"Reverse Tolerance" Hypothetical

Question

Let me use Caffeine as an example for this question, because it's a classically understood case of drug tolerance.

Caffeine is an adenosine antagonist; it works by blocking the adenosine receptors in your brain, preventing adenosine from binding to them. Since adenosine has an inhibitory effect on the central nervous system, the effect is stimulation.

Your brain adapts to Caffeine pretty quickly by making more adenosine receptors, increasing the required dosage of Caffeine to get the same effect. Of course this means if you stop Caffeine, you will be absorbing more adenosine than baseline before Caffeine, because of all the new adenosine receptors. Over time off Caffeine, your body removes the excess adenosine receptors until you're back to normal.

My Question: Can you hack this process in reverse? Instead of taking an adenosine antagonist, say you took adenosine itself for some period of time. Following the same logic, would your body adapt by removing adenosine receptors below normal baseline? And then when you stop adenosine, would your "withdrawal" symptoms be a caffeine-like stimulation?

Answer 1

Drug tolerance (desensitization) is complicated, featuring many possible mechanisms. There certainly is reverse tolerance (sensitization) as described as well:

The two notions are not incompatible, and tolerance may sometimes lead to reverse tolerance.

Scott Alexander posted an amusing article on this (note that it's not well referenced, and mentions a lot about anecdotal reports). A couple of excerpts:

Supposedly if you have ADHD you can just stay on Adderall forever. ... people who abuse Adderall develop tolerance all the time, and keep having to up the doses just like heroin abusers do. This is a little weird – my pet theory is that people only develop tolerance to drug effects that aren’t FDA-approved uses – though how your receptors know what the FDA says I haven’t quite figured out.

Some percent of people who abuse opiates like heroin get what’s called a post-acute withdrawal syndrome (PAWS) ... There is a poorly-studied but anecdotally very helpful treatment for PAWS: low-dose naltrexone. Naively, this sounds like the stupidest possible thing to try. It’s an opiate antagonist, meaning that you’re taking somebody who is undersensitive to opiates and blocking the tiny number of functioning opiate receptors they already have. It should be the only thing capable of making this already bad condition worse. Yet people swear by it. The theory is supposed to be the tolerance reaction again. Your body reacts to this opiate-blocking agent by releasing more opiates. So we’re treating a condition in which drugs that increase opiates cause you to have fewer opiates, by giving you a drug that decreases opiates which will cause you to have more opiates. How annoying is that?!

The article also mentions tachyphylaxis, yet another complication where drug tolerance happens randomly and suddenly.

Basically, if you take adenosine, then it may counteract the effects of tolerance, or your body may increase the number of receptors, or reduce its own production of adenosine, or trigger sudden random acute tolerance, or it might check what the FDA says about it on the label and do that.

Answer 2

While theoretically possible it seems impractical since adenosine has a half life of 0.6 - 10second.

Adenosine is rapidly cleared from plasma by the cellular elements of the blood and by vascular endothelial cells and subjected to enzymatic metabolism. The drug has a half-life of 0.6 to 10 seconds. Adenosine in the episodic treatment of paroxysmal supraventricular tachycardia

Also, adenosine is usually administered intravenously at dosages in the mg range further complicating practical application as neuroenhancer

Adenosine is administered intravenously in specific clinical cases. For the management of SVT, adenosine is ideally given through a peripheral intravenous (IV) access initially as a 6 mg dose followed by a 20 mL saline flush for rapid infusion. Subsequent doses start at 12 mg, also followed by 20-mL saline for rapid infusion.

Since you were explicitly asking for theoretical possibility: I couldn't find any literature regarding the usage of adenosine as a neuroenhancer. However drug tolerance is a characteristic of all drug use, although variability exists. (for example alcohol vs. THC) So tolerance to external adenosine application should be expected.

Since you mention "reverse tolerance". This is a term already defined in the medical literature describing increased sensitivity to drug use due to psychological / physiological damage due to drug use. (https://en.wikipedia.org/wiki/Reverse_tolerance)

A further interesting fact is that certain drugs may potentially "reset" receptor alterations induced by other drugs. This is a field under investigation. For further references consider (https://en.wikipedia.org/wiki/%CE%9A-opioid_receptor)