Creatine Monohydrate for Mild Traumatic Brain Injury: a Randomised Controlled Pilot Study

INTRODUCTION Mild traumatic brain injury (mTBI), often synonymous with the term 'concussion',1 affects approximately 0.6%-1.2% of the global population each year. Among these, 10-30% experience persistent post-concussive symptoms (PPCS), including headaches, difficulties with concentration and memory, fatigue, sleep disturbances, dizziness, irritability, and anxiety. PPCS not only affects the individual's health but also results in considerable socioeconomic challenges. Research has indicated a 4.2% decrease in the earnings of concussion patients five years after the injury and an increased risk of unemployment. Given the lack of universally effective treatments for PPCS, researchers are exploring alternative approaches such as nutritional supplementation.

One supplement under investigation is creatine monohydrate (CRM), a well-known ergogenic aid among athletes. CRM is considered a potential intervention for PPCS owing to its presence in the brain and its established role in muscle development. The metabolic changes that occur in the brain after an mTBI (e.g. disrupted energy homeostasis and impaired mitochondrial function), suggest that CRM supplementation may offer benefits by reducing PPCS. Although evidence of brain creatine alterations in the acute phase is limited, animal studies suggest concussion-related pathophysiological changes which indicate that creatine supplementation may reduce the severity of concussions. The presence of brain-specific isoforms of creatine kinase, which is essential for the ATP-phosphocreatine system further supports the role of creatine in the central nervous system's energy metabolism. Research has shown that creatine supplementation can enhance cellular energy availability and raise brain phosphocreatine content by up to 15%, thereby improving brain metabolism.

In addition, CRM has demonstrated strong anti-inflammatory properties, such as reducing cytotoxic effects in cells exposed to oxidative stress and inhibiting the formation of reactive oxygen species-induced mitochondrial permeability transition pores. This is relevant given the connection between concussion-induced neuroinflammation and symptomatology. By addressing neuroinflammation, CRM supplementation may contribute to symptom relief. Moreover, CRM may enhance several cognitive and psychological domains that are often compromised in PPCS, such as fatigue, working memory, and mood state. Creatine has also been associated with reductions in chronic fatigue, depressive symptoms, and anxiety, further indicating its potential for managing PPCS. Recent findings indicate possible benefits in stressed populations, which may be relevant for individuals experiencing PPCS after concussion.

The aim of this study was to examine the effect of CRM on PPCS, as assessed using the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and to explore the feasibility of this pilot study.

METHOD Patient and public involvement No patient or public involvement was undertaken at this stage although public input informed a protocol amendment extending the concussion timeframe from 6-12 to 6-18 months. For the planned larger RCT, patients will contribute to study design, recruitment processes, and the selection of outcome measures.