Creatine loading for chronic migraine?

To the Editor:

A recent paper by Niddam and co-workers published in Cephalalgia (1) nicely demonstrated an impaired brain metabolism in chronic migraine patients with medication overuse headache. Besides other findings, the authors reported reduced total creatine levels (as quantified by 3 Tesla ¹H MR spectroscopy) in the left thalamus of 32 chronic migraine patients with and without medication. Creatine acts as a high-energy buffer in the brain by maintaining a constant concentration of adenosine triphosphate (ATP), the energy currency of the cell. A brain creatine deficiency found in this study is thus highly suggestive of altered energy homeostasis in chronic migraine, a phenomenon already identified in a secondary headache (2), where patients with semi-acute mild traumatic brain injury experienced higher creatine levels in the white matter and splenium, perhaps signaling a higher creatine turnover in the mildly compromised brain as a compensatory response in the face of the increased needs (3). The question that inevitably arises from the Niddam et al. study (1) is, could the low brain creatine be a new biological target for therapeutics (including exogenous creatine) in chronic migraines?

A disbalance in brain creatine levels has been found in various brain pathologies, including inherited creatine deficiency syndromes, neurodegenerative diseases, and stroke (4). A reduction of brain creatine modifies the energy requirements of cells and eventually leads to oxidative stress and neuronal death that typically affects certain brain areas (e.g. thalamus, cerebellum, white matter tracts, cortical grey matter), with the restoration of cerebral creatine after therapeutic creatine supplementation accompanied by an improvement of clinical outcomes in certain conditions (e.g. Parkinson’s disease, Huntington’s disease, amiotrophic lateral sclerosis, stroke). Tackling brain creatine deficit with oral creatine (C₄H₉N₃O₂) following traumatic headaches can also lead to favorable alterations in biological markers related to specific neuropathology and improves patient-reported outcomes in clinical studies (5). Specifically, creatine loading could enable maintaining/restoring the cell membrane potentials and ATP buffering, and might reduce migraine-like symptoms (e.g. headache, dizziness, light and sound sensitivity) after mild traumatic brain injury in the pediatric population (6,7). These promising results in secondary headaches should be extended to chronic migraine and verified by direct investigation of the relationship between brain creatine levels and clinical outcomes after an intervention.

It remains unclear whether exogenous creatine can result in a clinically meaningful increase in brain creatine in a distinct location for chronic migraine patients (e.g. the thalamus), and whether acute headache medications taken for chronic headaches can alter creatine transport through the blood-brain barrier (BBB) and/or modulate gut absorption of oral creatine. The most used prophylactic medications (such as calcitonin gene-related peptide blockers) are likely effective without crossing the BBB (8), so the impact of abortive treatments may be greater on the absorption of oral creatine than on a hypothetical passage through the BBB. Despite the potentially poor BBB permeability for creatine, a few studies demonstrated that creatine loading (e.g. 20 grams per day) can result in a significant increase in brain creatine in healthy humans (for a review see (3)), though this should be corroborated in chronic migraine patients. In addition, common creatine protocols used in previous trials might have a limited capacity to increase brain creatine (9–11), which partly dampens its therapeutic potential in neurology and propels the research community to search for better alternatives in terms of creatine dosages, routes of administration and analogs. Finally, oral creatine appears to improve cognitive function in healthy individuals (9), particularly in situations whereby cognitive processes are stressed (e.g. during sleep deprivation, experimental hypoxia, or performance of more cognitively demanding tasks) (10). Whether this translates to better short-term memory, executive function, and other cognitive domains in patients with chronic migraine after creatine intervention remains unknown at the moment.