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NMDA antagonists for tolerance, a collection of the evidence and anecdotal reports

mesmer said:
I've been on relatively low does of kpin (.5/day) for about 4 or 5 years now for sleep/anxiety issues. I wish I had never got on it, but c'est la vie. Within the past month I seem to have found myself in some sort of "tolerance withdrawal" hell of intermittent panic, tinnitus, burning skin, chills and sweats, etc. I'd like to avoid playing the chase the tolerance with upping the dose game, in fact I want to taper off. Interested in these reports of memantine and DXM being useful for up-regulating GABA receptors. Could possibly get rid of this tolerance withdrawal or allow an easier taper??

My only concern is that I am also on Zoloft for 5+ years for depression (am now tapering to Vibryyd, essentially an SSRI with a little extra 5HT1A agonism - may explain the side effects some people are getting on high doses of "trippiness")

I don't think a low dose of DXM is particularly worrisome for serotonin syndrome, others may disagree, would adding in, say a normal therapeutic dose of DXM and moving upwards to see if it reverses any of these symptoms (tinnitus especially) be an alright course of action. Memantine sounds more promising, but would have to scope a source.
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The 'promise' seems limited, and that is irrespective of the zoloft issue. A better choice maybe high dose gabapentin.

Your situation is somewhat reminiscent of the case report on page 75 (of the PDF):

Topiramate use in alprazolam addiction
 
yes, Topamax has it's own problems though. Not the least of which that it makes you as dumb as a rock. I will try a week of DXM and see if any symptoms disappear.
 
Certainly; it was just an example. I recommend high doses of gabapentin to facilitate the final dose reductions (particularly, X mg - 0mg). There is no easy fix however. Ultimately, the only way out of the BZD conundrum is to reach 0mg. Your physician should help you determine the dose, but at some point you are better off jumping to zero than playing an endless dose reduction game. High doses of gabapentin or potentially pregabalin may reduce the risk of potential seizure (rare) from total discontinuation, and can reduce some of the somatic symptoms of the acute withdrawal. In theory, all quitting is 'cold-turkey', but again, safety is a concern with BZD.

Take care with the DXM use, as it may be contraindicated in your case, and its efficacy for your intended purpose is at best anecdotal. When it comes to BZD withdrawal, prominent symptoms are unlikely to disappear as a result of any form of pharmacological intervention.
 
I've mentioned Huperzine A in a few other threads: it's possibly a very useful NMDA antagonist as it is available cheap as a supplement, does not produce dissociative effects, and is not anticholinergic (the opposite, it inhibits AChE). I haven't experimented with it for the purpose of tolerance yet; however, I just spent 9 days off of amph while taking huperzine for most of those days, so I will try taking my usual dose and see how that works out. There are confounding variables though, since I have been taking other supplements, including curcumin.

Edit: Took my usual amph dose (20 mg adderall IR) a few minutes ago, with usual accompanying supplements & antacid. I haven't yet taken my evening dose of huperzine, and my morning dose should be cleared out by now, so this should show the cumulative effect of huperzine on drug tolerance (although as I mentioned a change could be due to other factors), rather than acute. Later on I'll add in my evening dose to see how that effects it. As far as positive mood effects go, it doesn't look promising with huperzine's acetylcholinesterase inhibition: http://www.sciencedirect.com/science/article/pii/S0091305707003723

T+0:45: Feeling the effect more strongly than usual. I have an urge to talk to people and a willingness to go out of my way to be friendly which I haven't felt in a long time on amph.

T+2:00: Took a dose of huperzine at T+1:00, doesn't seem to have potentiated it, but it did seem to smooth out some of the amph tunnel-vision/introversion which I appreciate. Probably not a hugely effective potentiator, but it's hart to tell since the euphoriant effects were already starting to wear off when I took it.
 
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Context:
First attempt at using MXE for it's antidepressant qualities. Ideally it'll also lower my minimal amphetamine tolerance. You can probably tell from my adderall/4-FA dosages that my tolerance isn't high. These dosages have consistently worked well for me. They're not working today.

About 30 minutes after taking the magnesium I felt really tired. Hence the stimulant use. Suddenly, inexplicably tired/weak (slept well last night; I've eaten plenty).

Questions:
1. Why have my muscles felt weak since taking the magnesium? (This hasn't happened in the past; the only new factor is MXE.)
2. Is MXE blocking the stimulants?
3. Does MXE's DRI qualities bar it from reducing/preventing tolerance the way DXM/ketamine does? (Obviously anecdotal evidence is welcome.)

T 0h 5mg MXE insufflated
1.5h 5mg MXE insufflated
3.0 h 400mg magnesium malate
3.5h 15mg adderall, 1000mg calcium carbonate
4.0 h 30mg 4-FA, 500mg calcium carbonate (this time because the chewy ones taste good)
5.5h Bluelight post (hah, for relative timeline)

Amphetamines primarily work as DRI's in this dosage range, correct? One explanation could be that MXE has a stronger affinity as a DRI and is blocking the amphetamines.

Google suggests myasthenia gravis can be triggered by parenteral magnesium. This isn't my area of expertise.
 
Amphetamines are primarily DRIs only in very low doses, I think lower than 15 mg actually, unless you have a good tolerance. Still, DRIs block the action of amphetamine to some extent (whether or not this outweighs the additive stimulant properties) because amphetamine must be taken up through the dopamine transporter to work. However it's my impression that that much MXE should not significantly block the action of amph/4-FA. You're probably accruing tolerance. NMDA antagonists don't work for everyone, anecdotally.
 
Following my respiratory depression scare from the memantine, I had lingering breathing issues for a few months. Just a heads up0 purely anecdotal of course
 
It had to be a very strong dose of Memantine.. I can assure you 10mg puts me a little alert, and it works incredible for uppers (any kind) tolerance.

But once I did like.. I don't know, +100mg Memantine and I felt some breathing and cardiac issues too. Also if I would concentrate really hard in silent with my eyes closed I swear I would remember the feeling of a K low dose. But it was very subtle and mild. Never again.
 
Yeah I was doing the regime and I worked my dosage up too fast I think. I knew the half-life was extremely long but I underestimated it.
 
A couple of months ago I was sick with a minor cold and started taking cough syrup (~30mg DXM HBr) twice a day. This lasted about 4-5 days. My DOC is tramadol, and I was not using it during this period. I usually go one week on the tram followed by two weeks off with it...and have been holding to this pattern for a few months now. After my minor sickness was over and I returned to tramadol use, I discovered my tolerance had been noticeably reduced. I needed about 30% less tramadol to get to where I normally get on my first dose after 2 weeks of abstinence.

After some research, I found this thread and read through it. I wanted to test it out, so I have been taking ~120mg of DXM polistirex daily for almost a week now. I hope this is a good amount to start with. I will continue to do so until I start my tramadol cycle again, perhaps a week from today. I have been keeping a close eye on my use habits, particularly in relation to tolerance. I will report back to this thread soon with an update on my findings.
 
I finally got around to this. Took my normal dose of tramadol recently. As I thought, opioid activity (itching, propensity to nod) was noticeably heightened. The stimulant effects were also affected, but not nearly as much. I wonder why. I would say that the effects were slightly higher than the 30% I experienced upon without intentionally attempting to reduce tolerance. I cannot say that this lasted too long however, as I found myself increasing the dosage to get to the same point as I did on the first day of tramadol use.

This is certainly something I will continue to experiment with -- will take a longer break from tramadol (at least 4 weeks) and half the DXM (to 60mg a day) to see how that affects it.
 
Just before my post, I'm really tolerant to GHB/GBL, and tried memantine to kill tolerance. It worked a lot (2,8mL to 1,5mL in a few weeks with 20 or 40mg memantine a day), I already report that before on the topic, but memantine wasn't able to bring back euphoria. I understood that memantine is perfect to cure the GABA aspect of GHB/GBL tolerance, but keep intact the GHB receptor downregulation.

I read something really interesting in wikipedia (maybe you already know this but anyways! :) ).

The benzamide neuroleptics (including sulpiride, amisulpride, and sultopride) have been shown to activate the endogenous gamma-hydroxybutyrate receptor in vivo at therapeutic concentrations.[1] Sulpiride was found in one study in rats to upregulate GHB receptors.[2] GHB has neuroleptic properties and it is believed binding to this receptor may contribute to the effects of these neuroleptics.
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http://www.ncbi.nlm.nih.gov/pubmed/9652377

And more especially this study:
Sulpiride, but not haloperidol, up-regulates gamma-hydroxybutyrate receptors in vivo and in cultured cells.
Five days of gamma-hydroxybutyrate (GHB) administration (3 x 500 mg kg(-1) day(-1) i.p.) to rats resulted in a significant decrease in the density of GHB receptors measured in the whole rat brain without modification of their corresponding affinity. Similar administration of (-)-sulpiride (2 X 100 mg kg(-1) day(-1) i.p. for 5 days) induces an up-regulation of GHB receptors without change in their dissociation constants (Kd). Haloperidol (2 X 2 mg day(-1) i.p. for 5 days) showed no effect. Administered chronically via osmotic minipumps directly into the lateral ventricles, (-)-sulpiride (60 microg day(-1) for 7 days) and GHB (600 microg day(-1) for 7 days) up-regulated and down-regulated rat brain GHB receptors, respectively. Finally, in a mouse hybridoma cell line (NCB-20 cells) expressing GHB receptors, the treatment of these cells with 1 mM GHB, 100 microM (-)-sulpiride or 1 mM GABA decreases, increases and induces no change, respectively, in the density of GHB receptors after 3 days of treatments. These results indicate that chronic GHB treatment modifies the expression of its receptor and that sulpiride also induces plastic changes in GHB receptors perhaps via antagonistic properties.
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Do you know more about this? Did somebody tried with some success to renew his GHB receptors with sulpiride or amisulpride/sultopride? My girlfriend is on valium, risperdal and memantine for her GBL dependance. Maybe sulpiride is far better in her case than risperdal? Thanks a lot for any input!
 
Risperdal for G dependency wtf? Ap's shouldnt ever be used for anything else then shizophrenia due to their severe toxiticy problems and long term issues; a short course of amisulpiride wont be a problem tough.
 
Do you know more about this? Did somebody tried with some success to renew his GHB receptors with sulpiride or amisulpride/sultopride? My girlfriend is on valium, risperdal and memantine for her GBL dependance. Maybe sulpiride is far better in her case than risperdal?
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Why would you want to up-regulate the excitatory GHB receptor if you are going to be withdrawing from GHB/GBL. Me thinks this would greatly exacerbate the delirium/psychosis associated with GHB abstinence syndrome, as well as likely increasing the excitotoxicity.

Personally I wouldn't mess with neuroleptics just so I could "get the euphoria back." If its not doing much in the way of fun, then maybe its best to get off the stuff with a Baclofen/Phenibut taper.
 
/navarone/ said:
Campral (acamprosate) could also be a relatively available or rather easy to get prescribed NMDA antagonist and GABAa agonist. It has been approved in the US as well since 2004, however it is not very cheap.

http://en.wikipedia.org/wiki/Acamprosate
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*cough* just buy homotaurine *cough*
Pretty sure the whole deal with acamprosate's N-acetyl group was to make it patentable seeing as homotaurine is found in several seaweeds.
 
MeDieViL said:
Risperdal for G dependency wtf? Ap's shouldnt ever be used for anything else then shizophrenia due to their severe toxiticy problems and long term issues; a short course of amisulpiride wont be a problem tough.
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Yes I was a little puzzled when she came back with a script of this shit. She have sleep problems, and it was a good choice according to the doctor, because it's non addictive. (?!?) She take valium (prescribed by the doctor) too and memantine, and funnily she said to me that increase memantine from 10mg to 20mg decrease her lever of anxiety and depression. Maybe reach 30 or 40mg memantine a day could be even more beneficial? I was reluctant to let her mix memantine (the doctor don't know that) with her other medications, but after a few weeks it seems that memantine is far better than 3 valium a day (she took one valium a day max!), she is already more alive than a few months ago and want to quit risperdal.

Why would you want to up-regulate the excitatory GHB receptor if you are going to be withdrawing from GHB/GBL. Me thinks this would greatly exacerbate the delirium/psychosis associated with GHB abstinence syndrome, as well as likely increasing the excitotoxicity.
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I'm not addicted physically to GHB now, but don't feel euphoria anymore. In fact, i feel really depressed and exhausted after a single dose of GBL now so I try to don't take that anymore. It makes me think that my GHB/GABA system is still weak, and tried to find something do balance it a little bit, if possible but I don't have great expectations hehe :)
 
Anecdote of a personal friend says that DXM allowed GBL to stay working well; its possible DXM is more effective for GBL perhaps give that a trial run and eventually amisulpiride. Id be curious for your results.
I cant try it as G gives me abscence seizures at every dose.

now i think about it...

When tolerant to gbl it feels more sedating and far less euphoric this would indicate the problem is in the GHB receptor; G does indeed downregulate the ghb receptor wich amisulpiride upregulates again altough im sure GABAB downregulates as well.

Ibogaine has been reported on drugsanddogsforum to reverse G tolerance too.

Anecdotally its know the racetams potentiate several drugs (personally i experience massive mpa potentiation of mpa) however the racetams likely accelerate the formation of new tolerance (eg look up ethanol aniracetam) however one anecdote suggests that the combo of a racetam and a nmda antagonist offers the best of both worlds.
 
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In response to some of your (stimulant induced?) musings, (please for the love of your_deity_here use the edit button) -

DXM allowed GBL to stay working wel
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From what I have heard, GHB/GBL is pretty reliable in terms of producing effects, pleasurable or otherwise, unless dosed very frequently.(seeing as it's an endogenous n/t and all). 1-3x a day is probably nothing to worry about. I guess it varies between people.

G gives me abscence seizures at every dose.
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*Every* dose? And is it an absence seizure you're experiencing, or simply somnolence/"microsleeps"? GHB is a known & powerful inducer of sleep in many individuals.
From what I have heard, the stimulating f/x of GHB are more prevalent at lower doses (less than the typical 2-3g) due to the relatively low affinity for GABAb vs GHBr. Or you may even try combining it with e.g. caffeine or another, (even amphetamine-type) stimulant as long as you don't overdo it.

Racetams do indeed potentiate stimulants, I believe that it has something to do with increased activity at certain metabotropic glutamate receptors (of which racetams likely modulate & amphetamine derivatives interact with). Do note that NMDA/AMPA are ionotropic & not metabotropic so this would still be a 2nd order effect.

On the topic of ibogaine & DXM, they are both pretty broad-spectrum drugs and are much more than a "pure" NMDA antagonist. I know Ibogaine at least is a SNDRI (S>D>N in terms of potency) plus opioid agonist (mu and kappa) and also interacts with 5-HT receptors. It's not very potent but people take it in multi gram boluses so I would expect a real fireworks show. DXM is "only" a SNRI (N>S) but has all this funky rate-order mechanics shit with the conversion to DXO (which is more potent as a NMDArA, and from what I can tell seems more like a version of ketamine with activity at SERT). In addition both drugs are calcium channel/nicotinic blockers (as is ketamine/MXE/memantine). There is also sigma-1 and 2 agonism to consider as well... truly rhese drugs that are thought of as NMDA antagonists may be working through other modes of action.

I wonder how much of it is all psychological, though, from people simply becoming 'entrained' to drug use... like riding the same roller coaster every day, if you will. You can ride that coaster every day until you no longer find pleasure in it, and when that point is reached you can definitely come back after months or years of being in a different mind state & recapture that thrill. Of course it will never be quite as exciting as the first time because some of the novelty has gone, but it likely won't be 'boring' as it were if you were riding it daily for 3 weeks. Continuing to ride the coaster over and over when you don't like the experience should be reserved for roller-coaster test pilots & sadomasochists. I'm not denying that some drugs develop a physical tolerance, but in some cases I bet it's just a case of your 'escape of choice' becomign boring.

Re: risperidone for ... well, anything but major delerium & schizophrenia - wtf? I do not understand why this industrial strength antidopaminergic is prescribed as frequently as it is. From whatI have read it seemms incredibly effective at makiing you not care about a single fucking thing, be unwilling/unable to think, and possibly inducing black, death-like sleep and/or motion dyskinesias/tics. I can't remember reading anything that suggest widespread blockade of the dopamine/5ht systems is good for any sort of drug dependence. Maybe for an out of control acid trip, or a schizophrenic meltdown, or sedating someone as a last-resort, but not GHB dependence.

MXE has a stronger affinity as a DRI and is blocking the amphetamines.
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On trhe topic of MXE, I think it's a damn strong DRI & definitely not an "anti-addictive" agent any more than PCP/ketamine is. (Probably due to this property,) I have also seen it precipitate quite the washout similar to cocaine when overused or used in naive individuals (probably in combination with stimulants)... consisting mainly of inattention, head fog, & sleepiness. 6-24h after last dosing Relieve it with a solid dose of caffeine if you have to work.
 
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