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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 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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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
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
“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 7
“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
“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
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
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
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
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
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
“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
“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
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
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
“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
Radiation-Induced Neurodegeneration
Zedde, M., & Pascarella, R. (2026) · Biomedicines · doi:10.3390/biomedicines14020357 · Cited by 4
“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
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
“…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
“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
Malbari, F. (2023) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001360 · Cited by 2
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
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
“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
“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
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
Willis, A., Jeong, D., Liu, Y., Lithopoulos, M. A., Yuzwa, S. A., Frankland, P. W., Kaplan, D. R., & Miller, F. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.22.586277
Metadata
- 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 › Oncology › Cancer-related cognitive impairment studies
- Health Sciences › Medicine › Oncology › 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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