Posted September 29, 2023

Dr. Chris Marx, Duke University School of Medicine and Durham VA Health Care System

Traumatic brain injury (TBI) frequently involves co-occurring psychological health challenges such as depression and posttraumatic stress disorder (PTSD), as well as pain, neurological and functional difficulties, all of which impact quality of life. Although civilians are also affected, military Service Members have a higher risk of sustaining a TBI, with more than 450,000 U.S. Service Members having been diagnosed with a TBI between 2000 and 2021.^1,2 Currently, there are no U.S. Food and Drug Administration (FDA)-approved medications for TBI treatment, leaving a critical care gap unfilled.

With support from a fiscal year 2021 Traumatic Brain Injury and Psychological Health Research Program Clinical Trial Award-Research Level-2, Dr. Chris Marx’s team will conduct a phase 2 randomized controlled clinical trial (RCT) to evaluate whether a neurosteroid (pregnenolone) can improve psychological health, PTSD, and pain symptoms that are associated with chronic complex TBI. Neurosteroids are naturally occurring molecules that are most prevalent in the brain and provide pain relief, as well as neuroprotective, neuroregenerative, and anti-inflammatory effects. Dr. Marx’s team has shown that neurosteroids appear to be reduced in Veterans with TBI³ and in Veterans reporting pain symptoms,^4,5 so replenishing these molecules could be clinically therapeutic. They have also determined that pregnenolone treatment increases downstream allopregnanolone levels,^3,6 a neurosteroid with regenerative and neuroprotective effects.

Dr. Marx and Dr. Jennifer Naylor, the senior and lead authors, recently published an RCT evaluating pregnenolone for the treatment of chronic lower back pain in Iraq and Afghanistan-era Veterans, and this study showed promising results.⁶ Participants receiving pregnenolone experienced an overall reduction in pain compared to the placebo group. Pregnenolone also reduced the degree to which pain interfered with participants’ activities, mood, sleep, and enjoyment of life. In a joint effort with neuroimaging experts Drs. Martha Shenton, Inga Koerte, and Raj Morey, Dr. Marx also demonstrated that higher neurosteroid levels are correlated with greater cortical thickness in the brain, suggesting that neurosteroids support neuroregeneration, which may be beneficial in alleviating complex symptoms associated with TBI.^7,8

Based on these preliminary findings and successful clinical trial outcomes, Dr. Marx and her team will now evaluate pregnenolone treatment for psychological health, cognition, pain, PTSD, depression symptoms, and functional outcomes associated with TBI in Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn. The study is designed to explore potential biomarker predictors of treatment response and determine an ideal pregnenolone dose that offers the most benefit with the fewest side effects.

The team has started to prepare for the clinical trial and plans to begin enrolling participants in the coming months. Clinical trial data will be uploaded to Clinicaltrials.gov and to the Federal Interagency Traumatic Brain Injury Research (FITBIR) database. Building on this phase 2 study, Dr. Marx’s team plans to conduct a larger, pivotal phase 3 trial and explore intramuscular or transdermal patch delivery of pregnenolone to make this promising treatment convenient, easy to use, and accessible. If successful, these studies may lead to FDA approval of pregnenolone for TBI treatment and fill a critical care gap in the treatment of this complex injury.

References:

¹Military Health System and Defense Health Agency. 2023. Traumatic Brain Injury Centers of Excellence. https://health.mil/Military-Health-Topics/Centers-of-Excellence/Traumatic-Brain-Injury-Center-of-Excellence.

²Centers for Disease Control and Prevention. 2022. TBI Among Service Members and Veterans. https://www.cdc.gov/traumaticbraininjury/military/index.html.

³Marx CE, Naylor JC, Kilts JD, et al. 2016. Neurosteroids and traumatic brain injury: translating biomarkers to therapeutics; overview and pilot investigations in Iraq and Afghanistan era veterans. Translational Research in Traumatic Brain Injury, Ch7. https://pubmed.ncbi.nlm.nih.gov/26583188/.

⁴Naylor JC, Kilts JD, Szabo ST, et al. 2016. Allopregnanolone levels are inversely associated with self-reported pain symptoms in U.S. Iraq and Afghanistan era veterans: Implications for biomarkers and therapeutics. Pain Medicine 17(1):25-32. https://doi.org/10.1111/pme.12860.

⁵Kilts JD, Tupler LA, Keefe FJ, et al. 2010. Neurosteroids and self-reported pain in veterans who served in the U.S. Military after September 11, 2001. Pain Medicine 11(10):1469-76. https://doi.org/10.1111/j.1526-4637.2010.00927.x.

⁶Naylor JC, Kilts JD, Shampine LJ, et al. 2020. Effect of pregnenolone vs. placebo on self-reported chronic low back pain among U.S. military veterans: A randomized clinical trial. JAMA Network Open 3(3):e200287. https://doi.org/10.1001/jamanetworkopen.2020.0287.

⁷Kinzel P, Marx CE, Sollman N, et al. 2020. Serum neurosteroid levels are associated with cortical thickness in individuals diagnosed with posttraumatic stress disorder and history of mild traumatic brain injury. Clinical EEG and Neuroscience 51(4):285-299. https://doi.org/10.1177/1550059420909676.

⁸Morey RA, Davis SL, Haswell CC, et al. 2019. Widespread cortical thickness is associated with neuroactive steroid levels. Frontiers in Neuroscience 12(13):1118. https://doi.org/10.3389/fnins.2019.01118.

Link:
Public and Technical Abstracts: Novel Intervention for Chronic Complex TBI in OEF/OIF/OND Veterans

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