A first-of-its-kind study led by the Medical University of South Carolina raises questions about the value of fish oil supplements for people with repetitive mild traumatic brain injuries. In an article in the journal Cell Reports, researchers say the supplements, often seen as neuroprotective, may actually impair the healing process after brain injury.
Neuroscientist Onder Albayram, Ph.D., an associate professor at MUSC and member of the National Trauma Society Committee, was the lead investigator for the mechanistic study. It examined biological pathways that shape cerebrovascular repair after injury.
For context, the research comes at a time of growing demand for the omega-3 fatty acids in fish oil, according to Fortune Business Insights. Fish oil is even showing up in some drinks, dairy alternatives and snacks.
The demand comes as no surprise to Albayram. “Fish oil supplements are everywhere, and people take them for a range of reasons, often without a clear understanding of their long-term effects,” he said.
“But in terms of neuroscience, we still don't know whether the brain has resilience or resistance to this supplement. That's why ours is the first such study in the field.”
Albayram worked with Eda Karakaya, Ph.D., and Adviye Ergul, M.D., Ph.D., on that study, along with several other researchers at MUSC and beyond. That includes his longtime collaborator Semir Beyaz, Ph.D., at the Cold Spring Harbor Laboratory Cancer Center in New York.
The researchers uncovered a context-dependent metabolic vulnerability, meaning a shift in how cells handle energy that may leave tissue less able to recover, linked to the buildup in the brain of one omega-3 fatty acid found in many fish oil supplements. That fatty acid is eicosapentaenoic acid, better known as EPA. In the study’s models, higher brain EPA was associated with a reduced capacity for repair after injury.
Albayram said there is strong evidence supporting the benefits of docosahexaenoic acid, or DHA, the omega-3 fatty acid in fish oil that is a major structural component of neuronal membranes. In contrast, EPA follows a different biological path in the brain, with more limited membrane incorporation and effects that can vary with exposure duration and physiological context. As a result, the long-term implications of sustained omega-3 intake, particularly for cerebrovascular adaptation and recovery following injury, have remained less well-defined.
So the team took a step-by-step approach across models that let them connect diet, brain biology and recovery. In mouse models, they examined how long-term fish oil supplementation shaped the brain’s response after repeated mild head impacts, focusing on signals tied to vascular stability and repair.
They then looked more closely at the brain’s vascular lining using human brain microvascular endothelial cells, which help maintain the barrier between the brain and the bloodstream. In these experiments, EPA, but not DHA, was linked to weaker endothelial repair-related functions, consistent with the broader pattern seen in animal studies.
Finally, to place the work in a human disease context, the researchers analyzed postmortem superior frontal cortex tissue from neuropathologically confirmed chronic traumatic encephalopathy (CTE) cases with a history of repetitive traumatic brain injury.
Their findings were striking, with “implications for precision nutrition, therapeutic strategies and the design of dietary interventions targeting brain injury and neurodegeneration,” the researchers said in the report.
The researchers cited key findings
The wording from their report comes first, followed by brief explanations.
1. EPA-driven neurovascular instability triggers perivascular tauopathy and cognitive decline following TBI.
“In a sensitive brain state modeled in mice, long-term fish oil supplementation revealed a delayed vulnerability. The animals showed poorer neurological and spatial learning performance over time, together with clear evidence of vascular-associated tau accumulation in the cortex, linking impaired recovery to neurovascular dysfunction and perivascular tau pathology,” Albayram said.
2. EPA reprograms cortical transcriptional responses and suppresses angiogenic signaling following traumatic brain injury.
“In the injured cortex, the team observed a coordinated shift in gene programs that normally support vascular stability and repair,” Albayram said. “The pattern included reduced expression of genes tied to extracellular matrix organization and endothelial integrity, alongside broader changes consistent with altered lipid handling after injury.”
3. EPA utilization under permissive metabolic conditions impairs angiogenesis and endothelial integrity, recapitulating post-traumatic brain injury cerebrovascular dysfunction.
Albayram said that in human brain microvascular endothelial cells, EPA did not act as a universal toxin. “Instead, when cells were placed in conditions that encouraged fatty acid engagement, EPA was associated with weaker angiogenic network formation and reduced endothelial barrier integrity, matching key features of the neurovascular repair deficit seen in vivo.”
4. CTE brain reveals neurovascular and fatty acid metabolic reprogramming consistent with EPA-linked vulnerability.
“In postmortem cortex from neuropathologically confirmed CTE cases with a history of repetitive brain injury, the researchers found evidence of disrupted fatty acid balance and broad transcriptional changes affecting vascular and metabolic pathways,” Albayram said. “This human arm was used to provide translational context, asking whether chronic disease tissue shows convergent signatures of altered lipid handling and reduced vascular stability.”
So what does it all mean?
Albayram emphasized that the study is not a call for the public to abandon fish oil supplements. “I am not saying fish oil is good or bad in some universal way,” he said. “What our data highlight is that biology is context-dependent. We need to understand how these supplements behave in the body over time, rather than assuming the same effect applies to everyone.”
He and his colleagues hope the findings encourage scientists, health care providers and the public to take a closer look at both the promise and the limits of omega-3 supplementation. The work focused on a specific biological setting, repeated mild traumatic brain injury and used CTE tissue to provide observational alignment, not to claim direct cause and effect.
“As with any study, there are important boundaries,” Albayram said. “In the human CTE tissue, we can observe patterns, but we cannot prove what drove them. We also cannot capture every variable that shapes omega-3 handling in real life, including overall diet, health status and lifestyle.”
The team said the next step will be to define how EPA is taken up, transported and distributed in the body, with particular attention to fatty acid transport mechanisms. “This paper is a starting point,” Albayram said, “but it is an important one. It opens a new conversation about precision nutrition in neuroscience, and it gives the field a framework to ask better, more testable questions.”
