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What can be doen (chemically) to prevent/limit tolerance to benzodiazepines ?

K

Kdem

Bluelighter
Joined
Mar 14, 2015
Messages
334
Other than not taking them ...

I'm inclined to switch to a different benzo for tapering, but I'm also concerned about developing diazepam specific (partly: alpha 1 subunit and alpha 5 subunit) tolerance. Once I would develop tolerance/dependence (currently: clonazepam) to this drug, shit could hit the fan.

There have been a few old threads about NMDA antagonists.

Is there anything I can take (safely) that will limit developing tolerance to diazepam ? I find it more sedating than clonazepam, although it is a very different kind of sedation.
 
Agmatine has been working well for opioid tolerance for myself, and i have heard it does similar things for benzo tolerance. I also have not noticed any side effects, beware though, as it does potentiate most things, so start with a lower dose
 
So finally agmatine works? I keep reading about that, but seeing it's a supplement taken by bodybuilders in loads, somehow I can't believe that it has significant NMDA antagonism (or we'd see the gyms filled with tripping people) ... but it would be appreciable enough if it is a mild one like memantine.
 
If low dose naltrexone works for opioid tolerance, does low dose flumazenil work for benzo tolerance?

Agmatine must be taken parenterally?
 
Solipsis said:
If low dose naltrexone works for opioid tolerance, does low dose flumazenil work for benzo tolerance?
Click to expand...

Flumazenil, at relatively low doses, does reduce BZ withdrawal symptoms. It acts as as a partial BZ agonist at GAB-A receptors containing the alpha6 subunit.
 
Knockout studies don't suggest the alpha6 subunit being really that significant for our interests, it's allosteric I assume or are gamma subunits also involved indirectly?

Wiki suggests it has more to do with upregulation?

On a neuronal level the antagonism can lead to upregulation because signal feedback basically says the signal is 'too low' due to the antagonism? But what I don't understand is how that would not temporarily worsen withdrawal symptoms.

How could one gain more in terms of lost tolerance than is lost as withdrawal? Where is the disparity that makes this possible.
 
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Solipsis said:
Wiki suggests it has more to do with upregulation?
Click to expand...

Upregulation wouldn't explain why withdrawal symptoms decrease immediately.

Solipsis said:
On a neuronal level the antagonism can lead to upregulation because signal feedback basically says the signal is 'too low' due to the antagonism? But what I don't understand is how that would not temporarily worsen withdrawal symptoms.
Click to expand...

I think you answered your own question -- the explanation you are repeating doesn't make any sense. In order for flumazenil to work through upregulation, it would have to reduce GABA-A signaling, which would produce withdrawal. On the other hand, the idea of it working through alpha6 is a reasonable proposal, because alpha6 is normally BZ-insensitive, so flumazenil (at the low doses used to relieve withdrawal) bypasses the receptors that BZ agonists target.

Action through alpha6 explains why flumazenil can be used in patients maintained on BZs -- if it was working through BZ receptors then to produce any noticeable effect it would have to displace the agonist that the patients were taking, which would induce noticeable withdrawal.
 
Interesting thanks, what is confusing to me perhaps is that it seems my question about flumazenil potential departing from naltrexone seems to be a coincidence if the antagonism doesn't really anything to do with it!
 
Solipsis said:
Interesting thanks, what is confusing to me perhaps is that it seems my question about flumazenil potential departing from naltrexone seems to be a coincidence if the antagonism doesn't really anything to do with it!
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To tell you the truth, neither of these strategies is probably based on classical concepts of antagonist action. The theory behind ULD naltrexone is that mu receptors can couple to inhibitory (Gi/o) and excitatory (Gs) G-proteins. There are two key concepts here: 1. Coupling of mu receptors (MOR) to Gs increases the binding affinity of MOR, so at low concentrations opioids preferentially bind to the population of MOR that is coupled to Gs. 2. As opioid addiction develops, many receptors shift from Gi/o to Gs coupling.

The idea here is that withdrawal occurs because when opioid use is discontinued the residual levels of agonist in the CNS preferentially activate Gs, with little Gi/o activation to offset it. This explains why the time course of opioid withdrawal generally follows the clearance rate.

So what ULD naltrexone supposedly does is preferentially block opioid activation of Gs-coupled MOR, without blocking receptors coupled to Gi/o.
 
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Very interesting... two questions regarding the concept of receptors changing their coupled G proteins - 1. do you have a study handy that goes over this phenomenon, and 2. Might this phenomenon occur to other types of receptors, such as dopamine and serotonin?

Also, as I understand it there are even opoid receptors on immune system cells. Are there implications for this G protein coupling changing phenomenon in regards to low dose naltrexone's possible efficacy for auto immune disease? What I mean to say is, if normally opiates suppress the immune system, but naltrexone helps with auto immune disease, then maybe it is due to a G protein coupling change in the immune system cells leading to an irregular response (an antagonist suppressing the immune system). I am very curious about auto immune disease lately, as I have been struggling with one.

Thanks in advance.
 
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Thought the effects of ULD naltrexone were mainly because it's an inverse agonist ...? Also flumazenil appears to be a adenosine RI(?)

Does administering a low dose of an antagonist together with an agonist really help limiting tolerance beyond just diminished effects? Could the same be done with e.g. an antipsychotic and a dopamine agonist (or a stimulant)?
 
Cotcha Yankinov said:
Very interesting... two questions regarding the concept of receptors changing their coupled G proteins - 1. do you have a study handy that goes over this phenomenon, and 2. Might this phenomenon occur to other types of receptors, such as dopamine and serotonin?

Also, as I understand it there are even opoid receptors on immune system cells. Are there implications for this G protein coupling changing phenomenon in regards to low dose naltrexone's possible efficacy for auto immune disease? What I mean to say is, if normally opiates suppress the immune system, but naltrexone helps with auto immune disease, then maybe it is due to a G protein coupling change in the immune system cells leading to an irregular response (an antagonist suppressing the immune system). I am very curious about auto immune disease lately, as I have been struggling with one.

Thanks in advance.
Click to expand...

I wouldn't describe this as "changing" their coupling. Receptors can potentially couple to different G protein alpha subunits; that is the reason functional selectivity can occur. I would think of this as an equilibrium that involves the binding of MOR to one of several possible G proteins, driven by agonist occupation. Here, for some reason, the equilibrium is shifting from MOR-Gi/o to MOR-Gs.

The following study suggests that MOR couples to Gs due to interactions with an intracellular protein known as filamin A:

http://www.ncbi.nlm.nih.gov/pubmed/19172190

palmanita said:
Thought the effects of ULD naltrexone were mainly because it's an inverse agonist ...?
Click to expand...

The ULD naltrexone effect I am talking about is when it is used in combination with an agonist like morphine.

How would administering a very low dose of an inverse agonist do anything? At low doses of naltrexone there is negligible occupation of MOR because binding is driven by concentration; in this situation, with an agonist present, it would even be more difficult for naltrexone to bind because some of the receptors are occupied by an agonist.

But even if there was some naltrexone binding, in order for the inverse agonist effect to do anything, the dose would have to be high enough to reduce the response to the opioid. In other words, the opioid is producing an effect on some of the mu receptors and then the naltrexone would be producing the opposite effect at other mu receptors.

However, that isn't what is happening; ULD naltrexone/naloxone supposedly increases the response to the opioid. So the mechanism cannot be as simple as inverse agonism or competitive antagonism.


palmanita said:
Also flumazenil appears to be a adenosine RI(?)
Click to expand...

Most benzodiazepines are adenosine re-uptake inhibitors. But it isn't relevant to their in vivo pharmacology because the concentrations required are too high .

palmanita said:
Does administering a low dose of an antagonist together with an agonist really help limiting tolerance beyond just diminished effects? Could the same be done with e.g. an antipsychotic and a dopamine agonist (or a stimulant)?
Click to expand...

My point is that with flumazenil and naltrexone the situation is probably not as simple as competitive antagonism at one site. So in general, no, this wouldn't happen with all antagonists.
 
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From that study - "While some level of Gs coupling has been previously detected in opioid-naïve or acute morphine exposed CHO cells [6]" - I'm curious what the possible implications are of this phenomenon regarding chronic pain/neuropathic pain.

Do you think it might be possible for endogenous endorphins (or something else?) to be causing this phenomenon of increased MOR coupling to Gs in pathological conditions? (I assume endogenous endorphins are elevated at least in the first stages of a painful condition, and might cause the shift to Gs in the same manner as opoids)

Might this increase in Gs coupling occur in immune system cells as well (Though it seems it could only be so persistent as the immune cells would only last so long compared to neurons, right?)?

Thanks for any input or a nudge in the right direction.

Edit: I see now that naltrexone's immunomodulatory effects are mediated through toll like receptor 4 and are independent of the opoid receptor.
 
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Take lower doses of them less often, but yes, I realize that's not the answer to the OP's question that s/he will probably like to be told. But hey, somebody's got to do it.
 
Cotcha Yankinov said:
From that study - "While some level of Gs coupling has been previously detected in opioid-naïve or acute morphine exposed CHO cells [6]" - I'm curious what the possible implications are of this phenomenon regarding chronic pain/neuropathic pain.

Do you think it might be possible for endogenous endorphins (or something else?) to be causing this phenomenon of increased MOR coupling to Gs in pathological conditions? (I assume endogenous endorphins are elevated at least in the first stages of a painful condition, and might cause the shift to Gs in the same manner as opoids)

Might this increase in Gs coupling occur in immune system cells as well (Though it seems it could only be so persistent as the immune cells would only last so long compared to neurons, right?)?

Thanks for any input or a nudge in the right direction.

Edit: I see now that naltrexone's immunomodulatory effects are mediated through toll like receptor 4 and are independent of the opoid receptor.
Click to expand...

I think these changes are primarily involved in tolerance and addiction and are probably not especially relevant to immune modulation or chronic pain.
 
Any speculations on whether or not you might see a more excitatory G protein coupling shift with psychostimulants/insomnia/chronic pain? Or is it more likely that chronic, strong MOR agonism is necessary, and endogenous endorphins wouldn't cut it?
 
Thats an easy one,

Ultra low dose flumazenil togheter with your benzo dose
NMDA antagonists like memantine or DXM, minocycline would likely work too

Pregnenolone and DHEA i think have been said to work for benzo tolerance but havent seen any anecdotes.

Depleting nitric oxide with for example 4 gram l lysine a day would work.

Forgot some things
 
Kdem I found what I was referring to when talking about benzo tolerance possibly having a component of altered subunit composition http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/ - "A future for subtype selective GABAa receptor modulators?" Not quite close to the concept of partial agonists maybe not inducing tolerance as much that I think you were asking about before but subtype selective ligands might be just the trick.

Whatever tolerance is being mediated by compensation of glutamate you might theoretically be able to diminish with some glutamate antagonism to diminish long term potentiation?? Or would the glutamate just upregulate even more?
 
Theres a shitload of anecdotes all over the net from when i was promoting memantine showing memantine work long term for pretty much all drugs without causing tolerance to memantine itself, eg glutamate upregulation as what occurs with ketamine and co.

I cant beleive ppl dont know this, ive spread all this information all over the internet with ppl keeping having long term succes, to see a thread like this wihout replys is mind baffling
 
noone is talking about theory here but about proven mechanisms in rodents and hundreds of anecdotes backing mem and dxm up for tolerance to benzos, opiates, stimulants etc
 
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