Do the cannabinoids CBG or CBD affect THC tolerance?

After a while, the old trusty cannabis strain will wear off. Tolerance, a notorious issue for chronic THC users, is partly to blame. But some may wonder if a THC tolerance break still counts when using other cannabinoids like CBG or CBD.

CBG and CBD are both unique non-intoxicating cannabinoids, but both are psychoactive. Additionally, cannabigerol has notable benefits documented during an observational study. (1) While CBD has proven benefits verified in placebo-controlled clinical trials. (2)

Cannabinoid doses and serotonin rewards

The preferred dose of a cannabinoid always depends on the individual and the condition. (3) Take note if you find yourself increasing the CBG dose. This is because higher and higher doses can cause mild tolerance and some withdrawal symptoms. 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 compared to CBG. While CBD may become less effective after chronic use, its tolerance is related to serotonin as opposed to cannabinoid receptors. (4)

What is cannabinoid tolerance?

THC binds and activates various targets in the brain, mainly CB1 and CB2 receptors. However, after chronic activation by an endogenous source such as THC, the receptors begin to compensate and change. Their numbers are declining throughout the brain and body while at the same time becoming more difficult to activate. (5-7)

Although this rule is not always easy. The endocannabinoid and neurotransmitter known as anandamide can activate CB1 receptors. But unlike THC, it doesn’t force the CB1 receptors to change or induce a high.

While 2-AG, another endocannabinoid, is non-intoxicating but desensitizes CB1 receptors and induces tolerance. This is because anandamide travels through the receptor in the reverse direction compared to 2-AG. (6)

How CB receptors respond to different endocannabinoids

CBD stops the breakdown of anandamide by blocking its metabolism (FAAH enzymes) in the post position of the CB1 receptor. While CBG prevents the breakdown of 2-AG in the preposition of the receptor.

This means that using CBD during a THC tolerance break is fine — receptors are not 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’s the theory. Unlike CBD, clinical studies of CBG and other minor cannabinoids are needed to better understand their effects on tolerance and withdrawal. (1, 2)

Avoidance of tolerance build-up

Self-administered doses are often recommended by doctors. But a suitable strain, or simply the perfect ratio of cannabinoids and terpenes, will help avoid unnecessarily elevated doses.

Although sorely absent from the clinical study literature, terpenes can be used to replace or supplement CBG and CBD. As an example – beta-caryophyllene works well to absorb 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-1, an enzyme that acts in the presynaptic cleft. MAG-1 degrades 2-AG, which is a full-biased CB1 receptor agonist that sends signals before and after the synapse. By inhibiting MAG-1, CBG brings forth presynaptic 2-AG.
• CBD inhibits FAAH and prevents the postsynaptic hydrolysis of anandamide. Elevated anandamide activates CB1 receptors after transport to pre.

Sources of research into CBG and CBD impact THC tolerance

1. Russo EB, Cuttler C, Cooper ZD, Stueber A, Whiteley VL, & Sexton M (2021). Survey of Patients Using Cannabigerol-Predominant Cannabis Preparations: Perceived Medical Effects, Side Effects, and Withdrawal Symptoms. Cannabis and Cannabinoid Research, 10.1089/can.2021.0058. Online Advance Release.
2. NCT02544763
3. MacCallum, CA, & Russo, EB (2018). Practical Considerations for Administering and Dosing Medical Cannabis. European Journal of Internal Medicine, 4912-19.
4. Russo EB, Burnett A, Hall B & Parker KK (2005). Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochemical research, 30(8), 1037-1043.
5. Stella N (2013). Chronic THC intake alters basic cerebellar functions. The Journal of Clinical Investigation, 123(8), 3208-3210.
6. Murataeva N, Straiker A, & Mackie K (2014). Analyzing 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, Vol. 167, 2022, 105670, ISSN 0969-9961,

footnote(s)

https://doi.org/10.1089/can.2021.0058
https://clinicaltrials.gov/ct2/show/NCT02544763
https://doi.org/10.1016/j.ejim.2018.01.004
https://doi.org/10.1007/s11064-005-6978-1
https://doi.org/10.1172/JCI70226
https://doi.org/10.1111/bph.12411
https://doi.org/10.1016/j.nbd.2022.105670