Pregnenolone for Autism

Overseen By Lawrence K. Fung, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Steroid medications

Disqualifiers: Schizophrenia, Schizoaffective, Alcohol use, 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: 14 weeks

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants have stable medications for at least 2 weeks before joining, and they cannot be taking steroid medications.

What data supports the effectiveness of the drug pregnenolone for autism?

Research shows that pregnenolone, a neurosteroid, can reduce irritability in adults with autism spectrum disorder, as seen in a study where participants showed significant improvement in irritability scores after 12 weeks of treatment. ^{1 2 3 4 5}

Is pregnenolone safe for use in humans?

Pregnenolone has been studied in people with autism and was generally well-tolerated, with no severe side effects reported. Some participants experienced mild issues like tiredness, diarrhea, and a low mood, but these were not common. ^{1 2 3 5 6}

How is the drug pregnenolone unique for treating autism?

Pregnenolone is a neurosteroid that may help reduce irritability in individuals with autism by modulating neurotransmission in the brain. Unlike other treatments, it is known for its role in enhancing neural development and memory, and it has been shown to be well-tolerated with minimal side effects. ^{1 2 4 5 6}

What is the purpose of this trial?

This trial is testing pregnenolone, a natural hormone in the brain, to see if it can help people with autism. Pregnenolone is part of a neurosteroid pathway that has been studied for its potential therapeutic value in stress and drug abuse-related disorders. The goal is to find out if it can reduce irritability and sensitivity to sensory differences, and improve social communication. Researchers hope this will lead to better treatments for autism.

Research Team

Antonio Hardan, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for healthy males and females aged 14-25 with Autism Spectrum Disorder (ASD), confirmed by specific diagnostic tools. Participants must have a certain level of irritability and severity of ASD symptoms, be in the late stages of puberty, and on stable medications without changes planned during the study. Those with unstable seizures, significant illness, other major psychiatric disorders, or women who are pregnant or not using contraception cannot join.

Inclusion Criteria

I am between 14 and 25 years old and have reached a late stage of puberty.

I am physically healthy.

My medications have not changed in the last 2 weeks.

Exclusion Criteria

I am not pregnant or I use birth control if sexually active.

I am currently taking steroid medications.

You have already tried the medication pregnenolone in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pregnenolone with increasing doses over 14 weeks to assess tolerability and effectiveness

14 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo
• Pregnenolone

Trial Overview The study tests pregnenolone's safety and effectiveness compared to a placebo in reducing irritability, improving sensitivity to sensory differences, and enhancing social communication in individuals with autism. Pregnenolone is a hormone thought to help various psychiatric conditions.

Participant Groups

Group I: Pregnenolone (up to 500 mg per day) Experimental Treatment 1 Intervention

Twice daily intake of orally administered Pregnenolone will occur on a schedule as described below. Weeks 1 and 2: 30mg twice daily (total 60mg per day) Weeks 3 and 4: 60mg twice daily (total: 120mg per day) Weeks 5 and 6: 90mg twice daily (total: 180mg per day) Weeks 7 and 8: 150mg twice daily (total: 300mg per day) Weeks 9 and 10: 210mg twice daily (total: 420mg per day) Weeks 11 to 14: 250mg twice daily (total: 500mg per day)

Group II: Placebo Placebo Group 1 Intervention

Placebo

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Simons Foundation

Collaborator

Trials

8

Recruited

101,000+

Findings from Research

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]

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 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]

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]

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. 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]

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

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

5. England pubmed.ncbi.nlm.nih.gov

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

6. 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]