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

Trial Summary

What is the purpose of this trial?

This trial is testing whether pregnenolone can help improve mental and physical health in veterans with long-term brain injuries. Participants will take pregnenolone daily for a period of time. The study aims to see if pregnenolone is effective in improving health outcomes and to find the best safe dose.

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.

What evidence supports the effectiveness of pregnenolone as a drug for chronic traumatic brain injury?

Pregnenolone has shown potential in reducing sedation effects when used with diazepam, a medication affecting the brain, and has been studied for its role in modulating alcohol intake in animal models. However, its direct effectiveness for chronic traumatic brain injury is not clearly established in the provided research. ^{1 2 3 4 5}

Is pregnenolone generally safe for humans?

Pregnenolone has been generally well-tolerated in studies with humans, showing no significant negative effects on mood, memory, sleep quality, or well-being. It appeared safe and well-tolerated in patients with mood and substance-use disorders, although it may increase certain risks in specific conditions, such as facilitating neuronal damage in animal models exposed to hypoxia. ^{2 4 5 6 7}

How is the drug pregnenolone unique for treating chronic traumatic brain injury?

Pregnenolone is unique because it is a neurosteroid that can modulate brain receptors like GABA(A), potentially affecting mood and cognition, which might be beneficial for brain injury recovery. Unlike other treatments, it has been studied for its effects on mood and cognitive functions in various conditions, suggesting it might offer novel benefits for brain injury patients. ^{2 4 5 6 7}

Research Team

Chris Marx, MD

Principal Investigator

Duke University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. [2019]

3. England 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. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

Differential effect of dehydroepiandrosterone and its steroid precursor pregnenolone against the behavioural deficits in CO-exposed mice. [2019]

6. Ireland pubmed.ncbi.nlm.nih.gov

Pregnenolone for cognition and mood in dual diagnosis patients. [2013]

7. United States 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? [2023]