Pregnenolone for Alcoholism

Recruiting at 1 trial location

Overseen By Rajita Sinha, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must not be taking: Opioids, Anticonvulsants, Sedatives, others

Disqualifiers: Substance use disorders, Psychotic disorders, others

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

Compensation: Varies

Number of Visits: 25

Duration: 12 weeks

150 Participants Needed

Trial Summary

What is the purpose of this trial?

This Phase 2 randomized cotrolled trial (RCT) will assess the safety and efficacy of pregnenolone (PREG; 300 mg/day, b.i.d dosing) vs. placebo (PBO) over a 12 week treatment period, and at 1-month post-treatment follow-up in individuals with Alcohol Use Disorder (AUD).

Will I have to stop taking my current medications?

The trial requires you to stop using certain medications like opioids, anticonvulsants, sedatives, and some steroid medications. However, stable prescribed medications for conditions like high blood pressure, heart issues, diabetes, depression, and anxiety may be allowed after review by the study physician.

What evidence supports the effectiveness of the drug pregnenolone for treating alcoholism?

Research suggests that pregnenolone, a neuroactive steroid, may help reduce alcohol intake in animal models, such as alcohol-preferring rats. Additionally, increased levels of pregnenolone have been observed in the brains of alcoholics, indicating a potential link between this steroid and alcohol use disorders. ^{1 2 3 4 5}

Is pregnenolone safe for human use?

Pregnenolone has been generally well-tolerated in humans, with studies showing no significant effects on mood, memory, sleep quality, or well-being when taken at doses of 15-30 mg per day over four weeks. ^{1 2 5 6 7}

How does the drug pregnenolone work for alcoholism?

Pregnenolone is a neuroactive steroid that may help reduce alcohol intake by affecting the GABAergic system, which is involved in brain signaling. It is unique because it is a natural precursor to other neurosteroids and has shown potential in animal studies to influence alcohol consumption, although its effects in humans are still being explored. ^{1 2 3 4 6}

Eligibility Criteria

This trial is for English-speaking adults aged 18-70 with Alcohol Use Disorder, confirmed by a positive alcohol test or reports from close contacts. Participants must consent to the study's procedures. Pregnant or nursing women, individuals not using effective birth control, opiate users, those on psychoactive drugs including anxiolytics, naltrexone or antabuse, and people with severe medical conditions or low blood pressure are excluded.

Inclusion Criteria

Subjects must meet current Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) criteria for alcohol use disorder; documented positive urine toxicology screen for alcohol at intake or collateral information from family members, significant others, room-mates etc., on recent use

Subject has voluntarily given informed consent and signed the informed consent document

Able to read English and complete study evaluations

Exclusion Criteria

Significant underlying medical conditions such as cerebral, renal, thyroid or cardiac pathology which in the opinion of study physician would preclude patient from fully cooperating or be of potential harm during the course of the study

Any current use of opiates or past history of opiate use disorder (assessed via urine toxicology and self report)

Meet current criteria for use disorder on another psychoactive substance, such as, heroin, amphetamines, hallucinogens/Phencyclidine (PCP), excluding alcohol and nicotine

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 300mg pregnenolone or placebo daily for 12 weeks, with bi-weekly assessments and behavioral counseling

12 weeks

24 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Placebo
• Pregnenolone

Trial Overview The trial tests Pregnenolone (300 mg/day) against a placebo over 12 weeks plus follow-up in treating Alcohol Use Disorder. It's a Phase 2 randomized controlled trial where participants are randomly assigned to receive either the hormone treatment or an inactive substance without knowing which one they're getting.

Participant Groups

Group I: patients receiving 300mg PREG Active Control 1 Intervention

Patients randomly assigned to receive 300mg of pregnenolone (PREG) daily.

Group II: placebo Placebo Group 1 Intervention

Patients randomly assigned to receive a placebo daily.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Findings from Research

Acute administration of pregnenolone significantly reduced alcohol intake and preference in alcohol-preferring rats, particularly at doses of 50 mg/kg and 75 mg/kg, indicating its potential to modulate alcohol consumption behavior.

Chronic treatment with pregnenolone over 10 days did not show significant effects on alcohol intake or preference, suggesting that while it may have short-term benefits, its long-term efficacy for treating alcoholism may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats. Rezvani, AH., Levin, ED.[2014]

Pregnenolone significantly reduced ethanol self-administration in alcohol-preferring rats without causing locomotor impairment, suggesting its potential as a treatment for alcohol abuse.

Ganaxolone showed a complex effect on ethanol reinforcement, increasing self-administration at low doses but decreasing it at high doses, along with a reduction in locomotor activity at the highest dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats. Besheer, J., Lindsay, TG., O'Buckley, TK., et al.[2021]

In a study of post-mortem brain samples from 14 alcoholics and 10 non-alcoholic controls, significant increases in the steroid hormones DHEA and pregnenolone (PREGN) were found in alcoholics, particularly in key brain regions like the nucleus accumbens and anterior cingulate cortex.

The study also revealed a negative correlation between PREGN levels and μ-opioid receptor binding, suggesting a potential link between altered steroid hormone levels and the opioid system in the context of alcoholism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased steroid hormone dehydroepiandrosterone and pregnenolone levels in post-mortem brain samples of alcoholics. Kärkkäinen, O., Häkkinen, MR., Auriola, S., et al.[2018]

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]

Allopregnanolone, a neuroactive steroid, shows promise as a therapeutic option for treating symptoms of alcohol use disorders (AUDs), supported by both basic science and clinical evidence.

The review highlights the importance of understanding how allopregnanolone and its precursor, pregnenolone, may help regulate stress and immune responses related to AUDs, while also addressing potential risks and management strategies for therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies. Morrow, AL., Boero, G., Porcu, P.[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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats. [2014]

2. England pubmed.ncbi.nlm.nih.gov

Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats. [2021]

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

Increased steroid hormone dehydroepiandrosterone and pregnenolone levels in post-mortem brain samples of alcoholics. [2018]

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

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies. [2021]

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

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

7. 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]