Do cannabinoids CBG or CBD affect THC tolerance?

After a while, the old faithful strain of cannabis quits working. Tolerance, an infamous topic for chronic THC consumers, is partly to blame. But some might wonder if a THC tolerance break still counts if you use other cannabinoids like CBG or CBD.

CBG and CBD are both unique non-intoxicating cannabinoids, but both are psychoactive. Moreover, cannabigerol has noticeable benefits that were documented during an observational trial. (1) Whereas CBD has proven benefits that were verified during placebo-controlled clinical trials. (2)

Cannabinoid doses and serotonin rewards

Preferred doses of any cannabinoid will always depend on the person and condition. (3) Take note if you find yourself ramping the dose of CBG. This is because higher and higher doses might cause mild tolerance and some withdrawal effects, far less intense than THC.

CBD, on the other hand, will have remarkably unique tolerance issues. This is because cannabidiol (CBD) affects a different endocannabinoid relative to CBG. While CBD might become less effective after chronic use, its tolerance is related to serotonin as opposed to cannabinoid receptors. (4)

What is cannabinoid tolerance

THC binds to and activates various targets in the brain, primarily CB1 and CB2 receptors. After chronic activation by an endogenous source like THC, though, receptors begin to compensate and change. They reduce in number throughout the brain and body while also becoming more difficult to activate. (5-7)

Although, this rule is not always straightforward. The endocannabinoid and neurotransmitter known as anandamide can activate CB1 receptors. But, unlike THC, it does not force CB1 receptors to change or cause any intoxication.

Whereas 2-AG, a different endocannabinoid, is non-intoxicating but will desensitize CB1 receptors and lead to tolerance. This is because anandamide travels in reverse through the receptor compared to 2-AG. (6)

How CB receptors react to different endocannabinoids

CBD stops anandamide from breaking down by blocking it’s metabolism (FAAH enzymes) in the post position of the CB1 receptor. Whereas CBG stops 2-AG from degrading in the pre position of the receptor.

This means that using CBD during a THC tolerance break be fine — receptors are not being desensitized. And while the same cannot be said for CBG, its effect on THC tolerance by protecting 2-AG will likely be negligible. At least, that is the theory. Unlike CBD, clinical trials on CBG and other minor cannabinoids are in demand to better understand their effects on tolerance and withdrawal. (1, 2)

Avoiding the tolerance build-up

Self-governed doses are often recommended by clinicians. But an appropriate cultivar, or simply, the perfect ratio of cannabinoids and terpenes helps to avoid needlessly increased doses.

Although sorely lacking in clinical trial literature, terpenes can be used to substitute or add to CBG and CBD. As an example — beta-caryophyllene works well to pick up the endocannabinoid, 2-AG, without risking tolerance.

Let us know in the comments if you have any experience with different cannabinoids like CBG and CBD during a tolerance break.

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• CBG inhibits MAG-l which is an enzyme that operates in the presynaptic cleft. MAG-l breaks down 2-AG which is a full, biased, CB1 receptors agonist that signals pre to post-synapse. By inhibiting MAG-l, CBG brings up presynaptic 2-AG. 
• CBD inhibits FAAH, preventing the hydrolyzation of anandamide post-synaptically. Increased anandamide activates CB1 receptors after transporting to pre.

Sources to explore CBG and CBD affect on THC tolerance

1. Russo, E. B., Cuttler, C., Cooper, Z. D., Stueber, A., Whiteley, V. L., & Sexton, M. (2021). Survey of Patients Employing Cannabigerol-Predominant Cannabis Preparations: Perceived Medical Effects, Adverse Events, and Withdrawal Symptoms. Cannabis and cannabinoid research, 10.1089/can.2021.0058. Advance online publication. 
2. NCT02544763
3. MacCallum, C. A., & Russo, E. B. (2018). Practical considerations in medical cannabis administration and dosing. European journal of internal medicine, 49, 12–19.
4. Russo, E. B., Burnett, A., Hall, B., & Parker, K. K. (2005). Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochemical research, 30(8), 1037–1043.
5. Stella N. (2013). Chronic THC intake modifies fundamental cerebellar functions. The Journal of clinical investigation, 123(8), 3208–3210.
6. Murataeva, N., Straiker, A., & Mackie, K. (2014). Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. British journal of pharmacology, 171(6), 1379–1391.
7. Shana M. Augustin, David M. Lovinger, Synaptic changes induced by cannabinoid drugs and cannabis use disorder, Neurobiology of Disease, Volume 167, 2022, 105670, ISSN 0969-9961,