Pregnenolone for PTSD

Recruiting in Palo Alto (17 mi)

Overseen by Jennifer C Naylor, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: VA Office of Research and Development

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests pregnenolone, a natural hormone booster, to see if it can help Iraq/Afghanistan-era Veterans with PTSD who need better treatment options. Pregnenolone works by balancing brain chemicals to improve mood and reduce PTSD symptoms. Pregnenolone has been studied for its brain-protective effects, particularly in relation to its conversion to estradiol.

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.

What data supports the idea that Pregnenolone for PTSD is an effective drug?

The available research does not provide direct evidence supporting the effectiveness of Pregnenolone for PTSD. The studies mentioned focus on other conditions like autism spectrum disorder and schizophrenia. For instance, in autism spectrum disorder, Pregnenolone showed some improvement in irritability, but this is not directly related to PTSD. In schizophrenia, the results were inconsistent and did not show significant improvement. Therefore, there is no clear data supporting Pregnenolone as an effective treatment for PTSD based on the provided information. ^{1 2 3 4 5}

What safety data exists for pregnenolone treatment?

Pregnenolone has been studied for its safety and tolerability in various contexts. In a study with normal volunteers, pregnenolone was generally well-tolerated with no significant effects on mood, memory, sleep quality, or well-being. In a study with adults with autism spectrum disorder, pregnenolone was modestly effective and well-tolerated, with no severe side effects reported. Some minor side effects like tiredness, diarrhea, and depressive affect were noted. Overall, pregnenolone appears to be safe with a good tolerability profile in these studies. ^{1 2 3 6 7}

Is the drug pregnenolone a promising treatment for PTSD?

Pregnenolone shows potential as a treatment because it can reduce stress, improve memory, and help with recovery from injuries. It has been effective in reducing irritability in autism and can enhance brain functions, which might be beneficial for PTSD. ^{1 2 3 6 8}

Research Team

Jennifer C Naylor, PhD

Principal Investigator

Durham VA Medical Center, Durham, NC

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Pregnenolone (Neurosteroid)

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.

Participant Groups

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+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

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 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]

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]

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]

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]

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]

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

Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial? [2023]

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

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

4. Germany pubmed.ncbi.nlm.nih.gov

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. [2021]

5. England 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. [2019]

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

Steroid potentiation and inhibition of N-methyl-D-aspartate receptor-mediated intracellular Ca++ responses: structure-activity studies. [2015]

7. England 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

A synthetic pregnenolone analog promotes microtubule dynamics and neural development. [2022]