Open questions: causality and sex mechanisms

Send us Fan Mail

Pharmacology & neurobiology of psychedelics & MDMA, focusing on isomers, sex-specific effects, and mechanisms in animal models. Not medical advice.

TOPICS DISCUSSED:

• Biased agonism: Different drugs activate the same receptor (e.g., 5-HT2A) but trigger varied intracellular pathways, explaining why LSD is psychedelic while similar lisuride is not.
• Enantiomers & isomers: Mirror-image versions of drugs like MDMA (S and R forms) and LSD (four isomers) often produce distinct effects; only one LSD isomer is psychedelic, for example.
• MDMA isomer effects: S-MDMA induces stronger head twitches (psychedelic proxy) via serotonin release, and increases dendritic spines in male mice but not females; R-MDMA has somewhat different effects.
• Sex-specific drug responses: In mice, females show stronger psychedelic effects (head twitches) from psilocybin and DOI at the same dose, but males exhibit greater post-acute benefits like reduced opioid withdrawal.
• Psilocybin in opioid addiction models: A single dose reduces place preference for oxycodone and withdrawal symptoms in male mice more than females, with opposite spine density effects in reward-related brain areas.
• Mechanisms beyond 5-HT2A: Psychedelics involve other receptors like metabotropic glutamate receptors, forming dimers with 5-HT2A to enable dual signaling pathways; effects in subcortical regions like nucleus accumbens are 5-HT2A-independent.
• Clinical implications: Street MDMA may vary in S/R ratios, affecting experiences; clinical trials often use racemic mixtures without weight-adjusted dosing, potentially missing sex differences.

ABOUT THE GUEST: Javier Gonzalez-Maeso, PhD is a professor of pharmacology and toxicology at Virginia Commonwealth University, with a PhD in medicine from Spain focused on G-protein coupled receptors and human brain studies in depression and addiction.

RELATED EPISODE:

• M&M 230 | Psilocybin & MDMA: Inflammation, Stress & Brain-Body Communication | Michael Wheeler

Support the show

Health Products by M&M Partners:

• SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
• Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off.
• AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
• Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
• KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)

For all the ways you can support my efforts