lui, M., He, L., & Wang, J. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385286 · Cited by 49 · see citing works
“Further work targeting endogenous neural stem cells in both rodent and human studies of radiation injury found that metformin improves the cognition of rodents and patients following radiation relative to a control/placebo (Ayoub et al., 2020; Derkach et al., 2021).”
BackgroundShao, T., Huang, J., Zhao, Y., Wang, W., Tian, X., Hei, G., Kang, D., Gao, Y., Liu, F., Zhao, J., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02616-x · Cited by 45 · see citing works
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Bernal, J. D. K., Recchia, F., Yu, D. J., Fong, D., Wong, S. H., Chung, P., Chan, D. K. C., Capio, C. M., Yu, C. C.-W., Wong, S. W. S., et al. (2022) · The Lancet Child & Adolescent Health · doi:10.1016/s2352-4642(22)00286-3 · Cited by 36 · see citing works
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Lei, T., Deng, S., Chen, P., Xiao, Z., Cai, S., Hang, Z., Yang, Y., Zhang, X., Li, Q., & Du, H. (2021) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2021.106086 · Cited by 31 · see citing works
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“Early clinical research indicates potential for therapies aimed at regenerating neural stem and precursor cells to alleviate cognitive impairment associated with cancer treatments [59, 60].”
Wen, H., Yang, F., Cai, R., Yao, X., Li, Y., Wang, X., Xue, C., Hu, Y., Li, M., & Luo, Z. Y. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121165 · Cited by 30 · see citing works
Long-Term Follow-Up of Pediatric CNS Tumor Survivors—A Selection of Relevant Long-Term Issues
Otth, M., Wyss, J., & Scheinemann, K. (2022) · Children · doi:10.3390/children9040447 · Cited by 29 · see citing works
“Even though the authors did not aim to assess the efficacy of metformin in this population, they could show that survivors treated with metformin in the first phase of the trial performed better than those first receiving the placebo [68].”
BackgroundHocking, M. C., Walsh, K. S., Hardy, K. K., & Conklin, H. M. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.20.02327 · Cited by 29 · see citing works
Bourget, C., Adams, K. V., & Morshead, C. M. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02487-x · Cited by 29 · see citing works
“The promising effects of metformin to support brain repair were further demonstrated in a study that examined metforminmediated recovery in a model of cranial radiation and a pilot clinical trial that demonstrated the safety and feasibility of metformin for children with acquired brain injury [3].”
BackgroundGilbert, E. A. B., Livingston, J. M., Flores, E. G., Khan, M., Kandavel, H., & Morshead, C. M. (2023) · Brain Research · doi:10.1016/j.brainres.2023.148648 · Cited by 29 · see citing works
“…respect to oligodendrogenesis, systemic administration of metformin at clinically relevant doses following brain injury leads to increased numbers of myelinating oligodendrocytes (Dadwal et al., 2015) and increased white matter volume in children following cranial radiation (Ayoub et al., 2020).”
BackgroundInfluentialRadiation-Induced Brain Injury: Mechanistic Insights and the Promise of Gut–Brain Axis Therapies
Li, M., Tong, F., Wu, B., & Dong, X. (2024) · Brain Sciences · doi:10.3390/brainsci14121295 · Cited by 29 · see citing works
“Despite considerable research e ff orts directed at understanding radiation-induced cerebral injury [16–19], the precise underlying mechanisms remain elusive. and consolidation.”
Brains in space: impact of microgravity and cosmic radiation on the CNS during space exploration
Wuyts, F. L., Deblieck, C., Vandevoorde, C., & Durante, M. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00923-4 · Cited by 29 · see citing works
Su, Y., Hou, C., Wang, M., Ren, K., Zhou, D., Liu, X., Zhao, S., & Liu, X. (2023) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2023.106375 · Cited by 25 · see citing works
Janelsins, M. C., Dyk, K. V., Hartman, S. J., Koll, T. T., Cramer, C. K., Lesser, G. J., Barton, D. L., Mustian, K. M., Wagner, L. I., Ganz, P. A., et al. (2024) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djae209 · Cited by 23 · see citing works
“Both agents have a favorable safety profile in children, and metformin has been safely combined with chemotherapy in early-phase trials for children with relapsed leukemia or solid tumors as well as in early-phase trials of survivors of pediatric brain tumors (85-87).”
Biodegradable stimulating electrodes for resident neural stem cell activation in vivo
Chen, T., Lau, K. S. K., Singh, A., Zhang, Y. X., Taromsari, S. M., Salari, M., Naguib, H. E., & Morshead, C. M. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122957 · Cited by 23 · see citing works
Metformin effects on brain development following cranial irradiation in a mouse model
Yuen, N., Szulc, K. U., Li, Y.-Q., Morshead, C. M., Mabbott, D., Wong, C. S., & Nieman, B. J. (2021) · Neuro-Oncology · doi:10.1093/neuonc/noab131 · Cited by 22 · see citing works
Serum metabolic profiling enables diagnosis, prognosis, and monitoring for brainstem gliomas
Li, K., Wang, R., Gu, Z., Weng, W., Liu, W., Huang, Y., Wu, J., Zhang, Z., Yang, S., Su, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61163-9 · Cited by 23 · see citing works
Yan, N., Li, Y., Xing, Y., Wu, J., Li, J., Liang, Y., Tang, Y., Wang, Z., Song, H., Wang, H., et al. (2022) · EMBO Reports · doi:10.15252/embr.202154147 · Cited by 21 · see citing works
“This finding is consistent with the reported role of MET in preventing alcohol-induced cognitive deficits through elevating DNA methylation (Tunc-Ozcan et al , 2018), and in promoting memory formation (Wang et al , 2012; Ayoub et al , 2020).”
Liu, J., Zhang, M., Deng, D., & Zhu, X. (2023) · Archives of pharmacal research · doi:10.1007/s12272-023-01445-2 · Cited by 23 · see citing works
Sienna, J. L., Kahalley, L. S., Mabbott, D., Grosshans, D. R., Santiago, A., Paulino, A. C., Merchant, T. E., Manzar, G. S., Dama, H., Hodgson, D. C., et al. (2023) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2023.11.035 · Cited by 21 · see citing works
Dahhan, N. Z. A., Cox, E., Nieman, B. J., & Mabbott, D. (2022) · Neuron · doi:10.1016/j.neuron.2022.04.009 · Cited by 21 · see citing works
Livingston, J. M., Syeda, T., Christie, T., Gilbert, E. A. B., & Morshead, C. M. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100119 · Cited by 20 · see citing works
Khaleqi-Sohi, M., Sadria, G., Ghalibafian, M., Kalantari, K. K., & Irannejad, S. (2021) · Journal of Bodywork and Movement Therapies · doi:10.1016/j.jbmt.2021.11.003 · Cited by 17 · see citing works
Gilbert, E. A. B., Livingston, J. M., Flores, E. G., Kehtari, T., & Morshead, C. M. (2023) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szad030 · Cited by 17 · see citing works
DDAH1 promotes neurogenesis and neural repair in cerebral ischemia
Gao, Q., Ni, P., Wang, Y., Huo, P., Zhang, X., Wang, S., Xiao, F., Li, Y., Feng, W. H., Yuan, J.-T., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.02.001 · Cited by 17 · see citing works
Derkach, D., Kehtari, T., Renaud, M., Heidari, M., Lakshman, N., & Morshead, C. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100231 · Cited by 18 · see citing works
“up to 25 days did not expand the SEZ NSC pool in juvenile mice.(31,36) Interestingly, we observed that expansion of the pool is transient in vivo, which was not predicted based on previous studies revealing continued expansion of passaged neurospheres in the absence of metformin derived from primary neurospheres initi…”
BackgroundResultInfluentialZhou, L., Chen, X.-Q., Yu, B., Pan, M.-X., Lu, F. Y., Li, J., Cui, X., Yao, M., & Lu, X. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.946879 · Cited by 16 · see citing works
Kirkman, M. A., Day, J., Gehring, K., Zienius, K., Grosshans, D. R., TAPHOORN, M. J. B., Li, J., & Brown, P. D. (2022) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011335.pub3 · Cited by 15 · see citing works
Disrupting the Mood and Obesity Cycle: The Potential Role of Metformin
Doan, S. N., Patel, S. K., Xie, B., Nelson, R. A., & Yee, L. D. (2023) · Obesities · doi:10.3390/obesities3010006 · Cited by 14 · see citing works
“Metformin has also been associated with enhanced declarative and working memory among survivors of pediatric brain tumors [144].”
BackgroundXu, Z., Zhang, H., Wu, C., Zheng, Y., & Jiang, J. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.944902 · Cited by 14 · see citing works
“Apart from its hypoglycemic effect, metformin has been found to confer protection against breast cancer (5), polycystic ovary syndrome (6), and neural recovery in patients with brain tumors (7).”
BackgroundHarnessing the power of molecular imaging for drug discovery and development
Luo, X., Tan, B., Zhao, X., Zhang, Z., Wang, G., Wang, T., Xing, B., & Song, A. (2023) · iRadiology · doi:10.1002/ird3.47 · Cited by 13 · see citing works
MEndR: An In Vitro Functional Assay to Predict In Vivo Muscle Stem Cell‐Mediated Repair
Davoudi, S., Xu, B., Jacques, E., Cadavid, J. L., McFee, M. C., Chin, C., Meysami, A., Ebrahimi, M., Bakooshli, M. A., Tung, K., et al. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202106548 · Cited by 13 · see citing works
Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease
Roberts, C.-T., Raabe, N., Wiegand, L., Shahib, A. K., & Rastegar, M. (2024) · Pharmaceuticals · doi:10.3390/ph17121601 · Cited by 13 · see citing works
“Especially in children, radiation-induced damage to the hippocampus and white matter leads to reduced neurogenesis, whereby the neural stem cell pool in areas such as the dental gyrus does not recover on its own [106].”
InfluentialReview: Neurological Complications From Therapies for Pediatric Brain Tumors
Nguyen, T. P., Mueller, S., & Malbari, F. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.853034 · Cited by 12 · see citing works
“Metformin has the potential to improve cognitive recovery in pediatric patients post-RT (30).”
BackgroundInfluentialSleurs, C., Fletcher, P. C., Mallucci, C. L., Avula, S., & Ajithkumar, T. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01096-9 · Cited by 12 · see citing works
“Finally, interventional studies including pharmacological studies have only recently shown some preliminary positive evidence for metformin [117].”
BackgroundYeung, J., DeYoung, T., Spring, S., de Guzman, A. E., Elder, M. W., Beauchamp, A., Wong, C. S., Palmert, M. R., Lerch, J. P., & Nieman, B. J. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2404042121 · Cited by 11 · see citing works
“Even where initial pathological presentations are not strongly sex biased, treatment outcomes may still differ based on sex ( 10 , 11 ).”
Integration and Intersection of Cancer Metabolism with Epigenetic Pathways in Gliomas
Natarajan, S. K., Pun, M. J., Haggerty-Skeans, J., & Venneti, S. (2025) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-111523-023424 · Cited by 11 · see citing works
Kasteler, R., Fuchs, P., Otth, M., & Scheinemann, K. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1150166 · Cited by 11 · see citing works
“Processing speed and attention was assessed mainly by the CANTAB test battery (11, 18, 19).”
BackgroundMethodInfluentialEDA2R reflects the acute brain response to cranial irradiation in liquid biopsies
Romero, A. L., Seitz, T., Zisiadis, G. A., Jeffery, H., & Osman, A. M. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae077 · Cited by 10 · see citing works
Willis, A., Jeong, D., Liu, Y., Lithopoulos, M. A., Yuzwa, S. A., Frankland, P. W., Kaplan, D. R., & Miller, F. D. (2025) · Cell Reports · doi:10.1016/j.celrep.2024.115194 · Cited by 10 · see citing works
Khan, S. S., Rangraze, I. R., Wali, A. F., Jhancy, M., Attia, R. A., Elshamy, H. A. H., Adam, S., & Elbeshbeishy, R. A. M. (2025) · Medicina · doi:10.3390/medicina61091577 · Cited by 9 · see citing works
“Research teams are now cataloging clues in four interlocking domains: DNA sequence variants, circulating metabolite signatures, volumetric imaging patterns, and integrative multi-omics assemblies [66–68].”
Servidei, T., Sgambato, A., Lucchetti, D., Navarra, P., & Ruggiero, A. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2804077 · Cited by 9 · see citing works
Zisiadis, G. A., Alevyzaki, A., Nicola, E., Rodrigues, C. F. D., Blomgren, K., & Osman, A. M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1202200 · Cited by 9 · see citing works
Metformin Protects Radiation-Induced Early Brain Injury by Reducing Inflammation and DNA Damage
Xiang, J., Lu, Y., Quan, C., Gao, Y., & Zhou, G. (2023) · Brain Sciences · doi:10.3390/brainsci13040645 · Cited by 9 · see citing works
“Metformin is capable of enhancing both cellular and functional recovery following juvenile cranial radiation [11], indicating that it is a promising candidate for further preclinical and clinical investigations of RIBI.”
BackgroundInfluentialCai, C., Gu, C., Meng, C., He, S., Lhamo, T., Draga, D., Zheng, Z., & Qiu, Q. (2024) · Pharmaceutical Research · doi:10.1007/s11095-024-03777-0 · Cited by 8 · see citing works
Neofytou, C., Bäcklund, A., Blomgren, K., & Hermanson, O. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02560-w · Cited by 9 · see citing works
“Clinical approaches for addressing the neurocognitive deficits in pediatric brain cancer survivors are varied; the development of novel radiotherapeutic techniques with precision-based algorithms offer hope of ameliorated side effects [20], while promising preclinical studies lay the groundwork for recent and ongoing…”
BackgroundTreating cancer therapy–related cognitive impairment
Gibson, E. M., & Monje, M. (2020) · Nature Medicine · doi:10.1038/s41591-020-1014-1 · Cited by 8 · see citing works
He, K., Li, Z., Ye, K., Zhou, Y., Yan, M., Qi, H., Hu, H., Dai, Y., & Tang, Y. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02534-w · Cited by 8 · see citing works
“Various studies have extensively reported the effects of metformin for cancer prevention and therapy [29, 30].”
BackgroundBadner, A., & Cummings, B. J. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335833 · Cited by 8 · see citing works
“Most importantly, there have also been encouraging preliminary results of metformin use in survivors of pediatric brain tumors after having undergone cranial radiation (Ayoub et al., 2020).”
BackgroundNeurocognitive Performance in Adults Treated With Radiation for a Primary Brain Tumor
Tsang, D. S., Khandwala, M., Liu, Z. A., Richard, N. M., Shen, G., Sekely, A. W., Bernstein, L. J., Simpson, R., Mason, W. P., Chung, C. D., et al. (2022) · Advances in Radiation Oncology · doi:10.1016/j.adro.2022.101028 · Cited by 8 · see citing works
“Age at RT, years, median (range) 42 (17-71)”
InfluentialBradley, S. S., de Holanda, L. J., Chau, T. T., & Wright, F. V. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1398459 · Cited by 7 · see citing works
Lin, Y., Luo, X., Wang, F., Cai, H., Lin, Y., Kang, D., & Fang, W. (2025) · Biology of Sex Differences · doi:10.1186/s13293-025-00684-w · Cited by 7 · see citing works
“Clinical and animal studies have shown that males are less likely to benefit from metformin on cognitive function [28, 29].”
Hutterer, M., & Oberndorfer, S. (2021) · memo - Magazine of European Medical Oncology · doi:10.1007/s12254-021-00690-9 · Cited by 7 · see citing works
Investigating the effect of metformin on chemobrain: Reports from cells to bedside
Leddy, E., Attachaipanich, T., Chattipakorn, N., & Chattipakorn, S. C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.115129 · Cited by 6 · see citing works
Neuropsychological function in childhood cancer patients and adult survivors of childhood cancer
Jacola, L. M., Peterson, R. K., Oswald, K., Sekely, A. W., Mabbott, D., & Edelstein, K. (2025) · Journal of Clinical and Experimental Neuropsychology · doi:10.1080/13803395.2025.2521018 · Cited by 6 · see citing works
“Lifestyle interventions that focus on physical activity and sleep have significant potential for addressing cognitive late effects (Cox et al., 2020; Lubas et al., 2022).”
Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity
Mohammadnia, A., Cui, Q., Weng, C., Yaqubi, M., Fernandes, M. G. F., Hall, J. A., Dudley, R., Srour, M., Kennedy, T. E., Stratton, J. A., et al. (2024) · Brain Communications · doi:10.1093/braincomms/fcae109 · Cited by 6 · see citing works
“4,5 In vivo and in vitro studies in animals indicate that myelination capacity decreases with age, reflecting intrinsic properties of the oligodendroglia (OL) lineage cells (differentiation and migration) 6 and the influence of positive and negative signals received from the local environment.”
BackgroundCerebellar mutism syndrome of non-tumour surgical aetiology—a case report and literature review
Laustsen, A. F., Børresen, M. L., Hauerberg, J., & Juhler, M. (2023) · Child s Nervous System · doi:10.1007/s00381-023-05947-8 · Cited by 6 · see citing works
“Although, a recent study using metformin to promote neurogenesis showed promising results on neurocognitive outcome [51], current suggested treatment is limited to rehabilitation of speech, neurocognition and motor skills.”
BackgroundYang, J., Yang, N., Zhao, H., Qiao, Y., Li, Y., Wang, C., Lim, K., Zhang, C., Yang, W., & Lu, L. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03463-9 · Cited by 6 · see citing works
Beyond the brain: socioeconomic status and race in pediatric brain tumor survivorship
Tsang, D. S., & Schulte, F. (2021) · Neuro-Oncology · doi:10.1093/neuonc/noab079 · Cited by 6 · see citing works
Drugs and Endogenous Factors as Protagonists in Neurogenic Stimulation
Chiareli, R. A., Marques, B. L., Carvalho, G. A., Souza, R. T. V., Santana, P. H. G., Santiago, H. C., Pinto, M. C. X., Birbrair, A., Parreira, R. C., Ulrich, H., et al. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10423-y · Cited by 5 · see citing works
Exploiting metabolic dependencies for therapeutic targeting of brain cancers
Martell, E., Kuzmychova, H., Grewal, A., Chawla, U., Jain, C., Anderson, C. M., & Sharif, T. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218426 · Cited by 4 · see citing works
Skocic, J., Richard, L., Ferkul, A., Cox, E., Tseng, J., Laughlin, S., Bouffet, É., & Mabbott, D. (2024) · Neuro-Oncology Practice · doi:10.1093/nop/npae003 · Cited by 4 · see citing works
Walsh, K. S., Pizer, B. L., Samargia-Grivette, S., Lux, A. L., Schmahmann, J. D., Hartley, H., Avula, S., & on behalf of the Posterior Fossa Society (2024) · Child s Nervous System · doi:10.1007/s00381-024-06411-x · Cited by 4 · see citing works
“Dr. Mabbott closed presenting preliminary targets for therapeutic approaches in this clinical population, highlighting their work assessing cognitive and neural recovery using metformin in pediatric brain tumor survivors [53].”
Spatiotemporal Mapping of Early Volume Loss in the Mouse Brain after Cranial Irradiation
Ayoub, R., Lau, K., Yuen, N., Fernandes, D., Elder, M. W., Yeung, J., Wong, S. C., & Nieman, B. J. (2021) · Radiation Research · doi:10.1667/rade-21-00013.1 · Cited by 4 · see citing works
“been observed in pediatric patients treated for brain tumors (35).”
BackgroundMini-review: Aplastic myelin following chemotherapy
Savchuk, S., & Monje, M. (2022) · Neuroscience Letters · doi:10.1016/j.neulet.2022.136861 · Cited by 4 · see citing works
Neuropsychological Outcomes in Pediatric Brain Tumor Survivors
Janzen, L. A., Mabbott, D., & Guger, S. (2024) · Springer eBooks · doi:10.1007/978-3-031-62017-1_25 · Cited by 4 · see citing works
Metformin for neurocognitive dysfunction in schizophrenia: a systematic review
Qin, Z.-J., Shi, Z.-M., Li, L., Wei, X., Hu, H.-L., Wei, W., Xie, Z.-Y., Ji, H. L., Wei, Y., & Zheng, W. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1540153 · Cited by 3 · see citing works
“Furthermore, several studies have demonstrated metformin's potential to enhance neurocognitive function in other neurological conditions, including Parkinson ’ s disease (48), Alzheimer ’ s disease (49), and pediatric brain tumors (50).”
Bhagya, V. R., Tilak, K., Kanimozhi, L., & Sushma, R. K. (2025) · Current Alzheimer Research · doi:10.2174/0115672050379003250520072717 · Cited by 3 · see citing works
Radiation-Induced Neurodegeneration
Zedde, M., & Pascarella, R. (2026) · Biomedicines · doi:10.3390/biomedicines14020357 · Cited by 4 · see citing works
“Despite the well-documented injuries associated with radiation therapy [28–31], the precise mechanisms at play remain elusive.”
Drabek-Maunder, E., Gains, J. E., Hargrave, D. R., Mankad, K., Aquilina, K., Dean, J., Nisbet, A., & Clark, C. A. (2025) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdaf053 · Cited by 2 · see citing works
Gupta, T., Dasgupta, A., Goswami, S. S., Chatterjee, A., Dhingra, S., Deodhar, J. K., Sonkusare, L. N., Prasad, M., Gollamudi, V. R. M., Kannan, S., et al. (2026) · BMC Cancer · doi:10.1186/s12885-026-15627-w · Cited by 2 · see citing works
“…dementia in survivors of brain tumors impacts the quality of life significantly, leading to the search for appropriate strategies to improve memory and neurocognitive function using advanced radiation techniques (e.g., proton beam therapy) or medical therapy (e.g., memantine, metformin) [3–5].”
Yu, Z., Xu, M., Liu, Z., Zeng, G., Fan, H., Tan, C., Tu, Y., Bu, X., & Wang, Y. (2022) · Neurotoxicity Research · doi:10.1007/s12640-022-00494-7 · Cited by 2 · see citing works
“It has been stated that radiation can cause damage to the structure of the brain, and those who have been exposed to radiation have shown cognitive impairment (Ayoub et al. 2020).”
BackgroundApproaches to Minimise the Neurodevelopmental Impact of Choroid Plexus Carcinoma and Its Treatment
Adamski, J. K., Langford, V., & Finlay, J. L. (2023) · Life · doi:10.3390/life13091855 · Cited by 2 · see citing works
Malbari, F. (2023) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001360 · Cited by 2 · see citing works
Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation
Li, Y.-Q., & Wong, C. S. (2021) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlab014 · Cited by 1 · see citing works
Safety and feasibility trial protocol of metformin in infants after perinatal brain injury
Hutchinson, A.-M., Pais, R., Endginton, A. N., Pilon, B., MacDonald, J. M., MacDonald, M. E., Lewis, T. R., Offringa, M., & Kalish, B. T. (2025) · BMJ Paediatrics Open · doi:10.1136/bmjpo-2024-002784 · Cited by 1 · see citing works
“9 17 Therefore, we will ask parents/guard-ians to record feeding patterns (feed frequency and volume), the number of stools per day and any vomiting in the study diary.”
InfluentialZhou, K., Wang, Y., Sun, W., Mao, Z., Wang, W., & Qu, Z. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05516-x · Cited by 1 · see citing works
“For instance, metformin has been found to promote cognitive recovery and brain repair in pediatric brain tumor survivors who underwent intracranial radiation therapy, with no clinically related safety concerns or serious adverse events reported [19].”
Preoperative chemotherapy in medulloblastoma: a change in treatment paradigm?
Khuong-Quang, D.-A., & Hansford, J. R. (2020) · Neuro-Oncology · doi:10.1093/neuonc/noaa213 · Cited by 1 · see citing works
Characterizing the Effects of Metformin on Brain Development following Cranial Irradiation
Yuen, N. (2020) · TSpace (University of Toronto)
Cognitive Recovery in Survivors of Pediatric Brain Tumors Using Metformin
Müller, C. (2023) · Springer eBooks · doi:10.1007/978-3-031-31797-2_8
Chubenko, V. A. (2023) · Practical oncology · doi:10.31917/2404383
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- Authors
- Ayoub, R., Ruddy, R. M., Cox, E., Oyefiade, A., Derkach, D., Laughlin, S., Ades-aron, B., Shirzadi, Z., Fieremans, E., MacIntosh, B. J., de Medeiros, C. B., Skocic, J., Bouffet, E., Miller, F. D., Morshead, C. M., & Mabbott, D. J.
- Affiliations
- University of Toronto (CA)
- New York University (US)
- Hospital for Sick Children (CA)
- Corresponding author
- Morshead, Cindi M.
- Mabbott, Donald J.
- ORCID
- Venue
- Nature Medicine
- Published
- 2020-07-27
- Volume
- 26
- Issue
- 8
- Pages
- 1285-1294
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC8176964
- OpenAlex
- W3044625941
- Cited by
- 117
- References
- 77
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 22 · 2023: 28 · 2022: 21 · 2021: 16 · 2020: 4
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Garron Family Cancer Centre
- Fondation Brain Canada
- Stem Cell Network
- Ontario Institute for Regenerative Medicine
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- metformin, pediatric brain tumor survivors, cognitive recovery, neural progenitor cells, neurogenesis, dentate gyrus, hippocampus, white matter, working memory, declarative memory, drug safety and tolerability, sex differences
- MeSH terms
- Cancer Survivors, Adolescent, Adult, Brain, Brain Neoplasms, Child, Child, Preschool, Cognition, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Metformin, Pediatrics, Pilot Projects, Treatment Outcome, Neurogenesis, Young Adult, Cognitive Dysfunction
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