Dose - How does tolerance go down?

[EscapeDummy]

Swim has dabbled in a few drugs, but the only ones he regularly partakes in are alcohol and marijuana. Swim's marijuana tolerance has skyrocketed since he started smoking daily/ several times daily. After a while he just wouldn't get high, period, so he went sober for 2 weeks, and his first day "back" he got SUPER high. Now he smokes 3-5x a week. Then there's alcohol, where Swim's tolerance honestly doesn't seem to change much. It slowly increases, but not by much, then again Swim is a weekend drinker, so maybe he doesn't do it enough to significantly raise tolerance.

This made him wonder about a more general question. Swim understands the basics of tolerance, how the body and brain adjust to the drug. (on a side note, those who work out may see an interesting parallel when doing the same excercises over and over even with increasing weights, fails to really build strength, and then you have to switch it up). However, Swim was wondering, physiologically, how does tolerance lower? Why doesn't the body "keep" its tolerance, even after breaks? It seems to, in some drugs like E and DXM, there are reports of users abstaining for months or years, doing the drug again, to little difference from when they stopped. On the other hand, marijuana tolerance seems to drop fairly quickly, just a week's break from daily smoking and BAM you get LIT!

[Ilsa]

Levine's Pharmacology (courtesy of google books) explains several mechanisms of tolerance, such as drug-disposition tolerance, which occurs when either absorption of the drug is inhibited or the reactivity of the receptor upon binding of the drug is down-regulated. ethanol and bariturates are good examples of the latter case: as consumption increases, so do the enzymes responsible for metabolizing them, so an individual who regularly drinks and/or takes barbiturates rapidly develops tolerance due to the body's adaptation and increased rate of metabolism of the substance.

when the stressor is no longer present, ie when the individual stops drinking or taking barbiturates, the body gradually reverts to baseline levels of enzyme production or receptor binding and reactivity. the net result of these reversions, which can take some time, particularly for chronic users, is sensitization to the drug and requirement of lower doses to acheive desired effects relative to the dose needed when the use is daily for extended periods of time.

this is just an educated guess as to the mechanism for loss of tolerance, feel free to disagree, add to, and bring in more info on the topic.

Reputation Comments on this post:

	Thanks for adding a substantial answer to a general area of interest for a lot of SWIMmers out there.
	thanks, fascinating article link

[EscapeDummy]

Fascinating article and explanation, I think I like it. I still wonder, though, how the "baseline" enzyme levels are set. Perhaps all those people who are "fried" now abused the drug to the point that they set a new baseline?

[Ilsa]

this is pure speculation, but 'burnouts', or people who have used to the point of making themselves mentally compromised....this could be genetic regarding that person's physiology and ability to re-equilibrate after ceasing use. it could also be that dopamine and/or serotonin (among many other neurotransmitters and their pathways and interactions) has been so depleted for so long that functional connectivity, or the 'talking' between/among brain regions, that makes us so cognitively nimble (well, in most cases, lol) is decreased, so that the brain can't integrate, assimilate and process information as efficiently as before.

just a guess, but given the amount of time i've seen it take for former addicts to regain emotional and mental stability seems to support the idea, although this is a small sample size--most of those i knwo still in that game are still burning out just like they always were :/