Psychedelic Neurobiology: Sex-Specific Effects of MDMA & Psilocybin in Addiction & Reward Behavior
Thu Feb 05 2026
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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 WheelerSupport the show
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Send us a text 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 WheelerSupport 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