Pregnenolone for Anxiety and Depression

Overseen By Christine E Marx, MD MA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Benzodiazepines, Opioids

Disqualifiers: PTSD, Bipolar, Schizophrenia, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

84 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if pregnenolone can help Veterans with anxiety, depression, poor sleep, and chronic pain. Researchers believe pregnenolone might address these issues simultaneously. The trial will compare pregnenolone to a placebo, a harmless pill with no active medication. Veterans receiving care at the Durham VAHCS and experiencing moderate to severe anxiety and depression symptoms may qualify for this study. As a Phase 2 trial, this research measures pregnenolone's effectiveness in an initial, smaller group, offering participants the chance to contribute to important findings.

Will I have to stop taking my current medications?

You won't have to stop taking your current psychiatric medications, but you can't change them for 4 weeks before starting the study. If you're using benzodiazepines or opioids, you can't participate in the trial.

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

Research has shown that pregnenolone is usually safe for use. In previous studies, participants reported only minor side effects, suggesting the treatment is likely safe for most individuals. Pregnenolone, a natural substance in the body, helps create other hormones. As a treatment, it has demonstrated a good safety record, meaning it doesn't cause major side effects. This makes it a potential option for those experiencing anxiety and depression symptoms. However, as with any treatment, consulting a healthcare provider is important to ensure it's appropriate. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Pregnenolone is unique because it is a naturally occurring steroid hormone that functions as a precursor to various other hormones, including those involved in mood regulation. Unlike traditional treatments for anxiety and depression, such as SSRIs or SNRIs, which primarily target neurotransmitters like serotonin and norepinephrine, pregnenolone offers a different approach by potentially modulating the stress response and enhancing neurosteroid activity. Researchers are excited about pregnenolone because it might offer a faster onset of action and fewer side effects compared to conventional antidepressants, providing a novel option for those who don't respond well to current therapies.

What evidence suggests that pregnenolone might be an effective treatment for anxiety and depression?

Research has shown that pregnenolone, which participants in this trial may receive, might help alleviate depression symptoms. One study found that it improved depression in individuals with borderline personality disorder (BPD). Another study discovered that pregnenolone can increase levels of allopregnanolone, a substance that calms brain areas linked to negative emotions. Pregnenolone affects GABA A receptors, which play a role in mood control. These findings suggest that pregnenolone could be useful for treating anxiety and depression. ^{6 7 8 9 10}

Who Is on the Research Team?

Jennifer C Naylor, PhD

Principal Investigator

Durham VA Medical Center, Durham, NC

Christine E Marx, MD MA

Principal Investigator

Durham VA Medical Center, Durham, NC

Are You a Good Fit for This Trial?

This trial is for veterans experiencing symptoms of anxiety and depression, who may also be dealing with poor sleep quality and chronic pain. To participate, they should not have any conditions that would exclude them from the study as per the trial's specific criteria.

Inclusion Criteria

I am using or will use a non-hormonal birth control method or cannot become pregnant.

I don't expect to change my psychiatric meds during the study.

Veterans enrolled for care at the Durham VAHCS

Exclusion Criteria

I do not have a serious illness like a stroke or cancer (prostate, uterine, breast) that is currently unstable.

Current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern

I don't have health issues that would make taking PREG unsafe.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Placebo Lead-in

Participants receive placebo for 2 weeks before randomization

2 weeks

Treatment

Participants receive either pregnenolone or placebo for 8 weeks with flexible dosing

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pregnenolone

Trial Overview

The clinical trial is testing pregnenolone, a medication thought to help with psychiatric symptoms and improve overall function in those suffering from anxiety and depression. Participants will either receive pregnenolone or a placebo (a substance with no active drug).

How Is the Trial Designed?

Group I: Pregnenolone Active Control 1 Intervention

Pregnenolone 250 mg BID x 14 DAYS, followed by Pregnenolone 500 mg BID x 14 DAYS, followed by Pregnenolone 1000 mg BID x thereafter for the remainder of the 8-week trial.

Group II: Placebo Placebo Group 1 Intervention

Same as active comparator, except placebo dispensed

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

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 12-week pilot study involving 12 young adults with autism spectrum disorder, pregnenolone significantly reduced irritability, as measured by the Aberrant Behavior Checklist, with scores improving from 17.4 to 11.2 (p = 0.028).

Pregnenolone was well-tolerated with no severe side effects reported, and only mild adverse effects like tiredness and diarrhea were noted, indicating its safety for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Fung, LK., Libove, RA., Phillips, J., 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]

In a study of 11 patients with bipolar depression and 4 healthy controls, serum MAP2 levels were found to be higher in the depressed patients, suggesting a potential biomarker for mood disorders.

Pregnenolone treatment showed a positive correlation between changes in MAP2 levels and improvements in depressive symptoms, indicating that MAP2 may play a role in the antidepressant effects of pregnenolone, although the results were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone. Daftary, S., Yon, JM., Choi, EK., et al.[2022]

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 80 adults with bipolar disorder, pregnenolone (500 mg/day) as an add-on therapy for 12 weeks significantly improved depressive symptoms, with a remission rate of 61% compared to 37% in the placebo group.

Pregnenolone was well tolerated and led to significant changes in neurosteroid levels, suggesting it may be a safe and effective option for treating depression in bipolar disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Brown, ES., Park, J., Marx, CE., et al.[2021]

In a study involving cynomolgus monkeys, naloxone increased pregnenolone (PREG) levels, while corticotropin-releasing factor (CRF) appeared to enhance the conversion of PREG to deoxycorticosterone (DOC), indicating a complex regulation of PREG by the HPA axis.

Dexamethasone reduced PREG levels despite increasing cortisol, and changes in PREG levels were linked to alcohol intake, suggesting that PREG responses could be a potential marker for alcohol consumption behaviors in non-human primates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma pregnenolone levels in cynomolgus monkeys following pharmacological challenges of the hypothalamic-pituitary-adrenal axis. Porcu, P., Rogers, LS., Morrow, AL., et al.[2013]

A new series of compounds derived from pregnenolone were synthesized and characterized, showing significant activity against EC109 cancer cells, indicating potential for cancer treatment.

The synthesis involved biotransformation using the fungus Mucor circinelloides, which highlights a novel method for creating these bioactive derivatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis of 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives and their cytotoxic activities. Shan, LH., Liu, HM., Huang, KX., et al.[2013]

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The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.

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These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion.

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The novel rapid-acting neurosteroid-based antidepressant ...

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