Endocannabinoid deficiency caused by AP-4 failure treated with CBG

Endocannabinoids are fatty acids that serve important functions in all vertebrae. But like other systems in our bodies, the broad endocannabididiome easily gets tangled up with errors. And deficiencies in these particular fats can cause a plethora of malignancies. However, drivers that lead to clinical endocannabinoid system deficiency are less well known than symptoms caused by IBD.

However, a new study from the Max Planck Institute in Germany has uncovered a cause for the deficient production of a particular endocannabinoid in the system. (1)

The broad endocannabinoid system, found throughout the body, is made up of various receptors and messengers. These all respond to exercise, various foods, and especially cannabis. Its job is to maintain a biological balance, so the system must be maintained.

Dys cannabiidioma

As early as 2007, poorly balanced endocannabinoid levels were discovered and linked to migraines, fibromyalgia and irritable bowel syndrome (IBS). Ethan Russo, MD, characterized the findings as a theory of clinical endocannabinoid system deficiency (IBD). But the official cause of the shortage was questioned in the initial research. (2)

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

Protein complexes and the production of 2-AG in neurons

Raphael Mechoulam, along with colleagues and his student Shimon Ben-Shabat, discovered 2-AG (2-arachidonylglycerol) in 1995. And just four years later, in 1999, independent research discovered a protein complex. As of 2013, few elaborations of the complex, AP-4, were made and knowledge remains scarce to this day.

Although the new adapter protein was known to play a role in neural function and intelligence. This was evident because AP-4 deficiency caused cognitive decline. However, at this point, the protein complex had no known connection to 2-AG or endocannabinology.

It turns out that one of several ways the body produces 2-AG is through the protein complex AP-4. The transport of the endocannabinoid through neurons is still protein-dependent. Therefore, global developmental delay, intellectual decline, progressive spasticity, and seizures are all symptoms of AP-4 deficiency that depend on 2-AG dysfunction.

(3)

How CBG 2-AG protects

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

While the cannabinoid CBG doesn’t mimic the synthetic drug used in the study, both inhibit a similar enzyme. And CBG is known to prevent the natural breakdown of 2-AG. Unfortunately, we don’t know if CBG can actually treat AP-4 deficiency by correcting a malfunction in the endocannabinoid system. However, at least there is a valid reason to further explore CBG as a treatment for neurological deficits.

Don’t forget to check this out story to learn how CBG and CBD a powerhouse by blocking the breakdown of the respective endocannabinoids. And stay tuned to learn how traumatic brain injury causes 2-AG deficiency.

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1. Davies AK, Alecu JE, Ziegler M et al. AP-4-mediated axonal transport controls endocannabinoid production in neurons. Nat Commun 13, 1058 (2022).
2. Russo EB (2016). Clinical endocannabinoid deficiency reconsidered: Current research supports the theory in migraine, fibromyalgia, irritable bowel and other treatment-resistant syndromes. Cannabis and Cannabinoid Research, 1(1), 154-165. https://doi.org/10.1089/can.2016.0009
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.