I am interested in knowledge about the inner workings of THC tolerance.

I have no direct sources, but know several (n = 7) individuals who say they build up a tolerance at chronic consumption and lose them after around 1-3 weeks of abstinence.

I suppose like every other receptor, CB1/2 desensitizes which in turn affects other signalling loops.

I assume emotional effects affected by tolerance are modulated in particular due to reduced CB1/2 signalling.

Endocannabinoid signaling critically regulates emotional and motivational states via activation of cannabinoid receptor 1 (CB1) in the brain. The nucleus accumbens (NAc) functions to gate emotional and motivational responses. Although expression of CB1 in the NAc is low, manipulation of CB1 signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders

I also assume that the psychosis inducing effects of THC are due to an increase of Dopamine availability in the Nacc as it is well known that a D2 hyperactivity in the mesolimbic area is a condition found in many individuals experiencing schizophrenia (see Dopamine Hypothesis).

This implies that the releas of Dopamine from the VTA to the NAcc, mediated by unknown CB1/2 projections influences the Dopamine availability in the mesolimbic area.

This may IMHO lead to dopamine induced psychosis (see DH)

This suggests to me that stronger positive psychotic symptoms at low tolerance levels correlate with increased dopamine availability. CB1/2 is known to increase dopamine release and

although CB1-mediated regulation of VTA-to-NAc dopamine release has been observed (43) ... there seems no within-circuit presynaptic CB1-mediated regulation through the entire VTA (dopamine)-NAc-VTA loop ... CB1-mediated regulation of dopamine release to the NAc (43, 44) must be mediated by other CB1-expressing projections. - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479600/

This at least makes sense to me on a theoretical level but I'm in doubt whether up regulation of CB1/2 alone is responsible for THC tolerance e.g. by affecting other CB1-expressing projections?



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