Wide release: May 15, 2026. Not medical advice.
Nick speaks with Dr. Sherwood Brown on the steroid hormone pathway and neurosteroids. Brown details the biosynthesis of steroids from cholesterol to pregnenolone, pregnenolone’s direct actions as a positive NMDA modulator and negative CB1 allosteric modulator, and his placebo-controlled trials showing antidepressant effects in bipolar disorder. They also examine corticosteroids’ impact on hippocampal volume and memory, hormone fluctuations across the female lifespan, and emerging research on neurosteroids for mood and substance use disorders.
TOPICS DISCUSSED:
Steroid Biosynthesis: Cholesterol converted to pregnenolone, the precursor for all steroid hormones including cortisol, aldosterone, and sex hormones.
Corticosteroids: Synthetic versions like prednisone primarily target glucocorticoid receptors for anti-inflammatory uses but can impact mood and cognition.
Pregnenolone Mechanisms: Positive allosteric modulator of NMDA receptors for cognition and negative allosteric modulator of CB1 cannabinoid receptors.
Allopregnanolone: GABAergic derivative of pregnenolone; its IV form Brexanolone is FDA-approved for postpartum depression.
Clinical Trials: Pregnenolone at 100-500 mg improved depressive symptoms in placebo-controlled studies of bipolar disorder patients.
Cannabis Interaction: THC robustly induces brain pregnenolone production; supplementation may reduce cannabis and alcohol use.
Corticosteroid Brain Impact: Prednisone use associated with smaller hippocampal volumes and memory deficits.
ABOUT THE GUEST: Sherwood Brown, MD, PhD is Vice Chair for Clinical Research in the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas. With a background in chemistry, his research focuses on steroids and comorbidities in people with mood disorders.
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PRACTICAL TAKEAWAYS:
Pregnenolone is sold as an OTC supplement and has been studied at doses of 100-500 mg with good tolerability in mood disorder trials.
Corticosteroids for conditions like asthma can cause measurable, often reversible changes in hippocampal volume and memory.
Cholesterol is essential for producing all steroid hormones including those supporting brain function and mood.
SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.
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