Medical Research News

Unraveling the Secrets of the Endocannabinoid System: A Conversation with Dr. Daniele Piomelli

The endocannabinoid system (ECS) is largely unknown amongst many medical professionals, which is a strange fact given all of the physiological processes that it is currently known to be involved in. We must ask why this is still the case. A brief survey of the scientific literature shows that the ECS is said to be involved in central nervous system development as well as modulating a diverse array of physiological and cognitive processes, including fertility [1], pregnancy [2], the immune system [3], appetite [4], mood [5], and memory [6].

Disturbances within the ECS are thought to lead to psychiatric conditions like schizophrenia, depression, anxiety, and addiction. [7] A 2018 review paper reported that “Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function.” [7] So, it’s quite clear that our ECSs are heavily involved in much that we are and do. So, again, why has this part of our bodies been shunned by the medical community, despite being so integral to our well-being? We can keep asking this question ad nauseum, and we surely should, but there’s another way to push the ECS into mainstream medicine and make it household knowledge, and that’s through science.

I chose to do this by speaking with Dr. Daniele Piomelli, a Distinguished Professor of Anatomy & Neurobiology at the University of California-Irvine School of Medicine. Dr. Piomelli is also the Director of the university’s Center for the Study of Cannabis. Piomelli’s distinguished career has provided a sizeable body of literature on the ECS and the endocannabinoids manufactured within us (anandamide and 2-arachidonoylglycerol).


Jason S. Lupoi, Ph.D.: How did you get started researching cannabinoids?

Daniele Piomelli, Ph.D.: When I was still in France, Raphael Mechoulam and Bill Devane (from the University of Jerusalem) published the ground-breaking paper that identified an arachidonic acid derivative, which they called anandamide, as an endogenous agonist for cannabinoid receptors. [8] Having worked on arachidonic acid and its metabolites during my graduate and postgraduate years in New York, I realized that anandamide’s structure could not be explained by known biochemistry and decided to figure out how it could be made. That led to my lab’s first paper on anandamide, which elucidated the pathways though which this lipid molecule is produced and deactivated. [9]


JSL: I’ve had medical doctors tell me that the endocannabinoid system (ECS) is not taught in medical school. What physiological processes has your research shown the endocannabinoid system to be involved in? Why do you think the ECS hasn’t been taught in medical schools given our production of endogenous cannabinoids?

DP: We actually do teach one class on the ECS system here at the University of California-Irvine, but you are correct, this signaling system is still largely ignored in most medical school curricula even though it is known to be involved in a staggering number of biological functions – both centrally and peripherally. The situation will not change until new editions of medical textbooks and curricula start covering it.


JSL: How is the ECS involved in social behaviors?

DP: That’s an ongoing line of research and I am sure that more surprises are lying ahead. But what we do know for now is that oxytocin, the famous peptide/hormone that plays such a fundamental role in everything social, works in part by stimulating anandamide formation in a region of the brain called the nucleus accumbens (aka, ventral striatum). Blocking the effects of anandamide stops the prosocial effects of oxytocin; boosting anandamide levels has the opposite effect. We can boost anandamide levels with drugs called ‘FAAH inhibitors’ (FAAH; fatty acid amide hydrolase). Don Wei, an MD-PhD student in my lab, found that these drugs are also effective in relieving autism-like symptoms in animal models. [10]


JSL: How can cannabinoid-derived treatments help with opioid addiction?

DP: We still don’t know if they do, but there are tantalizing ideas. The one I find most grounded is that cannabinoid- or endocannabinoid-based medications may work in synergy with opioids to reduce pain, while at the same time curbing the opioid’s pleasurable (and presumably addictive) effects. These are still initial data, however, and more work is needed.


JSL: What are the impacts of endocannabinoids and cannabinoids on symptoms from schizophrenia?

DP: This is a difficult question. There are data indicating that the endocannabinoid anandamide may be protective in schizophrenia. And there are data showing that the phytocannabinoid cannabidiol (CBD) may improve symptoms of schizophrenia, at least in part, by boosting anandamide levels. The jury is still out, however.


JSL: Where do you see cannabinoid medicine heading in 5 or 10 years? How extensive of a role do you think they will play as modern medicine evolves?

DP: Cannabis itself is here to stay. Whether or not the medical profession evolves to accept it is a different issue. I think it will, however, as the approvals of cannabis-based medicine in Canada, Europe, Israel, and partly the United States are suggesting. Endocannabinoid-based medicines are now in clinical testing. All we can do is cross our fingers – their success would be a step forward not only for science but also for so many patients around the world.



[1] Klein C, Hill MN, Chang SCH, Hillard CJ, and Gorzalka BB. Circulating endocannabinoid concentrations and sexual arousal in women. J Sex Med 2012;9:1588–1601. [journal impact factor = 4.699; times cited = 28]


[2] Wang H, Xie H, Dey SK. Endocannabinoid signaling directs periimplantation events. AAPS J. 2006;8(2):E425-E432. [journal impact factor = 4.743; times cited = 40]


[3] Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P. Endocannabinoids and immune regulation. Pharmacol Res. 2009;60(2):85-92. [journal impact factor = 7.65; times cited = 151]


[4] Kirkham TC. Endocannabinoids in the regulation of appetite and body weight. Behav Pharmacol. 2005;16(5-6):297-313. [journal impact factor = 2.293; times cited = 180]


[5] Hill MN, Gorzalka BB. The endocannabinoid system and the treatment of mood and anxiety disorders. CNS Neurol Disord Drug Targets. 2009;8(6):451-458. [journal impact factor = 3.926; times cited = 139]


[6] Kruk-Slomka M, Dzik A, Budzynska B, Biala G. Endocannabinoid system: The direct and indirect involvement in the memory and learning processes-a short review. Mol Neurobiol. 2017;54(10):8332-8347. [journal impact factor = 5.59; times cited = 45]


[7] Ibarra-Lecue I, Pilar-Cuéllar F, Muguruza C, et al. The endocannabinoid system in mental disorders: Evidence from human brain studies. Biochem Pharmacol. 2018;157:97-107. [journal impact factor = 5.858; times cited = 36]


[8] Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946-1949. [journal impact factor = 47.728; times cited = 5043]


[9] Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372(6507):686-691. [journal impact factor = 49.96; times cited = 1511]


[10] Wei D, Allsop S, Tye K, Piomelli D. Endocannabinoid signaling in the control of social behavior. Trends Neurosci. 2017;40(7):385-396. [journal impact factor = 13.837; times cited = 47]

About the author

Jason S. Lupoi, Ph.D.

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