Benzo withdrawal and NMDA agonists

We have a thread in this forum about Ketamine locked, but Colin noted the following:

This thread might have been allowed if you were more careful in your phrasing, and if you had posted it to a more appropriate board for this discussion.

I'm going to attempt to be more careful in my phrasing, as I have some experience in this regard. My basic conclusion was that this didn't work for me, nor would I recommend it to anyone, but the science behind it is interesting.

Ketamine is a schedule-III drug in the US, which means it's got established medical uses but also has abuse potential. For reference, the "big gun" narcotics (morphine, oxycontin) are Schedule-II (strongest legal drugs); the middle shelf narcotic preparations (vicodin, percoset) are also Schedule-III, and benzos are schedule-IV. There is one additional schedule, S-V, which contains things with much more limited abuse potential (tylenol + codeine, for example).

Ketamine has primarily been used as a veterinary anesthetic in the US, but it's also used as an anesthetic for small children because its safety profile makes it less dangerous than the typical midazolam + fentanyl 'twilight' medication for people with lower body weight. However, over the past several years, there has been interest in Ketamine specifically and NMDA agonists in general as antidepressants, and there are several studies which demonstrate their efficiency:

http://www.ncbi.nlm.nih.gov/pubmed/22339643

The past decade has not yielded a large number of new antidepressants and, with the possible exception of agomelatine, none of the newer medications that have been introduced have decisively addressed the several unmet needs in this area of therapeutics. Among the various novel strategies that are being evaluated, results of several small studies of ketamine suggest that drugs that modulate glutamatergic neurotransmission may hold the greatest promise for exerting rapid and large antidepressant effects in patients who have not responded to SSRIs or SNRIs.

I got interested in this when I was unstable on my dose of phenazepam (pre-crossover to Valium) and my tinnitus was at its worst. I read a lot of things which correlated tinnitus with excess glutamate activity, so my hypothesis was that if I antagonized NMDA receptors, working in opposition to glutamate, it might surpress glutamate activity and reduce the subjective severity of the symptoms.

Since Ketamine is not legal to obtain without a DEA license, the two NMDA agonists I chose were Dextromethorphan, a common ingredient in over-the-counter cough medication, and methoxetamine, an entirely new and novel research chemical which exhibits NMDA antagonism.

Dextromethophan was entirely ineffective in doing anything at any reasonable dose, and since I know that at higher doses it creates problematic alterations in cognition, I shelved that idea. I only tempted fate with methoxetamine once, and noted that my tinnitus got significantly _worse_ for several hours following ingestion. I also do not advise anyone to pursue that one until there is a lot more medical inquiry into exactly how methoxetamine works, and what the long-term effects might be. Ketamine at least has been around for decades and has well established pharmacokinetics and is considered 'safe' if administered (legally) under medical supervision.

It's possible that there might yet emerge a novel treatment for benzodiazepine withdrawal based on NMDA antagonism, but I'm skeptical. The bulk of work on BDZ withdrawal indicates that by far the best treatment modality is a gradual withdrawal that doesn't involve confusing the brain with any other drugs.

One other thing to note is that since glutamate and GABA work in opposition, mucking with suppressing glutamate activity is the flip side of trying to enhance GABA action. Campral, a drug used to treat alcoholism, is known to suppress glutamate activity, and has shown some limited efficiency in treating tinnitus. If, after a sufficient period of being completely off benzos, I am still bothered by my tinnitus (which I had pre-benzo) to a significant degree, I do plan on speaking with my doctor about trying out campral.

Just my .02 for a Monday afternoon.

There are other NMDA antagonists.

Memantine being one of those.

There used to be a thread on the bluelight forum (ADD?). But their perspective is of course a bit different from ours.

Presumably a NMDA antagonist could help, but there are always risks.

Anticonvulsants and some other drugs are used with some anecdotal success.

'It's possible that there might yet emerge a novel treatment for benzodiazepine withdrawal based on NMDA antagonism, but I'm skeptical. The bulk of work on BDZ withdrawal indicates that by far the best treatment modality is a gradual withdrawal that doesn't involve confusing the brain with any other drugs.'

That doesn't mean there cannot be supportive treatment for those who need it or those who feel they can use it to their benefit.

'no other drugs' doesn't work for everyone.

But their is no profit in developing such treatments

I don't think it's reasonable to say "presumably an NMDA agonist could help" when there's zero evidence to support such a claim. Extrapolating a hypothesis from a theoretical model just yields a hypothesis that could be tested, not evidence. There are lots of NMDA agonists, but by their nature they provoke potentially strong (and for many people, unpleasant) dissociative states when given at pharmacologically active doses.

Given that dissociative states which arise from benzo withdrawal itself are one of the most unpleasant symptoms that many people report, I don't think it's reasonable to suggest people experiment with this. I did, yes, but I knew what I was getting into because I have a lot more experience with these things than any healthy person would (and my anecdotal experience was that it increased symptoms).

It's an interesting theory that warrants clinical investigation, but that's all it is.

Other drugs that modulate GABA transmission are known to complicate benzo withdrawal; it seems to me that if you start pushing the NMDAR button, you're playing with fire because you're essentially doing the same thing from the other end of the regulatory system. Let's also not forget that NMDARs are suspected to be neurotoxic in a way that benzodiazepines simply are not. I know that the evidence for Olney's lesions in humans are pretty shaky, but it's well established in animal models, and I think it's a bit naive to assume there's some magic that keeps it from happening in humans (it's just much harder to analyze lacking Soviet Gulag-style human experimentation protocols).

There are two interesting articles about treating MDD using ketamine and some other meds here, that are in clinical trial:

http://www.npr.org/blogs/health/2012/01/31/146096540/i-wanted-to-live-new-depression-drugs-offer-hope-for-toughest-cases

http://www.npr.org/blogs/health/2012/01/30/145992588/could-a-club-drug-offer-almost-immediate-relief-from-depression

As someone that suffers from MDD that is treatment resistant, I'm always interested in new approaches to treating depression. Obviously, we need scrutinized and well-tested scientific studies on safety and efficacy for some of these newer treatments, but I have faith and hope in science that new theories and medicines can be developed to help those that suffer.

excellent post spengler. much appreciate it. btw i restarted the jaegerwilk thread: http://www.benzobuddies.org/forum/index.php?topic=52190.0

also, one more poster thinks campral might help during withdrawals: http://www.benzobuddies.org/forum/index.php?topic=51687.msg699202#msg699202

but that is strictly one person's "feeling" and not too much should be read into it. i'm interested in campral only because i'll be quitting alcohol soon.

I was on memantine (Namenda) for about 18 months, starting prior to any benzo tapering. I attempted to taper 3 times while I was on it. It did absolutely nothing to ameliorate the horrible withdrawal sxs and I had to reinstate each time.

Sparrow