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  • N&PD Moderators: Skorpio | someguyontheinternet

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

I wasn't necessarily saying NMDA antagonism for benzo user's glutamate upregulation but rather an AMPA antagonist like Perampanel.

Also in my opinion studies have shown that NMDA antagonists reduce sensitization to psychostimulants, what exactly it does to the human experience of euphoria is up in the air (I can't remember if any of the studies checked for effects on conditioned place preference) but there were 3 studies as I recall looking at NMDA antagonists effect on stimulants and they all had the same conclusions that NMDA antagonists reduced reverse tolerance that normally occurs with stimulants
 
, what exactly it does to the human experience of euphoria is up in the air

With the massive ammount of anecdotes weve got that may indeed be up the air, but next to me in my private yet, memantine and DXM significantly potentiate the euphoria of stimulants, confirmed by pretty much 90% of all anecdotes and my personal experience.

Everyone here talks about it like this is a new concept, back in my day after i posted about my intervention, inspired by rodent research and a few anecdotes particurally of one guy benson of mind and muscle this intervention became extremely well known and common.
 
I never felt most drugs which i took the first time, only after about 5 times i could feel each differened stim i tried, this was in combination with memantine, while it worked for tolerance, ampa antagonism is concerning for cognitive inhibition, atleast if i look at topiramate, memantine kinda only blocks excessive glutamate transmission and increases tau which relates to intelligence but i dont know the therapeutic implications of that
 
I think many people report potentiation of stimulants with NMDA antagonists but synergism isn't necessarily tolerance reduction, NMDA antagonists themselves cause release of monoamines an un-inhibition of the nucleus accumbens and also induce DeltaFosB so I don't know if we can conclude anything for the combination while the both substances are in our systems.

http://www.ncbi.nlm.nih.gov/m/pubmed/9560846/

http://www.ncbi.nlm.nih.gov/m/pubmed/2671566/

http://www.ncbi.nlm.nih.gov/m/pubmed/9838055/

Locomotion doesn't necessarily mean euphoria though so I am open to this studies not applying for the purpose of potentiation of stimulants for enjoyable reasons

NMDA antagonists for opiates on the other hand has a fair bit of research behind it as I recall
 
No mate, alot of people reported even reversal of tolerance and being to consistently take the same dose for therapeutic uses and lack having to escalate the dose,

Trust me ive been readin reports and talking to people for bloody ages.
 
I know people report that stuff but what I'm saying is this could still be due to synergism and stuff like expression of DeltaFosB, which is really addiction related pathology and not necessarily a good thing in the long run for people with mental health issues

It could also partly be placebo (because dopamine is more about expectation of reward anyways). I can't tell you how many different studies I've seen for all sorts of different classes of drugs where the placebo response rate was like 20%, which is really standard for antidepressant studies
 
With a low placebo rate that low im sure the reports wouldnt be that overwelmingly positive, i also beleive that the placebo effects is less likely to occur when using amphetamine long term therapeutically for things like social anxiety, drugs are powerfull chemicals and a placebo effect replicating that effect long term is imo harder then a placebo effect making you feel less depressed. Also for people abusing drugs, when my girlfriend combined dxm with gbl she kept on getting really hight for the month she used it and after that the high slowly tappered off again,

again the consisteny in the reports is convincing for me, and personally its pretty obvious to tell the difference btw just getting therapeutic effects of stims after a couple days no matter what dose, or remaining a powerfull high when dosing up.
 
The thing is we're not necessarily talking about a sugar pill, we're talking about NMDA antagonists that cause release of monoamines - anybody who gets really high because they combined stims and NMDA antagonists could be feeling the disinhibition and disso effects and not necessarily feeling the effects of something like dopamine receptor upregulation or impaired dopamine receptor downregulation.

I've heard from someone who used stims and NMDA antagonists every day for about a year and then had major league longterm anhedonia when they stopped - to me this indicates that the dopamine receptors were still down regulating even though they perceived at the time that their tolerance wasn't too bad

But just for the sake of clarity I'm talking about dopaminergics, I think NMDA antagonists work for opiates and I have no idea about other drugs

To me a drug that works directly by inhibiting the GABA neurons inhibiting the nucleus accumbens (NMDA provides a lot of input to the inhibitory medium spiny neurons that inhibit the Nacc) would synergize really well with a dopaminergic that's also acting on the Nacc, but when I'm talking about tolerance personally I'm thinking of receptor homeostasis. Even though when you're taking about things like benzo tolerance, compensation by downstream glutamate is playing a big role reduction of benzos effects with long term use.

So I might just be splitting hairs over the definition of tolerance lol
 
Memantine doesnt cause a high and is unpleasant in hogher doses, ove also used it after stims to reverse the tiredness, mood and anhedonic effects faster, what kind of nmda antagonist wat that guy using? and at what doses? the tolerance prevention doses arent psychotactive at all, that anecdote doesnt make any sense, souds like someone abusng dxm on top of amphetamine or something.

Id agree wth you about the defination of tolerance, my usual recommedation for social anxiety was 20-40mg mem a day with dexamphetamine and a one day break a weak in case theres still some slight downregulation occuring, also what definas somethoing to be a anti tolerance substance for me if it accerelates or removes withdrawal issues after sessation.
 
serotonin2A said:
Upregulation wouldn't explain why withdrawal symptoms decrease immediately.



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.
Click to expand...

What does the alpha 6 subunit do ?
I take it that flumazenil both displaces the original benzo and binds to the alpha 6 subunit ? From reading sources it seems that flumazenil has some sort of mild agonism, and is sometimes used in benzo detoxes.
 
Kdem said:
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.
Click to expand...


Bacopa Monnieri:

normalizes GABA receptor function

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306740/

[h=1]Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice.[/h]
http://www.ncbi.nlm.nih.gov/pubmed/18193203
 
Etizolam will just not cause downregulation of the BZD site as fast as other ligands, it won't really "neutralize" tolerance, so much as hinder it.
 
That doesn't mean it neutralizes tolerance by virtue of receptor upregulation, though: it still causes downregulation of the receptor; all agonists of a receptor do this.
 
If the same dose causes incremental efficacy the more the drug is taken, what else could be happening?

Personally I have no experience with this though. I've read wildly varying accounts of ETZ. I think anecdotes are muddied by the fact that a lot of people don't really know what they're taking unless they routinely send it for testing.
 
Not upregulation of the receptor. Which means it causes the cell to assemble more protein bound receptors on the cell surface. It causes downregulation; that is, it causes the cell to disassemble the receptors and bring them back into the neuron, to maintain homeostasis in the presence of synthetic increase in the increase activation GABA A receptors.

More activation necessitates the need for less receptors, and the above occurs: the process of receptor downregulation.
 
if i switch to etizolam, after 2 days im completely withdrawn of clonazepam, anecdotes are mixed tough
 
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