Key Takeaways
- New research explores Creatine HCl and brain injury: A preclinical study from the University of Nebraska Medical Center (UNMC) investigated the potential neuroprotective effects of CON-CRĒT® Creatine HCl following traumatic brain injury (TBI).
- Promising findings in brain-cell health: Researchers observed fewer degenerating neurons in certain brain regions and reduced markers of brain inflammation in specific treatment groups.
- Different responses in males and females: Male mice showed the clearest improvements in markers of neuronal degeneration, while female mice demonstrated changes in inflammatory activity and markers related to brain-cell connections.
- More research is needed: Although findings are encouraging, this study was conducted in mice. Human clinical trials are needed to determine whether Creatine HCl provides similar benefits following brain injury.
Traumatic brain injury (TBI) is one of the leading causes of death and disability in the United States, and concussion, its mildest and most common form, reaches into sport, the military, the workplace, and everyday life. Yet despite decades of research, there is still no FDA-approved medication that can heal or reverse the brain damage TBI causes.
I've spent my career where pharmacy, sports, and research meet: teaching the first sports pharmacy course in the nation, serving as the Big 12 Conference Drug Use Control Coordinator, and later working in neurology-focused medical affairs. So when researchers at the University of Nebraska Medical Center (UNMC) set out to test whether creatine HCl could protect the brain after injury, I looked forward to seeing the results.. The findings are early, but they're worth understanding for anyone who serves athletes, military personnel and active adults.
What Exactly Is a Concussion or Traumatic Brain Injury?
TBI is damage to the brain caused by an external physical force, such as a blow or jolt to the head or an object piercing the skull. Mild TBI includes concussions, which can result from falls, sports collisions, vehicle accidents, and explosive blasts near the head. A concussion causes a change in mental status or a disruption of normal brain function.
Brain injury unfolds in two phases. The primary injury is the mechanical damage at the moment of impact. The secondary injury develops over the following hours, days, and weeks, driven by inflammation, swelling, metabolic stress, and dysfunction in neurons and their support cells. Along the way, TBI can injure neurons and the synapses (the connections brain cells use to communicate). Since it builds over time, secondary injury is where researchers see the most room to intervene.
Why Creatine, and Why the Brain?
Creatine is best known for muscle, but its most basic job is energy. Through the creatine kinase/phosphocreatine system, creatine helps regenerate ATP, the cell's energy currency, in tissues whose energy demands are high and change quickly. About 95% of the body's creatine is stored in skeletal muscle. Most of the remaining 5% sits in other energy-hungry organs, including the brain, heart, and kidneys.
An injured brain faces an energy crisis at exactly the moment it needs energy for repair. Over the past decade, interest in creatine for brain health and cognitive function has grown, and early animal studies with creatine monohydrate reported neuroprotective effects after experimental TBI, often at very high doses that are hard to sustain in everyday supplementation, particularly in a person with a compromised neurological condition.
Creatine HCl is a novel compound with an improved pharmacokinetic profile compared to creatine monohydrate that was developed by our team while I was on faculty at UNMC. That work led to the formation of Vireo Systems. This new study is one of the first to examine CON-CRĒT® Creatine HCl specifically in a model of TBI.
Inside the UNMC Creatine HCl Concussion Study
Researchers in UNMC's Department of Neurological Sciences, studied adult male and female mice using Creatine HCl supplied by CON-CRĒT® Creatine HCl. The animals received a daily oral dose of either Creatine HCl or water (placebo) for 7 days before and 14 days after a controlled cortical impact (CCI). CCI is a widely used, highly reproducible laboratory model of brain trauma. NIH recognizes and utilizes it as a standard laboratory model for studying traumatic brain injury for producing CDE (Common Data Elements) for TBI. The study compared four regimens:
- Water before and after injury (injured control)
- Water before, then Creatine HCl at 100 mg/kg after injury
- Creatine HCl at 100 mg/kg before and after injury
- Creatine HCl at 100 mg/kg before, then 450 mg/kg after injury
Post-injury dosing began 30 minutes after the injury. At 14 days, the investigators, who were blinded to treatment groups, measured lesion size, tissue loss, blood biomarkers, brain immune-cell activation, degenerating neurons, and synapse-related proteins in the hippocampus (a region central to learning and memory) and the parietal cortex.
What the Researchers Found
The most consistent signals came from the regimen that combined pre-injury dosing with a higher post-injury dose (100 mg/kg before, 450 mg/kg after):
- Fewer degenerating neurons in males. Male mice on this regimen showed significantly less staining for degenerating neurons in two hippocampal regions than injured controls. Post-injury-only dosing also significantly reduced this staining in one hippocampal region.
- Lower markers of brain inflammation in females. Female mice on this regimen showed significantly lower activation of microglia, the brain's resident immune cells, in the hippocampus compared with injured controls. Markers of astrocyte activation, another glial cell involved in the inflammatory response, were also lower than with post-injury-only dosing. Males showed similar but non-significant trends.
- Signals involving brain-cell connections in females. Female mice on this regimen had more clusters of gephyrin than injured controls in one hippocampal region. Gephyrin helps organize the inhibitory connections that keep brain signaling in balance.
Some measures did not change. Creatine HCl did not reduce overall lesion size or tissue loss, and blood biomarkers of brain injury (NfL, total tau, and GFAP) did not differ between groups at 14 days. Many individual comparisons were not statistically significant.
Put simply, Creatine HCl didn't shrink the injury itself. However, in specific brain regions it was associated with fewer degenerating neurons, calmer immune cells, and changes in structures that support communication between neurons. Those are the cellular processes that drive secondary injury.
Why the Sex Differences Matter
Female mice had significantly larger injuries than males regardless of treatment, which is consistent with the published literature. In humans, female athletes show higher concussion rates than males in some comparable sports. The two sexes also responded differently to creatine HCl: the clearest neuron findings appeared in males, while the immune-cell and synapse findings appeared in females. That's a strong argument for including both sexes in brain-injury research.
What This Study Does and Doesn't Tell Us
As a pharmacist, I believe good science deserves unbiased analysis. This was a preclinical study in mice. It did not measure symptoms, cognition, behavior, or recovery, and it did not include an uninjured comparison group. Because the most effective regimen changed two things at once (adding pre-injury dosing and raising the post-injury dose), we can't yet say which factor drove the results. Most importantly, these findings don't show that creatine HCl prevents or treats concussion in people.
There is a meaningful human precedent for asking the question, though. A 2006 open-label pilot study of 39 children and adolescents with severe TBI reported encouraging differences in recovery and in several cognitive and behavioral outcomes with creatine at 0.4 g/kg per day for six months, a substantial dose. That study was small and uncontrolled, but it raises a compelling question: could creatine HCl produce clinically meaningful outcomes at a lower dose? Answering that will take well-designed human trials.
What's Next for Creatine HCl Brain Research
This study lays the groundwork for the next phase. During the study, technicians noticed differences in post-injury activity between groups. Because those observations weren't included in the original study methodology they were not reported. Planned follow-up research will assess behavior, cognition, and functional recovery directly. Companion cell-culture work is also underway to look at inflammatory signaling, mitochondrial energy production, and blood-brain barrier function. Those results will be shared once the full scientific review is complete.
Do the Results of This Study Change the Recommended Daily Use for CON-CRĒT® (Creatine HCl)?
No. At present, Vireo recommends following the directions for use on the label unless your healthcare provider advises otherwise for a specific situation. This study was conducted to explore brain health. It was not designed to replace professional medical advice or to evaluate changes to standard supplement use. Please consult your healthcare provider with any questions about your medical condition, and seek prompt medical care for any suspected head injury.
How is Creatine HCl different from creatine monohydrate?
Creatine HCl is creatine bound to hydrochloride. It was developed to improve on the pharmacokinetic profile of creatine monohydrate. This study did not directly compare the two forms.
Can these results be seen with Creatine Monohydrate?
No. The study compared creatine HCl to placebo. Creatine monohydrate was not studied. Thus, these results are specific to creatine HCl and cannot be generalized to other creatine formulations as a class effect.
About the Author
Jon C. Wagner, PharmD, earned his Doctor of Pharmacy from the University of Nebraska College of Pharmacy, where he later served as the college's first Associate Dean for Student and Professional Affairs and taught a first-of-its-kind sports pharmacy course. He was part of the research team that developed novel creatine compounds and formed what is now Vireo Systems. He also served as the Big 12 Conference Drug Use Control Coordinator. Dr. Wagner went on to a career in medical affairs with Novartis, Amgen, and Neurocrine Biosciences, with expertise spanning neurology, cardiology, gastroenterology, and osteoporosis.
References
- Zigmond JW, Lamberty BG, Simon GJ, Wood JM, Elliott NM, Stauch KL. Creatine HCl supplementation promotes neuroprotection in a mouse model of traumatic brain injury. University of Nebraska Medical Center. SEE STUDY HERE
- Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic brain injury. Ann Neurol. 2000;48(5):723–729.
- Sakellaris G, et al. Prevention of complications related to traumatic brain injury in children and adolescents with creatine administration: an open label randomized pilot study. J Trauma. 2006;61(2):322–329.
- Fahr J, Kraff O, Deuschl C, Dodel R. Concussion in female athletes of contact sports: a scoping review. Orthop J Sports Med. 2024;12(10):23259671241276447.
- Jamjoom AAB, Rhodes J, Andrews PJD, Grant SGN. The synapse in traumatic brain injury. Brain. 2021;144:18–31.
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
IACUC Statement
The research was conducted within IACUC and NIH (National Institutes of Health) guidelines and requirements for animal research. IACUC (Institutional Animal Care and Use Committee) is a standing independent committee at every research university and institution conducting animal research to ensure ethical treatment and care for animals used in research. University of Nebraska Medical Center IACUS reviewed and approved this research and its protocols.