Calling all football players, boxers, MMA fighters, ice hockey, soccer and rugby players!!
Now you might think “what do we have in common?” but you are all in risk of developing CTE. And if you have a dream of playing for many years, please read this. If not for your own sake, then for the sake of your relatives.
It all starts with a mild concussion, then another one and another one. Every time your head is exposed to a traumatic brain injury (TBI), there is a release of structural proteins into the liquid that surrounds the cells in your brain [1]. This triggers cellular and biological changes, which can spread to other areas in your brain over time, causing secondary injuries and after many years and repeated TBIs it can turn into CTE [2].
Figure 1 shows what happens in the primary and secondary injury phase of TBI and after repeated TBIs over the years.
Illustration created using BioRender.com
CTE is a degenerative brain disease that develops after repeated trauma to the head [3]. Under the microscope, CTE is defined by a buildup of a specific protein called tau that becomes mis-tagged (hyperphosphorylated) and clusters around tiny blood vessels in the brain [4]. After each concussion more mis-tagged tau can be deposited and you become one step closer to CTE [1], [5]. There is no cure yet for CTE, and it can only be diagnosed post-mortem [5]. But before you paint the devil on the wall and start preparing to develop CTE, here’s a proposed solution that will make your future look brighter.
The novel solution - Melatonin
The brain has different systems trying to avoid deposits of mis-tagged tau protein. One of them is called the glymphatic system [6]. “The glymphatic system is the brain’s primary mechanism for clearing neurotoxic waste” [1]. It is closely linked to our sleep cycle and circadian dynamics – both rhythms that are disturbed after a concussion. If you think of the brain as a city that needs cleaning every night, the glymphatic system is the cleaning team and melatonin supplement can make it more efficient.
Figure 2 shows how the glymphatic system works under optimal circumstances with sleep as the key. The figure is made in Biorender with inspiration from a description of the glymphatic system in Kureshi et al [1].
After TBI, the function of the glymphatic pathway has been observed to fall by up to 60% and remain reduced for at least a month [7],[8]. The same conclusion is made in a study from 2018. Here they demonstrated that TBI is associated with reduced overnight melatonin production in TBI patients compared to age and sex in a control group [6]. This means that if the brain can’t efficiently cleanse itself every night after a concussion, a buildup of mis-tagged (hyperphosphorylated) tau protein can occur. This makes optimization of the glymphatic system in the secondary post-concussion phase (just after the injury) crucial for keeping the deficit as small as possible. To do so, you need melatonin supplementation.
A more recent study from 2025 concludes that melatonin improves neurological function and restores glymphatic function [9]. This was further examined in another study from the same year, in which melatonin treatment improved glymphatic function in mice and lowered phosphorylated tau levels[10].
Hypothesis
Many studies have investigated the efficacy of post-TBI melatonin supplementation, but no study has yet tested whether melatonin supplementary after primary injury lowers the later-life risk of CTE in individuals with repeated mild TBIs over many years.
Supporting the brain’s nightly cleansing process with melatonin supplementary after each concussion could potentially reduce the risk of developing CTE. If the brain recovers completely after each concussion before the next occurs, there might be a chance that the brain will not develop CTE, or we can postpone the development and symptoms for many years.
So, if it’s possible to get football players, boxers, MMA fighters, ice hockey, soccer and rugby players to sleep better after TBIs by taking melatonin supplement, it could make the glymphatic system more efficient and better to remove mis-tagged tau from the brain, which will minimize the risk of developing CTE.
Figure 3 shows the potential of melatonin supplement leading to less neuroinflammation and minimizing the risk of developing CTE [11]. Illustration created using BioRender.com
Take home message
“Researchers find CTE in 345 of 376 former NFL players studied”[12], if you don’t what to be a part of this statistic, talk to your doctor and start taking melatonin now!
Future perspectives – A synergistic partner for melatonin?
Researchers have started investigating the use of Cannabidiol (CBD), a non-intoxicating compound from cannabis, in mice with TBI and it shows promising results. A 2024 study concludes that, in mice, CBD reduces harmful mis-tagged tau buildup in the brain and improves neurological outcomes by improving memory and cognitive functions [13].
Future studies should examine whether combining melatonin with CBD may lower the risk of developing CTE without side effects – fingers crossed!
References
[1] S. Kureshi, C. Stowe, J. Francis, and H. Djalilian, ‘Circadian therapy interventions for glymphatic dysfunction in concussions injuries: A narrative review’, Sci Prog, vol. 106, no. 3, Jul. 2023, doi: 10.1177/00368504231189536.
[2] N. Hegdekar et al., ‘Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes’, Autophagy, vol. 19, no. 7, p. 2026, 2023, doi: 10.1080/15548627.2023.2167689.
[3] ‘What is CTE? | Concussion Legacy Foundation’. Accessed: Oct. 30, 2025. [Online]. Available: https://concussionfoundation.org/cte-resources/what-is-cte/
[4] K. F. Bieniek et al., ‘The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy’, J Neuropathol Exp Neurol, vol. 80, no. 3, pp. 210–219, Feb. 2021, doi: 10.1093/JNEN/NLAB001.
[5] A. C. McKee et al., ‘Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts’, Acta Neuropathol, vol. 145, no. 4, pp. 371–394, Apr. 2023, doi: 10.1007/S00401-023-02540-W.
[6] N. A. Grima, S. M. W. Rajaratnam, D. Mansfield, T. L. Sletten, G. Spitz, and J. L. Ponsford, ‘Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial’, BMC Med, vol. 16, no. 1, p. 8, Jan. 2018, doi: 10.1186/S12916-017-0995-1.
[7] J. J. Iliff et al., ‘Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury’, J Neurosci, vol. 34, no. 49, pp. 16180–16193, Dec. 2014, doi: 10.1523/JNEUROSCI.3020-14.2014.
[8] N. A. Grima, J. L. Ponsford, M. A. St Hilaire, D. Mansfield, and S. M. Rajaratnam, ‘Circadian Melatonin Rhythm Following Traumatic Brain Injury’, Neurorehabil Neural Repair, vol. 30, no. 10, pp. 972–977, Nov. 2016, doi: 10.1177/1545968316650279.
[9] Y. Li et al., ‘Melatonin Enhances Aquaporin 4 and Alpha-Syntrophin Interaction by Inhibiting Cyclin-Dependent Kinase 5 Activity to Preserve Glymphatic Function in Neonatal Hypoxic-Ischemic Encephalopathy’, J Pineal Res, vol. 77, no. 4, Jul. 2025, doi: 10.1111/JPI.70063.
[10] H. Sun et al., ‘Melatonin Mitigates Sleep Restriction-Induced Cognitive and Glymphatic Dysfunction Via Aquaporin-4 Polarization’, Mol Neurobiol, vol. 62, no. 9, pp. 11443–11465, Sep. 2025, doi: 10.1007/S12035-025-04992-5.
[11] R. J. Reiter et al., ‘Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm’, Cell Mol Life Sci, vol. 80, no. 4, p. 88, Apr. 2023, doi: 10.1007/S00018-023-04736-5.
[12] ‘Researchers Find CTE in 345 of 376 Former NFL Players Studied | Chobanian & Avedisian School of Medicine’. Accessed: Oct. 30, 2025. [Online]. Available: https://www.bumc.bu.edu/camed/2023/02/06/researchers-find-cte-in-345-of-376-former-nfl-players-studied/
[13] D. Shiying et al., ‘Cannabidiol Alleviates Neurological Deficits After Traumatic Brain Injury by Improving Intracranial Lymphatic Drainage’, J Neurotrauma, vol. 41, no. 15–16, pp. e2009–e2025, Aug. 2024, doi: 10.1089/NEU.2023.0539.
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Amazing blog!
I really liked the parallelism between the glymphatic system and the city, creative analogy! :)
Your hypothesis also has great potential. I just have a question regarding the molecular effects of melatonin at the cellular level. If I understood correctly, you mentioned that melatonin supports the glymphatic system and helps clear misfolded proteins.
But how does this happen mechanistically? Are there any specific signaling pathways involved in melatonin’s action that could also help regulate other dysregulated processes observed in CTE?
Thanks a lot!
Melatonin can regulate the expression of a specific circadian protein called per2. Per2 maintains the circadian rhythm of astrocytic AQP4 polarization, which is really important for a good glymphatic flow [1]. A study from 2024 shows that rats had a disrupted rhythmicity of per2 mRNA expression after TBI [2]. When per2 is out of rhythm, AQP4 becomes redistributed more random around the cells and the glymphatic functions slows down. By regulating the expression of Per2 through melatonin, the cells can maintain the circadian rhythm of astrocytic AQP4 polarization and restore the glymphatic function [1].
An example of another melatonin specific pathway observed in CTE could be this:
It is shown in different studies that melatonin can downregulate GSK3β levels and reduce oxidative stress through Nfr2-translocation [3]. Nfr2 is a transcription factor which moves from the cytoplasm to the nucleus under Nrf2-translocation as a reaction of oxidative stress. Here Nrf2 binds to a specific region of the DNA called antioxidant response element (ARE), which upregulates antioxidants and detoxifying enzymes as HO-1 and NQO1. HO-1 and NQO1 both supress microglia activation and NF-kB signalling, reducing the release of proinflammatory cytokine. HQO1 also plays a key role in reducing reactive oxygen species (ROS) (to much ROS causes oxidative stress). The effect of Nrf2 translocation includes for example a reduction in tau hyperphosphorylation, which is observed in CTE patients [4], [5].
References
[1] Yao D, Li R, Hao J, et al. Melatonin alleviates depression-like behaviors and cognitive dysfunction in mice by regulating the circadian rhythm of AQP4 polarization. Transl Psychiatry. 2023;13(1):310. Published 2023 Oct 6. doi:10.1038/s41398-023-02614-z
[2] Kuo LT, Lu HY, Chen YH. Traumatic brain injury-induced disruption of the circadian clock. J Mol Med (Berl). 2024;102(3):403-414. doi:10.1007/s00109-024-02416-w
[3] Das R, Balmik AA, Chinnathambi S. Melatonin Reduces GSK3β-Mediated Tau Phosphorylation, Enhances Nrf2 Nuclear Translocation and Anti-Inflammation. ASN Neuro. 2020;12:1759091420981204. doi:10.1177/1759091420981204
[4] Kang KW, Lee SJ, Kim SG. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 2005;7(11-12):1664-1673. doi:10.1089/ars.2005.7.1664
[5] Íñigo-Catalina L, Ortiz-Cabello M, Navarro E, Esteras N, Rancan L, Paredes SD. Melatonin-Mediated Nrf2 Activation as a Potential Therapeutic Strategy in Mutation-Driven Neurodegenerative Diseases. Antioxidants (Basel). 2025;14(10):1190. Published 2025 Sep 28. doi:10.3390/antiox14101190
I really appreciated reading your blog - your title reeled me in and the analogy of the brain being a city that needed cleaning was very engaging, especially with the easy to follow images given!
Am I understanding correctly that the timing of using melatonin (either before or shortly after TBI) is key in offering the best improvement to the glymphatic system in clearing the neurotoxic waste? If so, how likely is it that if individuals with a long history of chronic TBI incidents started taking melatonin (years after their athletic career) that they could also see improvements in the clearing of the mis-tagged tau proteins?
Great blog! The idea behind this is very interesting.
My question is as follows - the blog focuses a lot on the affects melatonin can have on reducing CTE, but what is the optimal timing and dosage of melatonin supplementation after concussion to maximize brain recovery and minimize tau accumulation or does this require further research?
As someone with a partner who somehow keeps finding a way to get themselves a concussion :D, I found this really interesting and useful.
I was always under the impression, however, that prolonged use of melatonin was not recommended and even dangerous. Like this study here linking it to heart failure (of course, these patients also had sleep issues, so probably the situation is a bit more complicated): https://www.ahajournals.org/doi/10.1161/circ.152.suppl_3.4371606
But did you assess these facts in your research (the effect of prolonged use on health), and would that be something you’d be worried about, or do you think the pros outweigh the cons?