Yeah, i keep hearing the short-acting = worse for tolerance bit, it seems so counter-intuitive, it would seem like something that got one equally high for a longer period of time should produce more tolerance, not less - though I suppose i have to accept this on the basis of the large majority who feel this way.
Certainly, it's what i want to hear, as I generally prefer diazepam...
Short-acting is certainly way worse for the development of tolerance for both biological and behavioral reasons.
With all the discussion about benzodiazepine half-lives affecting their individual liabilities to produce tolerance, it should be noted that the half-life of a drug (for the most part) positively correlates with how much the drug is bound to plasma proteins in the bloodstream (higher half-life, more highly bound). When a drug is highly bound, its "bound" metabolites have formed protein-drug complexes that need to be broken in order to make the metabolite active. Because this happens at a fixed rate (freed metabolites are freed in order to replace those that have been metabolized), this is why a benzodiazepine like diazepam lasts so long experientially, with its primary active metabolite desmethyldiazepam having a half-life of 36-200 hours!
So it makes sense that benzodiazepines with short half-lives produce tolerance more quickly and generally produce greater withdrawal intensity because upon absorption of each short-acting dose by the body, one experiences more complete GABA facilitation immediately, rather than the same effect over time as bound metabolites are released and become active. To achieving this level of drug effect and experience the next time requires that much GABA facilitation immediately again, and so the bound metabolites of a longer half-life benzodiazepine are not going to be fulfill the required GABA impact; the same (or higher) dose of the short-acting benzo as before is needed to achieve effects.
Additionally, short-acting benzodiazepines produce an effect with greater intensity but shorter duration that can affect the user
behaviorally, such that the accumulation of tolerance is encouraged. As with differing routes of administration (intravenous vs. oral, for example) greater intensity yet shorter duration provides more powerful reinforcement for continuance of the same (or higher) doses. So by affecting benzo-taking behavior, short-acting benzodiazepines also indirectly facilitate the growth of tolerance by promoting one's habit.
Hopefully, this post made sense, and that I succeeded in helping to fortify the idea that short-acting benzos do indeed set the stage for greater development and maintenance of tolerance to the drug!
~ vaya
