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Doctor's Corner

Piecing Together the Endocannabinoidome: Charting the Next Frontier

Dr. Abraham Benavides

by Dr. Abraham Benavides

May 24, 2023 08:00 am ET Estimated Read Time: 8 Minutes
Medically reviewed by Dr. Abraham Benavides
Piecing Together the Endocannabinoidome: Charting the Next Frontier

Experts are taking a bird’s eye view of an exciting and rapidly evolving area in cannabis research known as the endocannabinoidome (eCBome). Simply put, the endocannabinoidome is like the expansion pack of the endocannabinoid system (ECS) (1).

The eCBome may hold the keys to regulating and balancing complex bodily processes and diseases. This includes the ECS, the microbiota-gut-brain axis, obesity, diabetes, metabolic syndrome, energy intake and storage, inflammation and oxidative stress, glucose and fat metabolism, and pancreatic and liver health (2,3,4).

While these are common health problems that modern medicine still hasn’t solved, the eCBome is a common thread among them. Understanding the bigger picture is the next step toward treating them.

  1. What Is the Endocannabinoidome (eCBome)?
    1. The Difference Between the ECS and eCBome
    2. Regulating and Balancing Key Bodily Functions
  2. How Does the Endocannabinoidome Work?
    1. Endocannabinoids vs. Endocannabinoid-like Molecules
    2. Cannabinoid Receptors
    3. Non-cannabinoid Receptors
    4. Unique eCBome Messengers
  3. How Do We Influence the Endocannabinoidome?
  4. How May the Endocannabinoidome Be Used Therapeutically?
  5. Final Takeaway

What Is the Endocannabinoidome (eCBome)?

At its core, the eCBome is an intricate signaling system. The eCBome includes the ECS plus all other components that are also influenced by cannabinoids, endocannabinoids, and endocannabinoid-like molecules. Outside of the ECS, the eCBome influences include a broad network of receptors, enzymes, immune and bacterial cells, minerals, neurotransmitters, and even hormones (5).

Soon after the discovery of the ECS in the ’90s, researchers found that endocannabinoids and similar compounds act not only on cannabinoid (CB1 and CB2) receptors but also on many other receptor families. The subsequent discoveries on endocannabinoids and non-CB receptors led to the idea of an expanded endocannabinoid system, coined the “endocannabinoidome” in 2013 by Dr. Vincenzo Di Marzo (6).

Cannabinoids and chemically similar compounds are multi-target molecules that influence many processes at the same time, opening many new and exciting therapeutic avenues. There is a lot left to discover and learn about how all the moving pieces fit together and balance each other out in wellness and disease.

The Difference Between the Endocannabinoid System (ECS) and Endocannabinoidome (eCBome)

Like the ECS, the eCBome is a complex signaling system that uses fatty-based molecules as messengers. However, there are a lot more components involved in the eCBome than the ECS.

There are only three categorical parts of the ECS, although they are enough to be present in virtually every organ system. The classic ECS components are the endocannabinoids anandamide and 2-AG, CB receptors (CB1 and CB2), and enzymes that make and break down endocannabinoids (NAPE-PLD, DGLα, DGLβ, FAAH, AND MAGL) (1,7,8). The eCBome starts with the ECS and continues its work elsewhere.

Beyond the ECS, the eCBome also includes over 100 fatty acid-derived signaling molecules and receptors, plus over 50 enzymes (9). Further key differences are that it includes our whole lipidome (fatty acid-based signaling network) and our microbiome (gut bacteria network) (5). These complex systems are communicating with each other as well as our brain,  affecting our inner balance of bacteria, inflammation, gut, and mental health. This is the idea behind the microbiome-gut-brain axis and why the eCBome holds missing pieces of the puzzle (3).

For a deep dive into the endocannabinoid system itself, check out this article: Cannabinoids and the Endocannabinoid System: A Match Made in Heaven

Regulating and Balancing Key Bodily Functions

The wider reach of the eCBome means it is involved in regulating pain, inflammation, mood, appetite, gut permeability, and energy balance (4,5,6). These are very similar functions to the endocannabinoid system but are now seen in an even more complex way with myriad actors on the cast that don’t always get along.

How Does the Endocannabinoidome Work?

The eCBome explains the expansive therapeutic benefits that cannabinoids may provide that aren’t explained by simply activating CB1 and CB2. All of our lipid signaling networks, including endocannabinoids and endocannabinoid-like compounds, are linked together through the eCBome because they share so many common pathways. These pathways are two-way streets of communication and have multiple intersections, causing the complexity.

Endocannabinoids vs. Endocannabinoid-like Molecules

The endocannabinoids anandamide and 2-AG are made on demand when needed. They are an important part of our homeostasis, or internal balance, in response to signals like pain, inflammation, behavior, appetite, and much more (1).

Endocannabinoids are known for being lipid (fat-based) messengers between and within cells. They have a special ability to travel against the flow of the original signals (retrograde transmission) to give cells feedback.

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In addition to anandamide and 2-AG, the eCBome includes over a hundred other chemically similar compounds called “endocannabinoid-like” molecules. They are also fat-based signaling molecules often mixed with amino acids (e.g., NAAAs, PEA, OEA) (10). These endocannabinoid-like molecules can come from our own cells as well as from gut bacteria, explaining how they communicate with us and change our body and mind.

Cannabinoid Receptors

Cannabinoid receptors CB1 and CB2 were actually first discovered using THC, not endocannabinoids. This sparked the interest in finding the endocannabinoids, which at first they thought only bound to CB1 and CB2 receptors.

However, researchers quickly discovered this was not true. Some researchers today, including Dr. Di Marzo, think that CB1 and CB2 receptors should instead be called “THC receptors” because there are so many more receptors that interact with other cannabinoids and endocannabinoids (9).

Non-cannabinoid Receptors

Endocannabinoids are known to also interact with receptors like TRPV1, PPARG, and GPR55 [10]. Other known eCBome receptors include PPARα, GPR18, GPR119, Cav3, TRPV2, and TRPV4. The variety of receptors outside of CB1 and CB2 explains the vast potential of the eCBome.

Unique eCBome Messengers

Outside of fat-based molecules, the eCBome also employs over 20 neurotransmitters, hormones, proteins, and minerals. Below is a table from the CannaKeys 360 research group summarizing each of these specialty signals and their associated implications (5).

Neurotransmitters, Hormones, and

other Communication Signals



Acetylcholine e.g., memory, wakefulness E. Murillo-Rodríguez et al., 2018
Cortisol e.g., stress response Kathmann et al., 2006
Cytokines anti-inflammatory L. Jean-Gilles et al., 2010
Cytokines pro-inflammatory F. Zádor et al., 2021
Dopamine e.g., motivation, reward A. Terzian et al., 2011
Endogenous opioids e.g., analgesia M. Kathmann et al., 2006
Epinephrine e.g., fight, flight, or freeze N. Niederhoffer et al., 2001
Gamma-aminobutyric acid (GABA) e.g., calming S. Lee et al., 2010
Ghrelin e.g., hunger L. Senin et al., 2013
Glucagon e.g., hungry, angry K. Patel et al., 2014
Glutamate e.g., excitement, excitotoxicity A. Köfalvi et al., 2020
Insulin e.g., energy, hungry A. Laguerre et al., 2021
Leptin e.g., satiated B. Bosier et al., 2013
Norepinephrine e.g., stress, attention R. Wyrofsky et al., 2019
Oxytocin e.g., trust, intimacy, bonding D. Wei et al., 2015
Serotonin e.g., happiness, well-being I. Ibarra-Lecue et al., 2021
Testosterone e.g., confidence, aggression J. Lim et al., 2023
Vasopressin e.g., social recognition, aggressions V. Luce et al., 2014
eCBome-Related Mineral Responsive to Modulating Components of the ECS Mental-Emotional Association Reference
Calcium (Ca2+) e.g., schizophrenia, ASD, bipolar T. Boszek et al., 2021
Sodium (Na+) e.g., ASD C. Milligan et al., 2022
Potassium (K) e.g., schizophrenia, ASD, bipolar Yu-Fung Lin 2021

Blesching, U. (n.d.). Endocannabinoidome (eCBome). Cannakeys.

How Do We Influence the Endocannabinoidome?

The eCBome, like the ECS, is influenced by a variety of genetic and environmental factors. Our genes are the underlying fabric of our eCBome network; alterations here propagate serious downstream effects. Environmental things like diet, exercise, mindfulness, and lifestyle choices can promote certain gut bacteria and eCBome molecules over others (9).

For instance, the ratio of omega-6 to omega-3 in our food proportionately changes our endocannabinoid tone because they are the building blocks of endocannabinoids (13). If there is too much omega-6 and not enough omega-3, typical for Western diets, then there may be too little endocannabinoids produced, leading to chronic conditions (14). The ideal dietary ratio of omega-6 to omega-3 should be around 5:1, but our modern diets are estimated to be around 20:1.

Negative factors like high-calorie, Western diets, lack or presence of nutritional factors, lack of physical activity, and uncontrolled recreational drug or even cannabis use can modify our eCBome balance and push us over the edge into chronic disease (9).

How May the Endocannabinoidome Be Used Therapeutically?

An imbalance of the eCBome is now being linked to disorders like idiopathic inflammation, metabolic disease, chronic enteropathies (gut problems), and neuroinflammatory diseases (11).

The current eCBome research focus is on understanding its relationships with the microbiome (gut bacteria), metabolism, and inflammation around the brain, gut, liver, and pancreas (4). Particularly in regard to pancreatic cancer, obesity, diabetes, depression, neuropathic pain, and chronic liver disease (4,10,11,12). These connections are just starting to appear, so there isn’t any conclusive clinical research regarding the eCBome yet.

Mapping and testing the complex relationships of the eCBome can help us make targeted or custom cannabinoid therapies for such diseases one day. It can also help guide patients to improve their eCBome through mind-body medicine, food and nutrition, the microbiome, lipidome, and the constituents of cannabis (5).

Final Takeaway

The eCBome is showing us that there is even more that can be done beyond CB1 and CB2 receptors. Understanding its complexities will take a lot more time and considerable research effort. Crossing this next frontier in cannabis medicine is inevitable but offers a high payout in the long run.

1. Benavides, A. (2022).  Cannabinoids and the Endocannabinoid System: A Match Made in Heaven. Veriheal. 

2. Veilleux, A., Di Marzo, V., & Silvestri, C. (2019). The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus. Current Diabetes Reports, 19(11), 117.

3. Forte, N., Fernández-Rilo, A. C., Palomba, L., Di Marzo, V., & Cristino, L. (2020). Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators. International Journal of Molecular Sciences, 21(5), Article 5.

4. Barré, T., Di Marzo, V., Marcellin, F., Burra, P., & Carrieri, P. (2023). Expanding Research on Cannabis-Based Medicines for Liver Steatosis: A Low-Risk High-Reward Way Out of the Present Deadlock? Cannabis and Cannabinoid Research, 8(1), 5–11.

5. Blesching, U. Endocannabinoidome (eCBome). (n.d.). Cannakeys. Retrieved April 27, 2023, from 

6. Maione, S., Costa, B., & Di Marzo, V. (2013). Endocannabinoids: A unique opportunity to develop multitarget analgesics. Pain, 154 Suppl 1, S87–S93. 

7. Benavides, A. All About Anandamide: Taking Cannabinoid Treatment to New Heights. (2021, October 25). Veirheal Cannabis Central.

8. Di Marzo, V. (2018). New approaches and challenges to targeting the endocannabinoid system. Nature Reviews Drug Discovery, 17(9), 623–639.

9. Di Marzo, V., & Silvestri, C. (2019). Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome. Nutrients, 11(8), Article 8.

10. Forteza, F., Giorgini, G., & Raymond, F. (2021). Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome. Cells, 10(4), Article 4.

11. Schiano Moriello, A., Di Marzo, V., & Petrosino, S. (2022). Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint. Animals, 12(3), Article 3.

12. Falasca, V., & Falasca, M. (2022). Targeting the Endocannabinoidome in Pancreatic Cancer. Biomolecules, 12(2), Article 2.

13. Omega-3 Cannabinoid Research. (n.d.). Cannakeys. Retrieved April 28, 2023, from

14. Bosch-Bouju, C., Layé, S., Bosch-Bouju, C., & Layé, S. (2016). Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases. In Cannabinoids in Health and Disease. IntechOpen.

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