Cannabinoid System: Metabolism, Evolution & Energy Storage | Giovanni Marsicano | 245

Aug 13, 2025

Giovanni Marsicano, a neuroscientist leading research on the endocannabinoid system in Bordeaux, shares fascinating insights into the complexities of the CB1 receptor. He explains how the endocannabinoid system helps regulate energy storage and influences appetite, highlighting its evolutionary role in fat accumulation during uncertain times. Marsicano discusses the biphasic effects of cannabinoids on various cell types and the powerful impact of diet, particularly omega-6 fatty acids, on endocannabinoid production and health.

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INSIGHT

Core Components And Lipid Origins

The endocannabinoid system is CB1/CB2 receptors plus lipid ligands and synthesis/degradation machinery.
Anandamide and 2-AG are arachidonic-acid-derived lipids that act as endogenous cannabinoid signals.

INSIGHT

On-Demand Lipid Signaling Versus THC Flood

Endocannabinoids are made on-demand and degraded rapidly, giving spatially and temporally precise effects.
Exogenous THC floods space and time, losing that precision and producing varied outcomes.

INSIGHT

Endostatic Versus Exostatic Motivation

Piazza's endostatic vs exostatic framing separates immediate need regulation from future-oriented accumulation.
Exostatic systems drive behavior toward external cues to build reserves for uncertain futures.

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What is the core evolved function of the endocannabinoid system?

Episode Summary: Dr. Giovanni Marsicano is a neuroscientist based in Bordeaux, France, where he leads a research group at INSERM focusing on the endocannabinoid system.

About the guest: Giovanni Marsicano, PhD discusses the endocannabinoid system, starting with its core components like CB1 receptors and lipid-based molecules derived from omega-6 fatty acids; its cellular signaling, evolutionary role in energy storage for uncertain futures (exostasis vs. homeostasis); effects across tissues; motivation, appetite, pain relief, and anxiety regulation; biphasic effects of cannabinoids.

Discussion Points:

The endocannabinoid system acts as an "exostatic" regulator, promoting energy accumulation for future needs by enhancing food palatability, nutrient absorption, and fat storage, unlike "endostatic" systems that address immediate hunger.
CB1 receptors appear in vertebrates with adipose tissue, suggesting an evolutionary link to storing fat for survival in unstable environments.
Endocannabinoids are lipids from omega-6 fats; high intake boosts their levels, potentially fueling obesity by creating a self-perpetuating cycle of overeating.
Activation of CB1 can have biphasic effects due to receptors on different cell types like excitatory vs. inhibitory neurons.
Pregnenolone, a steroid precursor, acts as a natural CB1 inhibitor to prevent excessive activation, blocking harmful effects like psychosis from high THC doses.
The system influences motivation beyond food, including sex and even human activities like sports or storytelling, by rewarding actions for potential future benefits.
In the brain, CB1 on mitochondria and astrocytes modulates energy use, olfaction, and social stress transmission, with implications for disorders like Alzheimer's.

Reference Paper:

CB1 Receptor as the Cornerstone of Exostasis

Related episode:

M&M 123: Endocannabinoids, Stress, Anxiety, Cannabis | Matthew Hill

*Not medical advice.

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