Wide release: Available for free by August 19, 2026, on Apple, Spotify, YouTube, etc.
Early access: Available to paid subscribers here on Substack.
Not medical advice.
Nick speaks with Dr. Nephi Stella about the endocannabinoid system as a distinct lipid signaling network. Stella explains how anandamide and 2-AG are produced by separate enzymes, trafficked by specialized proteins and microvesicles, and act primarily as retrograde inhibitors through CB1 receptors. The conversation covers developmental risks of adolescent THC exposure, the failure of early FAAH inhibitors, promising new therapeutic approaches, and lessons from rimonabant for metabolism-targeted therapies.
TOPICS DISCUSSED:
Anandamide vs 2-AG: The two major endocannabinoids with a shared arachidonic acid backbone but distinct head groups biological roles.
On-demand production: Calcium-dependent enzymes release cannabinoids from membranes in response to neuronal activity patterns.
Trafficking: Fatty acid binding proteins and extracellular microvesicles traffic endocannabinoids within and between cells.
Adolescent THC: Global receptor activation during circuit wiring may contribute to cannabis use disorder and psychosis vulnerability in susceptible individuals.
Enzyme inhibitors: Early FAAH clinical trial halted by off-target toxicity; MAGL inhibitors advancing in phase 2 for anxiety and addiction.
Peripheral CB1: Liver receptors regulate metabolism; restricted antagonists aim to reduce weight without central psychiatric risks of the weight loss drug rimonabant.
ABOUT THE GUEST: Nephi Stella, PhD is a professor at the University of Washington School of Medicine. He has studied endocannabinoid signaling for more than 25 years, focusing on therapeutic strategies that separate beneficial effects from side effects of cannabinoid-system modulation.
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Podcast | Plant Chemistry, Cannabinoids, Cannabis Terpenes & the Entourage Effect | Ryan Vandrey
KNOW YOURSELF:
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PRACTICAL TAKEAWAYS:
High-potency THC products, especially concentrates that produce rapid high brain levels, raise cannabis use disorder risk more than lower-potency forms; vulnerability is highest during adolescence.
Endocannabinoid “tone” may influence longer-term neuronal phenotype (including BDNF expression) while phasic release controls rapid transmission; dietary fatty acid changes could slowly alter tone, but this remains unproven.
SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.
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