I'm not sure if I fully understand your question. With other things being constant, yes, an increased endocannabinoid level will increase signalling. It's unknown if we have endogenous cannabinoid antagonists in the body.

No, I'm quite sure you have it, I just couldn't word it correctly.

Say there is an antagonist or reverse agonist; with the occurrence of event X, which leads to ant- or reverse-agonist binding to CB1, could one possibly find high serum levels of CB1 agonists?

Even though that's theoretically possible, so far there is no evidence for a compensatory increase in endocannabinoids due to long-term blockade or genetic deletion of CB1 receptors.

Does short-term blockade cause a rise in endogenous cannabinoid levels throughout the body, or has this not been observed?

Hi Jacob. I think that the increase in serum levels doesn´t mean a higher signalling. Because the system can be dessensitezed (if this rise happens during a long period). Also because the cannabinoid receptor expression is regulated to many factors and the signalling process needs the integrity of both (ligants and receptors).

And about your second question: As Mss. Ho said, I didn´t find experimental evidence in the literature. But I believe that long-term blockade can lead to it (feedback priciple), because Colombo et colleagues (1998) and Rigamonti et colleagues (2006) have demonstrated that dairly blockade of CB1 receptors leads to a tolerance, where the reduction in food intake is reversed! That can be result of a rise in the endogenous ligants (They don´t discuss that on the paper, but I believe that it´s a possible hypothesis).

I think increased endocannabinoid levels does indicate increased signaling for definite time span/period as ECS will be desensitized/receptors internalized after some time. Other aspect if increased endocannabinoid levels hint towards non-cb1,cb2 mediated actions of these prolonged elevated endocannbinoids

It depends. I think that an acute increase in endocannabinoids levels could increase the signaling while persistent increase for a longer period may not because of desensitization of the receptors. The answer to your second question is that a blockade of CB1 receptor could increase endocannabinoids. Attached please see our paper that indicates an elevation in both AEA and 2-AG levels following a treatment with CB1 receptor inverse agonist, rimonabant. The levels may vary depending on the dose and duration of treatment.

I would interpret the data with cannabidiol as a weak antagonist with caution. Cannabidiol is also a potent inhibitor of FAAH and anandamide transporter so the possible rise in endocannabinoids after cannabidiol may not be only due to weak CB1 antagonism. See file FAAH+AT.pdf attached.

I will add some papers on the functioning of the endocannabinoid system where you may find interesting information.