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Endocannabinoid deficiency caused by AP-4 failure, treated by CBG


Endocannabinoids are fatty acids that serve critical functions within all vertebrae. But like other systems in our body, the broad endocannabidiome easily becomes tangled with error. And deficient quantities of these special fats can cause a wealth of malignancies. Drivers that lead to a Clinical Endocannabinoid System Deficiency are, however, less understood than symptoms caused by CED.

A new study by the Max Planck Institute in Germany discovered one cause behind the deficient production of a particular endocannabinoid in the system, though. (1)

Found everywhere in the body, the broad endocannabinoid system consists of various receptors and messengers. These all respond to exercise, various foods, and especially cannabis. Its role is to sustain a biological balance so the system must be maintained.

endocannabinoid system


Poorly balanced endocannabinoid levels were discovered and connected to migraine, fibromyalgia, and Irritable Bowel Syndrome (IBS) as early as 2007. Ethan Russo, MD characterized the findings as a Clinical Endocannabinoid System Deficiency (CED) theory. But the official cause of the deficiency was left to question in the initial research. (2)

Chronic imbalances of the endocannabinoid messengers, anandamide or 2-AG, occur are poorly understood. Excessive degradation of the fatty acids is often blamed for the deficiency. More recently, however, researchers from Max Plank Institute discovered poor production and transport of 2-AG in neurons.

Protein complexes and producing 2-AG in neurons

Raphael Mechoulam, alongside colleagues and his student Shimon Ben-Shabat, discovered 2-AG (2-arachidonylglycerol) in 1995. And just four years later, a protein complex was discovered in unrelated research in 1999. By 2013, few elaborations on the complex, AP-4, were made and knowledge is still scarce today.

Although, the new adaptor protein was known to play a role in neural function and intelligence. This was evident because AP-4 deficiencies caused a cognitive decline. At time though, the protein complex had no known connection to 2-AG or endocannabinology.

As it turns out, one of several ways the body produces 2-AG relies on the protein complex, AP-4. Transportation of the endocannabinoid through neurons is further reliant on the protein. As such, global developmental delay, intellectual degradation, progressive spasticity, as well as seizures are all symptoms of an AP-4 deficiency that depend on 2-AG malfunction.

2 AG in Neurons

How CBG protects 2-AG

Accordingly, a specific protein deficiency leads to a specific endocannabinoid system failure. To prevent this, the researchers looked at enzymes that naturally degrade the endocannabinoid, 2-AG. A synthetic drug was used to inhibit one enzyme in particular with promising results.

While the cannabinoid, CBG, does not mimic the synthetic drug used in the study, they both inhibit a similar enzyme. And CBG is known to prevent natural 2-AG degradation. Unfortunately, we do not know if CBG can truly treat AP-4 deficiency by correcting an endocannabinoid system failure. At least, however, there is a viable reason to further research CBG as a treatment for neurological deficits.

Don’t forget to check out this story to learn how CBG and CBD create a powerhouse by blocking the degradation of respective endocannabinoids. And stay tuned to learn how Traumatic Brain Injury causes a 2-AG deficiency.


  1. Davies, A.K., Alecu, J.E., Ziegler, M. et al. AP-4-mediated axonal transport controls endocannabinoid production in neurons. Nat Commun 13, 1058 (2022).
  2. Russo E. B. (2016). Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Cannabis and cannabinoid research1(1), 154–165.
  3. Breijyeh, Zeinab & Jubeh, Buthaina & Bufo, Sabino & Karaman, Rafik & Scrano, Laura. (2021). toxins Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses. Toxins. 13. 117. 10.3390/toxins13020117.


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