Table 1.

Previous reviews on TBI, sleep dysfunction, and melatonin.

Citation	Title	Design	Key Findings
Kaleyias and Kothare, 2022 [30]	Sleep Disorders in Traumatic Brain Injury	Literature Review	Factors implicated in sleep disturbance following TBI include reduced hypocretin signaling, damage to histaminergic tuberomammillary neurons, disruption of circadian regulation impairing melatonin synthesis, and parenchymal damage involving the ascending reticular activating system, basal ganglia, and limbic system. Human observational studies implicate substantial loss of histaminergic neurons and impaired melatonin synthesis as significant pathophysiologic contributors up to 6 months after injury.
Naseem and Parvez, 2014 [31]	Role of Melatonin in Traumatic Brain Injury and Spinal Cord Injury: A Review	Literature Review 9 Studies	In animal models, melatonin has neuroprotective effects on both TBI and spinal cord injury (SCI). Mechanisms for observed benefit are largely owed to anti-inflammatory and anti-oxidative action leading to a reduction in cerebral edema, decreased NFkB, decreased AP-1, stabilization of Nitric Oxide Species (NOS), increased superoxide dismutase and glutathione peroxidase. Measurements of melatonin in the CSF increase acutely following TBI.
Stewart et al., 2022 [32]	Treating Sleep Disorders Following Traumatic Brain Injury in Adults: Time for Renewed Effort?	Systematic Review 18 Articles	Pathophysiology of sleep disruption following TBI remains poorly understood. Circadian rhythm dysfunction was common acutely (10 days), and low melatonin production is found up to a year post injury and associated with reduced sleep quality. Recommendation for clinical use of melatonin to treat sleep dysfunction following TBI is supported but cautioned against given the paucity of published data from human RCTs.
Gagner et al., 2015 [33]	Sleep-wake Disturbances and Fatigue after Pediatric Traumatic Brain Injury: A Systematic Review of the Literature.	Systematic Review	From over 20 identified pathologic characteristics from human and animal models from studies investigating neuropathology, only 4 were observed concurrently in both. Shared findings included decreased hypothalamic orexin, increased slow waveform during wakefulness on EEG, increased sleep fragmentation, and increased sleep time, suggesting higher validity and utility for these findings when investigating the pathophysiologic mechanism for sleep dysfunction after TBI.
Driver and Stork, 2018 [34]	Pharmacological Management of Sleep After Traumatic Brain Injury	Literature Review	Melatonin administration following TBI may improve subjective daytime alertness, but a comprehensive understanding of its restorative impact on sleep fragmentation is limited by a lack of rigorous RCTs with objective sleep data. In one double-blind placebo-controlled trial of 13 individuals with TBI, the melatonin agonist Ramelteon improved total sleep duration and cognitive performance following the 3-week trial.
Osier et al., 2018 [35]	Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence	Literature Review 22 articles	In animal models, melatonin conferred neuroprotective benefits following TBI via antioxidative action, downregulation of NFkB and AP-1, and decreased apoptosis leading to reduced contusion volume during the evening. Majority of reports support the potential use of melatonin in treating human patients following TBI.
Barlow et al., 2019 [36]	Melatonin as a Treatment after Traumatic Brain Injury: A Systematic Review and Meta-Analysis of the Pre-Clinical and Clinical Literature	Meta-analysis 17 studies	From 15 pre-clinical studies, melatonin had an overall beneficial effect on subject outcomes with improvement in cognitive performance and motor function. Pertinent clinical trials included a post-concussive pediatric population that benefited from melatonin supplementation to reduce post-traumatic headaches (N = 12).
Blum et al., 2021 [37]	Melatonin in Traumatic Brain Injury and Cognition	Literature Review 11 studies	Murine models continue to demonstrate melatonin exerting potent neuroprotective action via anti-inflammatory and antioxidant functions. Evidence for reduced expression of abnormal proteins, including AB and p-tau, following treatment with melatonin after injury highlight a potential future application in decreasing the risk of neurodegenerative disease for which TBI exposure is a risk factor. Longitudinal data on cognitive performance in a treatment population are lacking; however, some evidence for improvement in memory task function acutely after injury does exist.
Feinberg et al., 2021 [38]	Association of Pharmacological Interventions with Symptom Burden Reduction in Patients with Mild Traumatic Brain Injury: A Systematic Review	Systematic Review 23 studies	Review of 23 studies (11 randomized clinical trials, 7 prospective observational studies, 3 retrospective observational studies, and 2 case studies) examining 20 pharmacological interventions; while methylphenidate, sertraline hydrochloride, ondansetron, amitriptyline, and melatonin were adequately represented— consistent symptom burden reduction was limited.
Ali et al., 2022 [39]	Fatigue After Traumatic Brain Injury: A Systematic Review	Systematic Review	Review of 37 articles showed methylphenidate and melatonin were the only pharmacological agents associated with decreased fatigue in RCTs.
Samantaray et al., 2009 [40]	Therapeutic Potential of Melatonin in Traumatic Central Nervous System Injury	Mini Review	Mini review exploring and summarizing characteristics and benefits of melatonin as neuroprotectant/treatment for acute SCI or traumatic CNS injuries.
Reiter et al., 2016 [41]	Melatonin as an Antioxidant: Under Promises but Over Delivers	Literature Review	Review articles summarizing the evolutionary history of melatonin as well as its biochemical pathways and physiological effects in healthy and injured states.
Cassimatis et al., 2022 [42]	The Utility of Melatonin for the Treatment of Sleep Disturbance Following Traumatic Brain Injury	Literature Review 9 studies	A total of 5 RCTs on adults and adolescents showed that post-TBI melatonin treatment improved subjective and objective sleep measures as well as mental health symptoms, executive function, and cognition.