The mechanics of cross-tolerance

This is one I have seen rising among my blog search term hits. A lot of my traffic comes to the recreational substances posts, and I view the search terms that landed readers on those posts as questions that are out there waiting to be answered. People are asking: can you get tolerant to marijuana by smoking spice cannabinoids?

The blunt and brief answer is yes. But let's discuss what cross tolerance is about. I'll be using the cannabinoids as my example, to keep the context in place. Also, because the cannabinoid signaling system is pretty interesting and unconventional. I like unconventional.

Cannabinoid agonists work their psychotropic effects by targeting the CB1 cannabinoid receptor in the brain. While different molecular structures will activate the receptor in slightly different ways, the general effect is that neurotransmitter release is inhibited in the presynaptic cell. (And this bit is why I had reposted my cannabinoid pharmacology oldie-but-goodie.)

But when you repeatedly target that receptor in the same way, what happens? Tolerance! There are several mechanisms involved in tolerance, and they can vary by what exactly your target is (what receptor type, or if it's some non-receptor entity like an enzyme, these will have different mechanisms behind tolerance). For receptors, the typical events include changes of receptor number at the membrane (downregulate to reduce signal if your drug is an agonist, upregulate to increase signal in the drug is an antagonist). Additionally, changes in receptor sensitivity or transduction happen (desensitize to reduce signal for an agonist, sensitize for an antagonist). There are several others but we won't talk too much about them here because they're more complex. You can read more about tolerance in the post linked earlier in the paragraph, too.

Figure 1. Homeostatic responses to agonist drugs! Up top: downregulation. The number of receptors on the cell surface is decreased after prolonged exposure to a drug. On the bottom: desensitization. Receptors at the membrane will have a lesser effect on intracellular signaling pathways after prolonged exposure to a drug. (You can visualize the adaptations to antagonists by flipping the arrows in the middle, since they are essentially opposite.)

With prolonged exposure to agonist A, a cell will do some combination of downregulation and desensitization of the affected receptor to maintain homeostasis. But because the cell has adapted in this way, any other agonist that targets this same receptor will also have a lesser effect during this tolerance state. But generic discussion is less fun. Let's talk about the types of cannabinoids.

So let's say someone uses a spice cannabinoid preparation on a regular basis. After regularly stimulating the cannabinoid receptors with the agonist spice drug, their cells will undergo the downregulation and desensitization motions. As is typical for tolerance, with time and repeated exposures, the dose of spice drug required to cause the same effect increases.

Say this person grows tired of the less-effective spice cannabinoid. Maybe they wish to switch back to marijuana, for whatever reason. I don't judge, especially in theoretical situations. So this person, tolerant to spice cannabinoids, then goes back to using marijuana. THC, the principal psychotropic ingredient in marijuana, also works by stimulating the cannabinoid receptors. Since there are fewer and/or less effective cannabinoid receptors around for THC to stimulate, the effect of THC is quite diminished in a user that is tolerant to spice. And this is, in brief, how spice tolerance = marijuana tolerance.

(A caveat: There are nuances here regarding agonist efficacy and potency, but they are generally not dealbreakers for cross-tolerance once the cellular-level adaptations have taken place.)