Pregnenolone for Chronic Traumatic Brain Injury

Recruiting at 1 trial location

Overseen By Jason Kilts, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Christine Marx, MD

Must not be taking: Benzodiazepines, Opioids, Hormonal supplements, others

Disqualifiers: Seizures, Stroke, Bipolar, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 8 weeks

108 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether pregnenolone, a hormone naturally found in the body, can improve mental health, physical function, thinking skills, PTSD symptoms, and pain in veterans with long-term brain injuries. Participants will take either pregnenolone or a placebo (a look-alike pill with no active ingredients) for eight weeks to determine which is more effective. It suits veterans who have experienced a mild traumatic brain injury since 2001 and do not plan to change their psychiatric or pain medications during the study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications if they are for stable and well-controlled conditions, like hypertension. However, you cannot change psychiatric or pain medications during the study or in the two weeks before joining. Some medications, like prednisone, are not allowed as they could affect the study results.

Is there any evidence suggesting that pregnenolone is likely to be safe for humans?

Research has shown that pregnenolone is generally safe for people, without major negative effects on mood, memory, sleep, or overall well-being. Most individuals who have taken pregnenolone did not experience serious side effects. Although some risk exists with any treatment, current evidence suggests pregnenolone is a safe option for addressing issues related to long-term brain injury. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Pregnenolone is unique because it is a naturally occurring hormone that might offer new hope for those with chronic traumatic brain injury (TBI). Most existing treatments for TBI focus on managing symptoms rather than addressing underlying damage. Pregnenolone stands out due to its potential neuroprotective effects, which could help repair and regenerate brain cells. Researchers are excited because it targets the root of the problem rather than just alleviating symptoms, offering a promising new approach for enhancing recovery in TBI patients.

What evidence suggests that pregnenolone might be an effective treatment for chronic traumatic brain injury?

This trial will compare Pregnenolone with a placebo to evaluate its effects on chronic traumatic brain injury (TBI). Research suggests that pregnenolone may benefit individuals with long-term TBI. Some studies have shown it can improve learning and memory in animals. Pregnenolone, a hormone produced in the brain, supports brain functions, such as forming a protective layer around nerves. Evidence also indicates it might help with PTSD (post-traumatic stress disorder) symptoms and overall mental health. Although more research is needed, early results appear promising for those with TBI. ^{6 7 8 9 10}

Who Is on the Research Team?

Chris Marx, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for OEF/OIF/OND-era U.S. Military Veterans aged 21-65 with a history of mild TBI since 2001, who can read English and consent to the study. They must not plan to change psychiatric or pain meds during the study, have no recent psychotropic interventions, and if female and able to become pregnant, must use birth control.

Inclusion Criteria

Ability to read/understand English and to participate fully in the informed consent process

History of mild TBI since 2001 and service in the U.S. Military since 9/11/01 (OEF/OIF/OND era) adhering to the WHO diagnostic definition of mild TBI

No changes in psychotropic or behavioral interventions during the study or in the 2 weeks prior to study enrollment

Exclusion Criteria

Participants with current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern

Participants who report a history of seizures, a history of stroke, a history of prostate cancer (or any other cancer other than non-melanoma skin cancer), a history of myocardial infarction, the presence of congestive heart failure, or any other serious health condition that would likely preclude safe study participation in the medical opinion of the PI or in consultation with the participant's PCP/other health care provider

Substance use disorder (DSM-5), other than nicotine use disorder

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either pregnenolone or placebo daily at home over an 8-week period

8 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Pregnenolone

Trial Overview The trial tests whether pregnenolone improves psychological health, physical function, cognition, PTSD symptoms, and pain in veterans with chronic TBI compared to a placebo over eight weeks. It also examines biological effects of pregnenolone and its optimal safe dose.

How Is the Trial Designed?

Group I: Pregnenolone Active Control 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Christine Marx, MD

Lead Sponsor

Trials

1

Recruited

110+

Published Research Related to This Trial

Pregnenolone significantly reduced ethanol self-administration in alcohol-preferring rats without causing locomotor impairment, suggesting its potential as a treatment for alcohol abuse.

Ganaxolone showed a complex effect on ethanol reinforcement, increasing self-administration at low doses but decreasing it at high doses, along with a reduction in locomotor activity at the highest dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats. Besheer, J., Lindsay, TG., O'Buckley, TK., et al.[2021]

The study identified two metabolites, 7 alpha-hydroxy-PREG and 7 beta-hydroxy-PREG, produced in mouse brain microsomes, with different kinetic properties indicating distinct enzymatic pathways for their production.

Different cytochrome P450 (CYP) enzymes are involved in the hydroxylation of pregnenolone, with specific inhibitors revealing that 7 alpha-hydroxylation is primarily inhibited by certain compounds, while 7 beta-hydroxylation involves CYP 1A1 and other unidentified enzymes, providing insights for future research on these metabolic processes in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes. Doostzadeh, J., Morfin, R.[2019]

In a study of 64 adolescents with autism spectrum disorders, adding pregnenolone to risperidone treatment showed significant improvements in irritability, stereotypy, and hyperactivity, suggesting it may enhance the effectiveness of standard treatment.

The addition of pregnenolone did not increase the frequency or severity of adverse effects compared to placebo, indicating it is a safe adjunct therapy for managing symptoms of ASD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial? Ayatollahi, A., Bagheri, S., Ashraf-Ganjouei, A., et al.[2023]

In a study of 70 participants with bipolar disorder or major depressive disorder and a history of substance abuse, pregnenolone showed a statistically significant reduction in depression symptoms compared to placebo after 8 weeks, indicating its potential efficacy in mood improvement.

Pregnenolone was found to be safe and well tolerated, but it did not demonstrate significant effects on cognitive function, suggesting that its benefits may be more focused on mood rather than cognitive deficits in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone for cognition and mood in dual diagnosis patients. Osuji, IJ., Vera-Bolaños, E., Carmody, TJ., et al.[2013]

Pregnenolone exacerbates neurodegeneration and cognitive deficits caused by carbon monoxide exposure in mice, indicating it may enhance excitotoxic effects through NMDA receptor modulation.

In contrast, dehydroepiandrosterone (DHEA) demonstrates neuroprotective properties, effectively blocking cognitive deficits and neurodegeneration after carbon monoxide exposure, suggesting it may counteract excitotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential effect of dehydroepiandrosterone and its steroid precursor pregnenolone against the behavioural deficits in CO-exposed mice. Maurice, T., Phan, V., Sandillon, F., et al.[2019]

In a study with 17 volunteers, pregnenolone was found to be well-tolerated but did not significantly affect mood, memory, or sleep quality over a 4-week period.

In a follow-up study with 11 participants, those pre-treated with pregnenolone experienced significantly less sedation from diazepam, suggesting that pregnenolone may counteract some effects of benzodiazepines, indicating a potential for enhancing arousal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Meieran, SE., Reus, VI., Webster, R., et al.[2019]

Acute administration of pregnenolone significantly reduced alcohol intake and preference in alcohol-preferring rats, particularly at doses of 50 mg/kg and 75 mg/kg, indicating its potential to modulate alcohol consumption behavior.

Chronic treatment with pregnenolone over 10 days did not show significant effects on alcohol intake or preference, suggesting that while it may have short-term benefits, its long-term efficacy for treating alcoholism may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats. Rezvani, AH., Levin, ED.[2014]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10684848/

Neurosteroid Receptor Modulators for Treating Traumatic ... Recent evidence suggests that allopregnanolone may also be useful for post-concussive symptoms and post-traumatic stress disorder (PTSD) ...

2. clinicaltrial.be clinicaltrial.be/en/details/175294?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Novel Intervention for Chronic Complex TBI in OEF/OIF/OND... The main questions it aims to answer are: * Does pregnenolone improve psychological health, overall physical function, cognition, symptoms of PTSD, and pain ...

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK326734/

Neurosteroids and Traumatic Brain Injury - NCBI - NIH Pregnenolone is another neurosteroid that may merit further attention in TBI, as it enhances learning and memory in rodents, regulates myelination,, stabilizes ...

4. trialx.com trialx.com/clinical-trials/listings/302963/novel-intervention-for-chronic-complex-tbi-in-oefoifond-veterans/?&radius=50

Novel Intervention for Chronic Complex TBI in OEF/OIF ... The main questions it aims to answer are: Does pregnenolone improve psychological health, overall physical function, cognition, symptoms of PTSD ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03645096

Development of Pregnenolone as a Treatment ... Pregnenolone, an over-the-counter supplement, is a naturally occurring neurosteroid made in the adrenal glands and brain. Preclinical research suggests ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05671692

Novel Intervention for Chronic Complex TBI in OEF/OIF ... Does pregnenolone improve psychological health, overall physical function, cognition, symptoms of PTSD, and pain more than placebo over the 8-week study period, ...

7. cdmrp.health.mil cdmrp.health.mil/tbiphrp/research_highlights/23Chris_Marx_highlight

Traumatic Brain Injury and Psychological Health A neurosteroid (pregnenolone) can improve psychological health, PTSD, and pain symptoms that are associated with chronic complex TBI.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01336413

Neuroactive Steroids and Traumatic Brain Injury (TBI) in ... Trial duration will be 10 weeks, consisting of a 2-week placebo lead-in period for all subjects, followed by 8 weeks of treatment with either pregnenolone or ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9138587/

Current Clinical Trials in Traumatic Brain Injury - PMC Of the 44 studies, 30 showed no statistical difference between treatment and controls, 7 studies showed better results in the treatment arm but lacked ...

10. withpower.com withpower.com/trial/phase-2-brain-injuries-2023-6bcb0

Pregnenolone for Chronic Traumatic Brain Injury Pregnenolone has been generally well-tolerated in studies with humans, showing no significant negative effects on mood, memory, sleep quality, or well-being. It ...