If you survey the scientific literature on the endocannabinoid system, 2-AG (2-arachidonoylglycerol) seems like anandamide’s (AEA) neglected sibling. But 2-AG may be the more potent and important endocannabinoid. 

It’s certainly the most ubiquitous; the typical mammalian nervous system has about three times the amount of 2-AG floating around than anandamide. Though it’s hard to study, it’s clear this endocannabinoid has an important role in mood, homeostasis, immune and inflammatory response.

Schematic illustration of 2-AG’s chemical structure. The gray shapes are carbon, the white are hydrogen and the red are oxygen. Image courtesy of PubChem.

Part of the reason there aren’t as many studies on 2-AG is that its actions are much more complex than those of anandamide. While anandamide interacts mostly with CB1 receptors and a bit with CB2 receptors, 2-AG fully activates both CB1 and CB2, as well as the receptors from a neurosignaling system dealing with body temperature regulation, the TRVP1 receptor. This receptor can interact with a bunch of different chemicals and sensory stimuli other than endocannabinoids. 

When you accidentally grab the handle of a hot skillet, it’s your TRVP1 receptors telling your brain you’re burning yourself. The capsaicin in chili peppers also activates this receptor chemically rather than thermally.

And there are likely even more different signaling systems affected directly by this complicated cannabinoid, causing a host of different physiological responses.

These facts comprise a big reason 2-AG hasn’t received as much attention as anandamide. It’s harder to isolate and study because there are few ways of telling how this neurotransmitter leads to an observed effect on a study subject. 

For example, one study showed 2-AG to have anxiety-reducing effects in rats. But how? Was it through interaction with CB1 or CB2? Was it because of interaction with the TRVP1 receptors? Maybe the anxiety-reducing effect didn’t have anything to do with the activation of these receptors, and 2-AG was actually activating or blocking a whole different set of neuroreceptors or binding proteins we know nothing about. Or maybe this hard to pin-down endocannabinoid has to interact with all of these systems at once to produce the anxiety-reducing effect?

It’s hard to write a research grant proposal when the hypothesis you want to test is “Gee whiz, I bet 2-AG does something cool.”

Interestingly, researchers at Oxford in 2001 isolated a third endocannabinoid that is a more stable form of 2-AG called noladin. Whereas 2-AG gets broken down by an enzyme almost right after it’s used, noladin has a chemical structure that lets it float around in the brain for an hour or so. 

2-AG to Noladin

But there are tradeoffs. Being built for longevity reduces its potency by about tenfold, according to the U.S. government’s chemical library PubChem.

This illustrates another fact about both 2-arachidonoylglycerol and anandamide; your nervous system creates them on demand and destroys them almost immediately. This is because unlike most neurotransmitters, endocannabinoids are fat-soluble. Because all your cell membranes are mostly fat in the form of cholesterol, this means fat-soluble neurotransmitters can potentially wreak havoc by passing in and out of cells willy-nilly.

That’s why your brain keeps tight control over your endocannabinoid neurotransmitters, creating them on demand, using fatty acid binding proteins to lock them up and transport them around once they enter the cell, and destroying them immediately with specialized chemical enzymes.

The enzyme FAAH breaks down anandamide

MAGL breaks down 2-arachidonoylglycerol.

What is 2-AG made of?

2-AG and anandamide are similar in chemical structure in that they’re both based on arachidonic acid. Arachidonic acid is a chain of carbon atoms stuck together with hydrogen and a couple oxygens on the end, forming a hook- or C-shaped molecule.

When your body makes 2-AG, it uses certain enzymes to stick a glycerol molecule onto arachidonic acid. Glycerol is a simple, stable fat molecule ubiquitous in animal bodies and also used industrially in soap, food and as a vehicle for pharmaceuticals, among other applications.

The hook shape of arachidonic acid coupled with a glycerol that forms a two-pronged spike on one end of the acid makes 2-AG just the right shape to lock in and activate both CB1 and CB2 receptors in the brain and peripheral nervous system, respectively.

endocannabinoid locks to the body
endocannabinoid locks to the brain

The DAGLA gene, named for the enzyme diacylglycerol lipase, codes for 2-AG. The encoded enzyme diacylglycerol lipase is crucial for the biosynthesis of 2-AG.

How does 2-arachidonoylglycerol work?

As stated above, 2-AG is definitely more ubiquitous and probably more potent than anandamide. Even though it’s hard to isolate behavioral and subjective effects in test subjects as specifically related to 2-AG levels, it’s clear 2-AG is important to a host of vital processes.

It’s likely an anxiety reducer. Administering 2-AG kept mice cool and calm in the face of adversity in a 2013 Brain and Behavioural Research study, for instance. Rodents given extra 2-AG were more likely to explore and unfamiliar maze than control groups.

2-AG rat experiment
Rodents with extra 2-AG tend to explore unfamiliar areas less than their saline-drugged counterparts. Excess exploration is typically associated with anxiety, so it is thought that 2-AG assist with reducing anxiety levels.

It’s also important as a regulator of blood pressure, heart rate and inflammation of the circulatory system. But because it interacts with so many other signaling systems, it’s not clear how manipulating 2-AG levels could affect cardiovascular health in a clinical setting.

“Arachidonoylglycerol plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart,” states the translation of a 2014 study in a Polish medical journal. “Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis. Thus, it may be a novel attractive therapeutic target. However, because of rapid metabolism and opposite effects dependent on the experimental model, the function of 2-AG still remains to be established.”

Dopamine production is also dependent on 2-AG — dopamine being one of the brain’s principal reward chemicals. A study referenced by DrugAbuse.gov showed that 2-AG is vital for releasing dopamine. They tested this using cocaine-addicted rats. Cocaine works by flooding the brain’s nucleus accumbens with dopamine. Cokehead rats in the study treated with a chemical that blocked 2-AG showed a 50 percent lower concentration of dopamine in their brains. 

Check out our article on cannabis-induced psychosis to see the negative side effects of a disrupted dopamine system when it comes to smoking weed.

Though 2-AG seems to have an outsized role in suppressing inflammation and immune response in the peripheral nervous system as compared with anandamide, 2-AG also has marked psychotropic effects — perhaps due to its regulation of dopamine production.

As evidence, squirrel monkeys trained as intravenous drug users loved shooting up with 2-AG when scientists replaced their usual cocktail.
“Thus, 2-AG was actively self-administered by monkeys with or without a history of cannabinoid self-administration, and the reinforcing effects of 2-AG were mediated by CB1 receptors,” the 2011 Journal of Neuroscience study states. “Self-administration of 2-AG by squirrel monkeys provides a valuable procedure for studying abuse liability of medications that interfere with 2-AG signaling within the brain and for investigating mechanisms involved in the reinforcing effects of endocannabinoids.”

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