Evidence to Support the Use of S-Adenosylmethionine for Treatment of Post-Concussive Sequelae in the Military

Introduction: Since the year 2000, over 413,000 service members have sustained traumatic brain injury (TBI) and may present with post-concussive sequelae including headaches, fatigue, irritability, cognitive problems, depression, insomnia, and chronic pain. Although the focus of the article is on military TBI, the usefulness of S-adenosylmethionine (SAMe) would extend to both civilian and military populations. This narrative review examines the preclinical and clinical literature of SAMe's metabolism and alterations seen in disease states such as depressive disorders, pain disorders, fatigue, cognition, dementia, use in pregnancy and peripartum, children, adolescents, and adults, to the elderly with and without dementia, stroke, and neurodegeneration, in order to highlight its potential benefit in post-concussive sequelae after TBI. Materials and Methods: A MEDLINE/PubMed and Cochrane Database search was conducted between May 3, 2018 and July 30, 2019 by combining search terms for SAMe with terms for relevant disease states including depression, brain injury, dementia, Alzheimer's disease, Parkinson's disease, cognition, fatigue, and pain. This search retrieved a total of 676 references. 439 were excluded for being over a 10-year publication date, except where clinically relevant. After additional removal of repeated articles, the number of articles were totaled 197. An additional 59 articles were excluded: 10 not in English, 4 duplicates, 4 not original investigations, and 41 outside the scope of this article. The remaining 138 articles were used in this review and included 25 clinical studies, 46 preclinical studies, 63 reviews, and 4 case reports. Results: This narrative review examined the preclinical and clinical literature of SAMe's metabolism and alterations seen in MDD, pain disorders, fatigue, cognition and memory, dementia, and other disorders to highlight the potential benefit of SAMe in post-concussive sequelae in mTBI. The literature showed potential for improvement, safety, and tolerability in these symptom clusters commonly seen in military mild TBI (mTBI). Conclusion: There is evidence of a potential benefit of SAMe as an intervention to help with symptoms across the range of postconcussive sequelae and syndromes commonly seen in military mTBI. Since the discovery of SAMe in 1952, this pleiotropic molecule has shown the significance of its involvement in several metabolic cascades in such disparate systems as epigenetics, bioenergetics, DNA methylation, neurotransmitter systems, and potential usefulness in military TBI. Significant limitations include disparate presentations seen in patients with mild TBI, those with post-concussive syndrome, as well as those with comorbid depression and posttraumatic stress disorder. Also, over-the-counter medications are not regulated and SAMe products may vary widely in price and quality. Given the potential for mania in patients with bipolar disorder, evaluation and recommendations should be made by a physician able to evaluate the underlying bipolar diathesis. Furthermore, this narrative review serves as the rationale for future open-label and double-blind placebo-controlled trials in military mTBI and SAMe.