• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

Diazepam dependence prevented by glutamate antagonists.

hookedonclonics

hookedonclonics

Greenlighter
Joined
Sep 30, 2009
Messages
16
Location
Soviet Canuckistan
Long-term treatment leads to tolerance to and dependence on benzodiazepines. Abrupt termination of benzodiazepine administration triggers the expression of signs of dependence. Mice withdrawn from chronic treatment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontinuation. A period between withdrawal days 1 and 3 was symptom-free. Surprisingly, during this "silent phase" the susceptibility of mice to alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate (ATPA) and kainate seizures and the magnitude of monosynaptic reflexes mediated by non-N-methyl-D-aspartate (NMDA) mechanisms were enhanced. In apparent contrast, the "active phase", between withdrawal days 4 and 21, was characterized by increased susceptibility to NMDA seizures and enhanced magnitude of polysynaptic reflexes, which are NMDA dependent. Treatment of mice with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not with the NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) during the silent phase prevented signs of dependence. In contrast, treatment with CPP but not with GYKI 52466 during the active phase prevented the symptoms. The development of tolerance to and dependence on diazepam was prevented by concurrent treatment of mice with CPP but was not prevented by GYKI 52466. These data indicate that NMDA-dependent mechanisms contribute to the development of tolerance to diazepam and to the expression of signs of dependence in mice after termination of long-term treatment with diazepam. Nevertheless, the non-NMDA-mediated silent phase is essential for triggering the symptoms. Therefore, AMPA antagonists may offer a therapeutic approach for preventing dependence on benzodiazepines that is an alternative to NMDA antagonism.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC47038/#reference-sec
here's a link to the entire paper:
http://www.pnas.org/content/90/14/6889.full.pdf+html?sid=0ac1398f-1342-4209-8051-c47e06946ed8

I'm wondering if anyone out there has any more info on utilizing NMDA antagonists for benzo w/d. The benzo community in general doesn't seem to be aware of this research and I can't quite figure out why. I would think if something did indeed help with the withdrawal, it would be fairly well known. Any information would be greatly appreciated.
Thanks,
HOC
 
How about because NMDA antagonists produce strong psychoactive effects that would make it difficult to use as WD treatment? AMPA antagonists probably make more sense, but I know little about their pharmacology.
 
Is it truly the case that all NMDA antagonists would have a psychoactive effect?
I understand that most of them do (ie ketamine, DXM, methadone etc) but always thought that it was secondary. What of the ones utilized in this study?
Are there common drugs that possess AMPA antagonism?
 
hookedonclonics said:
Is it truly the case that all NMDA antagonists would have a psychoactive effect?
I understand that most of them do (ie ketamine, DXM, methadone etc) but always thought that it was secondary. What of the ones utilized in this study?
Are there common drugs that possess AMPA antagonism?
Click to expand...

Memantine has anecdotally been used succesfully to slow tolerance to stimulants, in the normal doses (10 or 20mg) it is not psychoactive.
 
I have personally used Ketamine to help with the initial phases of benzo withdrawal.

Not only did it work, but it also stopped my cravings AND caused my tolerance to actually go down considerably.

p.s. It also helped with opioid withdrawal, but not as much.
 
hookedonclonics said:
Is it truly the case that all NMDA antagonists would have a psychoactive effect?
Click to expand...
Well, I've tried Amantedine, which is an NMDA antagonist. It had mild stimulant-like effects but I mean REALLY mild, even a bit creepy.

I also tried cat's claw,which contains an NMDA antagonist whose name I forget, and it didn't produce any noticeable psychoactive effects, even at very high doses.

So my subjective answer to your question is no.
 
Jamshyd said:
I have personally used Ketamine to help with the initial phases of benzo withdrawal.

Not only did it work, but it also stopped my cravings AND caused my tolerance to actually go down considerably.

p.s. It also helped with opioid withdrawal, but not as much.
Click to expand...

There is research behind NMDA antagonists to slow benzo tolerance:

NMDAR and benzodiazepine tolerance:

 
Jamshyd said:

p.s. It also helped with opioid withdrawal, but not as much.
Click to expand...

It's helped me quite a deal whilst going through Opiate withdrawal and, when using it with Opiates, it does seem to lessen the dramatic rise of tolerance also :)
Such a strange and wonderful set of chemicals NMDA antagonists.
 
Jamshyd said:
I have personally used Ketamine to help with the initial phases of benzo withdrawal.

Not only did it work, but it also stopped my cravings AND caused my tolerance to actually go down considerably.

p.s. It also helped with opioid withdrawal, but not as much.
Click to expand...

When you say 'initial phases' do you mean a cold turkey or during a taper?
How long did you use it for and did it eliminate or merely mask the withdrawal?
I wonder too why the larger benzo community doesn't seem to know about this. I realize getting wasted on ketamine isn't a great solution but I would still think it would be known; people in withdrawal are sometimes willing to try anything to help.
 
Jamshyd said:
Well, I've tried Amantedine, which is an NMDA antagonist. It had mild stimulant-like effects but I mean REALLY mild, even a bit creepy.

I also tried cat's claw,which contains an NMDA antagonist whose name I forget, and it didn't produce any noticeable psychoactive effects, even at very high doses.

So my subjective answer to your question is no.
Click to expand...
I have to ask: did you take these during your benzo withdrawal and if so, were they effective? Did you try any others?

I've been tapering off of .75mgs of klonopin (now below .015mgs) and I also take methadone at 41mls/day. My symptoms have been minimal and I wonder if the NMDA antagonism of meth is enough to have that effect. Thoughts?
 
hookedonclonics said:
When you say 'initial phases' do you mean a cold turkey or during a taper?
How long did you use it for and did it eliminate or merely mask the withdrawal?
I wonder too why the larger benzo community doesn't seem to know about this. I realize getting wasted on ketamine isn't a great solution but I would still think it would be known; people in withdrawal are sometimes willing to try anything to help.
Click to expand...

I was never really able to taper all the way to 0 with any of the drugs I quit. With benzos, I tapered for a few months then quit at the 2.5mg mark (Diazepam) cold-turkey. I still exerienced significant withdrawals since I have Anxiety disorder anyway.

I took K in small doses - small enough to keep me fully-coherent and mobile, so I doubt it merely "masked" the effects. Although K at low doses is a great anti-depressant, it doesn't help much with panic attacks. So I doubt it was masking the w/d.

hookedonclonics said:
I have to ask: did you take these during your benzo withdrawal and if so, were they effective? Did you try any others?
Click to expand...
No, I was not on benzos or withdrawals when I took those.

Do keep in mind that "NMDA antagonist" is a very very broad umbrella-term. There are several sub-classes of these, depeding on their site of interaction with the receptor and what they do at that site.

The most useful ones seem to be those classed as "non-competitive" and "channel blocker" - which is what Ketamine and PCP are. I think the adamantanes are also classed here.

Which leads us to your second question - I honestly have no idea how Methadone interacts with the NMDA receptor complex.
 
thanks a bunch Jamshyd! very informative posts. I see your withdrawal is documented elsewhere on the site. I'll peruse it and be back at you with more questions, I'm sure.
 
Re: nmda antagonists are psychoactive

In my experience with stimulants and opiates, the dosage of an NMDA antagonist required to slow/stop my tolerance had no noticeable psychoactive effects. I could do it with 60mg/day of DXM or ~500mg/day of Magnesium which is about the recommended daily value anyway.
 
The Reanimator said:
In my experience with stimulants and opiates, the dosage of an NMDA antagonist required to slow/stop my tolerance had no noticeable psychoactive effects. I could do it with 60mg/day of DXM or ~500mg/day of Magnesium which is about the recommended daily value anyway.
Click to expand...
There is an awful lot of anecdotal reports of mag helping in benzo w/d so this could be the reason. (although some people do report a spike in symptoms)
 
Last edited:
Treatment of mice with (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466)...
Click to expand...

200px-GYKI_52466.png


...or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline...
Click to expand...

nbqx.png


...but not with the NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP)...
Click to expand...

Racemic_CPP.png


What the fuck is this? I mean, I see and read that it's a potent NMDA antagonist that blocked the diazepam comeoff, but is it legal? Toxic? Fun? Better than the huge 3-day-old bird in my fridge?

I'm wondering if anyone out there has any more info on utilizing NMDA antagonists for benzo w/d. The benzo community in general doesn't seem to be aware of this research and I can't quite figure out why.
Click to expand...

What is it that you understand from the study you quoted? The authors identified 2 distinct phases of bzd withdrawal--a silent (less-shitty) phase and the familiar firebombing-of-Dresden active phase. Their interest was on non-NMDA-antagonist drugs (the 2,3-benzodiazepine in the 1st pic and the quinoxaline in the 2nd. The point is (so as not to get lost in the tangled glutamatergic neurophysiology) the point is that the ampa-antagonists eased the initial stage of the diazepam w/d and possibly would help a motivated addict taper and quit. There's also the added bonus that ampa-antagonists are, in general, not fun--so you're not gonna trade one habit for another.

There is no buprenorphine for benzodiazepines--at least not yet (see below). To mask sudden withdrawal from a strong addiction you need to essentially put yourself into an ambulant coma with potent NMDA antagonists for weeks. And then what?

....

And then but so then can anyone say something about that CPP thing in my 3rd pic?

....

Have you read about imidazenil? It's essentially estazolam with a fluorine instead of a chlorine at the 7 spot, a bonus bromine at the 2' spot and a caboxamide on the imidazole ring:

140px-Imidazenil.png


You read the wiki synopsis of it and your like what the fuck? Partial GABA-A agonist, anxiolytic, anticonvulsant; non-sedating, non-amnestic (competitive antagonist to diazepam in this respect), non-tolerance-building, non-addictive. Something to keep an eye on.
 
So my use of Methadone (It's an Opioid Mu Receptor Agonist and NMDA Antagonist) will help reduce the risk of tolerance and addiction to benzo's?
 
You must log in or register to reply here.
Top