Pregnenolone for PTSD

Overseen By Jennifer C Naylor, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Benzodiazepines, Hormonal therapies

Disqualifiers: Bipolar, Schizophrenia, Cancer, 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: 7

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if pregnenolone, a natural hormone, can alleviate symptoms of PTSD (post-traumatic stress disorder) in Veterans who served in Iraq or Afghanistan. Participants will receive either pregnenolone or a placebo (a non-active pill) over 10 weeks. Veterans who have experienced PTSD and do not plan to change their psychiatric medications soon might be suitable for this trial. Participants will attend six in-person visits and have several short phone check-ins to monitor their progress. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important PTSD research.

Do I need to stop taking my current medications to join the trial?

You don't need to stop taking your current psychiatric medications, but you can't change them for 4 weeks before the study starts. Hormonal therapies and birth control are not allowed.

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

Research has shown that pregnenolone is a hormone precursor, meaning it helps the body produce other hormones like estrogen and testosterone. It also supports the body's stress response and normal adrenal function.

Regarding safety, pregnenolone has been used in other situations without major issues. Some people use it to help with mood, memory, and sleep. However, like any treatment, possible side effects should be considered. Some individuals might experience mild side effects, but serious problems have not been commonly reported in the available research.

Since this trial is in an early phase, researchers are still learning about the treatment's safety. While some evidence supports its safety, more research is needed to fully understand how well it is tolerated in people with PTSD. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PTSD?

Most treatments for PTSD, like SSRIs or psychotherapy, focus on altering neurotransmitter levels or cognitive behaviors. But pregnenolone works differently, targeting neurosteroid pathways. Researchers are excited about pregnenolone because it's a naturally occurring steroid that might modulate stress responses more directly, potentially offering quicker symptom relief. Additionally, pregnenolone's role in brain health could mean fewer side effects compared to traditional medications, making it a promising option for those who haven't found success with existing treatments.

What evidence suggests that pregnenolone might be an effective treatment for PTSD?

Research suggests that pregnenolone, which participants in this trial may receive, could be a promising treatment for PTSD. Studies have found that people with PTSD often have lower levels of certain brain chemicals, such as allopregnanolone, believed to affect mood and stress. Pregnenolone may help increase these chemical levels, possibly improving PTSD symptoms. Early findings indicate that pregnenolone might also help with related issues, such as sleep problems and depression. Although more research is needed, this treatment shows potential for helping veterans with PTSD. ^{6 7 8 9 10}

Who Is on the Research Team?

Jennifer C Naylor, PhD

Principal Investigator

Durham VA Medical Center, Durham, NC

Are You a Good Fit for This Trial?

This trial is for Iraq/Afghanistan-era Veterans with PTSD who can commit to a 10-week study without changing their psychiatric medications. They must not have severe medical conditions, be pregnant or breastfeeding, use hormonal therapies, or have substance abuse issues. Stable non-hormonal birth control is required for women.

Inclusion Criteria

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

Birth control methods must be non-hormonal

I am using approved birth control or cannot become pregnant.

Exclusion Criteria

You have had an allergic reaction to pregnenolone in the past.

Standard pharmacological interventions for PTSD will not be exclusionary, including, but not limited to: antidepressant medications such as SSRIs, SNRIs, tricyclics, bupropion, mirtazapine, venlafaxine, and nefazodone; mood stabilizers such as carbamazepine, divalproex, lamotrigine, topiramate; atypical antipsychotics, and other agents including prazosin. However, there may be no changes in psychotropic medications for PTSD 4 weeks prior to study randomization; Benzodiazepine use; Current diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than mild TBI (assessed at screening); Initiation or change in psychotherapy within 3 months of randomization (i.e., psychotherapy must be stable for 3 months prior to study start); Participants on hormonal therapies such as finasteride or hormonal birth control; Female participants who are pregnant or breast-feeding; As indicated by the DSM-5, moderate or severe Substance Use Disorders (excluding caffeine and tobacco) within 1 month of study entry; Mild Alcohol Use Disorder is not exclusionary, at the judgment of the PI and her medical team

I don't have health issues that worsen with pregnenolone or PTSD treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Placebo Lead-in

Participants receive a single-blind placebo for 2 weeks

2 weeks

1 visit (in-person)

Treatment

Participants receive either pregnenolone or placebo for 8 weeks

8 weeks

5 visits (in-person), several short 'check-in' phone calls

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 study tests if pregnenolone improves PTSD symptoms compared to a placebo over 10 weeks. Participants will receive either the hormone or placebo and undergo regular health assessments during six in-person visits and check-in calls.

How Is the Trial Designed?

Group I: Pregnenolone Experimental Treatment 1 Intervention

Placebo lead in 14 DAYS, followed by Pregnenolone 50 mg BID x 14 DAYS, followed by Pregnenolone 150 mg BID x 14 DAYS, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial

Group II: Placebo Placebo Group 1 Intervention

Same as pregnenolone (active study medication), 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

A new compound, 3-beta-pregnenolone acetate (compound #43), was developed as a non-metabolizable derivative of pregnenolone (P5) and was found to effectively promote microtubule polymerization, similar to P5.

Compound #43 demonstrated significant effects in live cells, including increased neurite outgrowth and stable microtubule formation in zebrafish, suggesting its potential as a therapeutic candidate for neurodevelopmental diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A synthetic pregnenolone analog promotes microtubule dynamics and neural development. Kolas, V., Bandonil, JSA., Wali, N., et al.[2022]

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 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 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]

Pregnenolone at a dose of 10 μM was found to be optimal for promoting the proliferation of neural stem cells (NSCs), significantly increasing the number of neurospheres compared to controls.

Lower doses of pregnenolone (5 and 10 μM) enhanced NSC differentiation into oligodendrocytes, while higher doses (15 μM) promoted differentiation into neurons, indicating that pregnenolone can regulate NSC fate depending on the concentration used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone enhances the proliferation of mouse neural stem cells and promotes oligodendrogenesis, together with Sox10, and neurogenesis, along with Notch1 and Pax6. Negintaji, K., Ghanbari, A., Frozanfar, M., et al.[2023]

Pregnenolone sulfate and its derivatives significantly enhance NMDA-induced calcium responses in rat hippocampal neurons, with a 300% increase observed at a concentration of 50 microM, indicating a strong potentiation effect on NMDA receptor activity.

Some steroids, like 3 alpha-hydroxy-5 beta-pregnan-20-one sulfate, can inhibit NMDA-induced calcium responses, suggesting that these steroids may act as modulators of NMDA receptor function, potentially influencing synaptic events in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steroid potentiation and inhibition of N-methyl-D-aspartate receptor-mediated intracellular Ca++ responses: structure-activity studies. Irwin, RP., Lin, SZ., Rogawski, MA., et al.[2015]

In a randomized double-blind trial involving 82 female inpatients with chronic schizophrenia, pregnenolone (50 mg/day) did not show a significant difference in overall symptom improvement compared to placebo after 8 weeks, as measured by the PANSS total score.

Although pregnenolone showed some initial positive effects on negative symptoms and general psychopathology, these results were not statistically significant after adjusting for multiple comparisons, indicating that more research is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone as an adjunct to risperidone for treatment of women with schizophrenia: A randomized double-blind placebo-controlled clinical trial. Kashani, L., Shams, N., Moazen-Zadeh, E., et al.[2019]

In a randomized controlled trial involving 120 participants with schizophrenia, pregnenolone treatment for 8 weeks significantly improved functional capacity compared to placebo, particularly in communication skills.

While pregnenolone did not show significant effects on cognitive symptoms, it was well-tolerated and serum levels of pregnenolone correlated with functional improvements in female participants, suggesting potential as a therapeutic option for schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. Marx, CE., Lee, J., Subramaniam, M., et al.[2021]

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