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Can benzos continue to exert a significant effect after the plasma concentration has decreased below 10% of therapeutic dose?

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WilliamSSS

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Feb 12, 2020
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Hi everyone.

I have a very peculiar situation for you all. Would very much appreciate any insights or answers.

I have been tapering diazepam for the past 8 months. Finally got to around 7mg daily, when all of a sudden that usual dose got extremely sedating and felt way too strong. It honestly felt like 30mg diazepam to me. In response, I lowered my dose rapidly and tapered from 7mg daily to 0 in about 3 weeks. It has been 6 weeks since my last dose and i'm still feeling very much sedated and 'high'. This feeling usually comes on in 'waves' during the day, where i'll suddenly be high as a kite and completely calm for several hours.

This got to the point where i had my blood plasma checked for diazepam or metabolites. The results indicated that 5 weeks after my last dose, there was 2ug/ml diazepam and 19ug/ml nordiazepam (demethyldiazepam) left in my blood (therapeutic range 125-250ug/ml for diazepam and 200-800 ug/ml for nordiazepam). Oxazepam or Temazepam were not found. Additionally, urine screening for any benzos was negative, presumably due to the extremely low blood concentration.

Is it somehow possible for diazepam or its metabolites to directly cause this sedated feeling, even though blood concentration is low? Can drugs still exert a significant effect on the CNS with such low blood concentration? The blood test also revealed slightly elevated liver enzymes (AST & ALT, 50 and 135 respectively).

Very much looking forward to your insights.
 
Hi all,

I see plasma concentration being used as a proxy for strength of effects, and half-life as a proxy for duration of action. I know this not to be the case, as for example diazepam has an incredibly long half-life but short duration of action, supposedly because of its high lipophilicity.

I'll continue with the example of diazepam. As i understand it, the relatively short duration of action is explained by diazepam and metabolites quickly dispersing into body tissue. This supposedly causes a quick drop in plasma concentration and hence a short duration of action. However, upon chronic dosing, plasma concentrations are relatively stable. Nevertheless, the strength of the effect is never as strong as when taking a new dose.

Why is this the case?

And further, could drugs/medications/diazepam in specific somehow still exert an effect at very low plasma-concentrations? Are there any health issues that could cause a significantly potentiated response to the same dose?

Very much looking forward to your insights.
Thank you.
 
It's called acute tolerance. The effects of diazepam that are most easy to notice by the user him/herself, namely, loss of motor coordination and a feeling of heaviness, only last a short time after the dose because the brain gets accustomed to the presence of the drug.
 
Redistribution to fatty tissues does account for shortened duration of effect in extreme cases of very lipophilic drugs (methadone, diazepam, THC, fentanyl) and in this case, serum/blood concentrations may not track the duration of effects unless you administer the dryug chronically.
 
Then there's the special case when a drug dissociates from receptors really slowly, or binds permanently to them, and the effect lasts much longer than there are detectable amounts of the substance in bloodstream.
 
polymath said:
Then there's the special case when a drug dissociates from receptors really slowly, or binds permanently to them, and the effect lasts much longer than there are detectable amounts of the substance in bloodstream.
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Is this actually possible with diazepam? Can it get 'bound to the receptor' permanently?
 
Definitionally, if the plasma concentrations are orders of magnitude lower than the Ki of the drug at the benzodiazepine site, the drug won't have significant binding and ergo won't have an effect.

That doesn't mean drug use can't precipitate changes in psyche. Plenty of people report thinking/feeling different (not neccesarily in a negative way) after taking hallucinogens for instance. Ketamine therapy can have effects lasting 7-10 days which is well after the drug has cleared your system. So if a drug gets you into a negative mental feedback loop you can easily reach the conclusion that it must be the drug persisting when in reality it's no different than how your brain would handle any other tramatic life event.
 
Title says it all. Is there any mechanism by which benzos (eg. diazepam, clonazepam, lorazepam,...) to continue to exert an effect after blood concentration has decreased to say 10% of the lower border of therapeutic range? Could impaired liver/kidney function or blocked bile ducts cause anything like this, or would they simply increase the plasma concentration of said medication through impaired metabolism?
Thank you.
 
I'd guess liver and kidney function would be what gets it to such plasma levels, excretes it out. So if it's at ten percent, that had nothing to do with it's dynamics once it gets to 10%, as you propose at the bottom of your OP.

Perhaps, (best case scenario) is: benzos trained your gaba system to calm itself down. Neural plasticity seems to, sometimes after your initial exposure to a drug, tell your body that your natural condition needed up or down regulated and once off have "fixed" the underlying issue. Like training yourself how better to react to a internal system
 
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Nagelfar said:
I'd guess liver and kidney function would be what gets it to such plasma levels, excretes it out. So if it's at ten percent, that had nothing to do with it's dynamics once it gets to 10%, as you propose at the bottom of your OP.

Perhaps, (best case scenario) is: benzos trained your gaba system to calm itself down. Neural plasticity seems to, sometimes after your initial exposure to a drug, tell your body that your natural condition needed up or down regulated and once off have "fixed" the underlying issue. Like training yourself how better to react to a internal system
Click to expand...
Thank you for your comment. So there's no mechanism besides gaba system up/downregulation through which diazepam could exert an effect if plasma concentrations are way below therapeutic concentration?
 
WilliamSSS said:
Thank you for your comment. So there's no mechanism besides gaba system up/downregulation through which diazepam could exert an effect if plasma concentrations are way below therapeutic concentration?
Click to expand...
Oh I'm sure there are a ton of things, just probably none that are overtly perceptive beyond placebo. See if someone here doesn't have some tables regarding the affinity to other sites noticeable by science at low concentrations.

See if someone can get the full "PMID: 41930" or search that with quotations on an outside search engine (though that seems to be binding *to* plasma; perhaps that is your answer, when bound to plasma it's undetectable in blood concentration? Likely not the answer I'd venture)
 
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Isn't this the 3rd time you've asked this question in some way, shape or form?

I'm merging the 3 threads. Please don't just keep asking this same question over and over, the answer isn't going to change.
 
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