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

Trial Summary

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.

What evidence supports the effectiveness of the drug pregnenolone for anxiety and depression?

Research suggests that pregnenolone may help improve mood in people with mood disorders, as one study found it led to a reduction in depressive symptoms in patients with a history of substance use. Additionally, it showed some effectiveness in reducing irritability in adults with autism spectrum disorder, which may indirectly suggest potential benefits for mood-related conditions. ^{1 2 3 4 5}

Is pregnenolone generally safe for humans?

The research does not provide specific safety data for pregnenolone in humans, but it does mention that pregnenolone can affect anxiety levels in mice and interacts with other substances like ethanol. Further studies are needed to determine its safety in humans. ^{5 6 7 8 9}

How is the drug pregnenolone unique for treating anxiety and depression?

Pregnenolone is unique because it is a neurosteroid that may improve mood and depressive symptoms by affecting brain receptors and possibly interacting with microtubule associated protein 2 (MAP2), which is a novel target for antidepressant therapy. It has shown potential benefits in mood disorders, especially in patients with bipolar disorder, and is generally well-tolerated. ^{1 3 7 10 11}

What is the purpose of this trial?

Anxiety and depression symptoms occur at high rates in Veteran populations and can significantly impact function, compromising the ability to work and to successfully form and maintain valued relationships. Several other symptoms commonly occur with anxiety and depression, including poor sleep quality and chronic pain. Since all these symptoms frequently occur together, they may have a common underlying biological basis. A single medication that could effectively treat all these symptoms would be ideal. Converging data suggest that pregnenolone is a promising pharmacological agent for treating multiple psychiatric symptoms and functional impairment. The investigators thus propose to conduct a clinical trial of pregnenolone in Veterans with anxiety and depression symptoms. Pregnenolone has minimal side effects, and the prior research demonstrates that pregnenolone is well-tolerated by Veterans. Treatment with pregnenolone could thus be an efficacious new therapeutic for Veterans experiencing depression, anxiety, poor sleep quality and chronic pain conditions.

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

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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 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 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 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]

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]

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]

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 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]

References

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

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

2. United States pubmed.ncbi.nlm.nih.gov

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. [2021]

3. Ireland pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Plasma pregnenolone levels in cynomolgus monkeys following pharmacological challenges of the hypothalamic-pituitary-adrenal axis. [2013]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Synthesis of 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives and their cytotoxic activities. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on the plus-maze. [2019]

8. France pubmed.ncbi.nlm.nih.gov

Effect of the position of the cyano-group of cyanopregnenolones on their drug metabolic inducing activity. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

The Knoevenagel reactions of pregnenolone with cyanomethylene reagents: synthesis of thiophene, thieno[2,3-b]pyridine, thieno[3,2-d]isoxazole derivatives of pregnenolone and their in vitro cytotoxicity towards tumor and normal cell lines. [2013]

10. England pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone. [2022]