CBG is a minor cannabinoid that has a variety of pharmacological activities, but the most unique one is not yet proven.

Cannabigerol (CBG) is a cannabinoid that has been studied since the 60’s and 70’s. CBG-dominant plants were recognized as a distinct chemotype in 1967.

Although CBG is the precursor for cannabinoids such as THC and CBD, it also has pharmacologic activity of its own. While non-intoxicating, it is anecdotally reported to help with pain. Read on to see what is unique about CBG pharmacology.

CBG Is an Adrenergic Receptor Agonist (Or Is It?)

A 2010 study shed some light on the pharmacology of CBG. It did not act as a CB 1 agonist (not surprising, given that it is not intoxicating), but it was a highly potent α 2 adrenergic receptor agonist.

The properties of α 2 agonists have been well-studied for many decades. They have a variety of effects on the cardiovascular system, but they also have sedative, anxiolytic, and analgesic properties.

On one hand, this would be a unique pharmacologic activity among the cannabinoids, with possible utility for reducing pain. On the other hand, there are already several approved drugs that act on this receptor, such as clonidine, tizanidine, and dexmedetomidine, so it is not truly novel.

The other issue is that there are conflicting data that brings into question whether CBG can really activate the α 2 receptor in vivo. Although the original study reportedly incredibly high potency at the α 2 receptor (EC 50 = 0.2 nM), CBG did not produce sedative effects in mice (at doses up to 240 mg/kg) and did not produce cardiovascular effects in dogs. These are effects that we would expect of α 2 receptor activation.

CBG Can Activate The CB 2 Receptor

A recent study confirmed that CBG is a CB 2 receptor partial agonist with minimal effects on the CB 1 receptor. This CB 2 mechanism can explain many of the anti-inflammatory effects that have been reported:

Keep in mind that this is not a unique activity. Several other phytocannabinoids and synthetic cannabinoids can activate the CB 2 receptor. Plus you also have the cannabis terpene β-caryophyllene, which is a full CB 2 agonist.

CBG Is A Serotonin 5-HT 1A Antagonist

People talk about the entourage effect like it is always a good thing, but that is not really the case here. CBG is a moderately potent antagonist of the 5-HT 1A receptor. It was able to block the anti-nausea effects of CBD. This probably also extends to anything mediated by 5-HT 1A , including both the anti-nausea and anti-anxiety effects of CBD and CBDA.

However, 5-HT 1A antagonists may also have some therapeutic properties. Studies suggest that overactive presynpatic 5-HT 1A receptors can reduce prefrontal serotonin release and inhibit the effects of antidepressants. Therefore, inhibition of 5-HT 1A receptors has been proposed as a strategy to accelerate the effects of antidepressants.

Although CBG did not have an antidepressant effect in mice after a single dose, an effect may be seen with multiple doses or when given in combination with SSRIs.

However, this pharmacology is not unique. Some approved drugs have 5-HT 1A antagonist activity (e.g. pindolol) and several drugs have been developed specifically as 5-HT 1A antagonists, although it is not clear whether any are still in active clinical development. Pindolol was tested in combination with antidepressants, but with mixed results.

Other Activities of CBG

CBG has a variety of other activities, but for the most part, they seem to either not be unique, or not be potent enough to be relevant.

•Isolated CBG was able to increase food intake in rats as did a CBG-rich plant extract. However, the doses needed to stimulate food intake were 120 mg/kg or above, which is crazy high (the equivalent of 9 grams in a 75 kg human). People might take these huge doses for a serious disease like cancer, but probably not to suppress appetite.

•CBG could inhibit COX-2 activity, but only with very low potency

•CBG reduced bladder contractility (not through CB 1 or CB 2 ).

CBG could activate TRPA1, TRPV1, and TRPV2

•CBG was a TRPM8 antagonist.

•CBG could inhibit GABA reuptake, but it is not clear this occurs in vivo since CBG did not affect anxiety behaviors in mice.

•CBG could inhibit growth of various cancer cell lines, including colon (through TRPM8 inhibition), oral cancer, breast, prostate, and stomach.

Semi-synthetic CBG Derivative

A semi-synthetic derivative of CBG, called VCE-003.2, has been developed. It showed positive results in several mouse models of neurodegenerative diseases, including Huntington’s Disease, Parkinson’s Disease, and ALS.

Although VCE-003.2 works through activation of PPARγ, it may have a unique binding site that gives it different properties from the existing PPARγ agonists.

Clinical Trials of CBG in Pain?

CBG has not yet been studied in any clinical trials. For me, there is not enough rationale to go directly into clinical trials without some further preclinical studies.

The most obvious direction for more research would be pain. This is the most commonly cited condition for using CBG and CBG has activity in models of visceral pain and neuropathic pain (according to data in the GW Pharma patent).

But to justify a clinical trial, I would want to see further evidence that CBG is actually working through a unique mechanism. Although α 2 adrenergic activation could give CBG a unique mechanism for reducing pain among cannabinoids, I would want to see more convincing evidence of this. There are data showing that CBG does not activate the α 2 receptor in vivo and effects on pain could be explained by CB 2 receptor activation or other non-unique mechanisms.