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Tolerance prevention with NMDAR antgonists

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doppelgänger1

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Joined
Feb 24, 2012
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Can someone fill me on the current consensus about tolerance prevention with NMDA-receptor antagonists, in general and regards to which substance and dosage are recommended?
My first guess would have been memantine, if I remember correctly however there was an explicit advice not to use it and take Magnesium instead.
But is Mg really that effective? After all I am yet to experience any dissocative effects from taking Mg supplements.
 
doppelgänger said:
Can someone fill me on the current consensus about tolerance prevention with NMDA-receptor antagonists, in general and regards to which substance and dosage are recommended?
My first guess would have been memantine, if I remember correctly however there was an explicit advice not to use it and take Magnesium instead.
But is Mg really that effective? After all I am yet to experience any dissocative effects from taking Mg supplements.
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They're going to be a lot more neuroprotective if anything.

What tolerance are you trying to prevent?
 
Does anyone know if tolerance with ketamine is actually localized neuronally though? For all we know it could be a metabolic thing..
 
Seriously, if you don't want to develope tolerance then take low doses and take long enough breaks. Tolerance is a natural reaction and to try to avoid it with other substances, which might lead to interactions, is not a good idea. Take it and live with the risk or don't do it at all, simple as that.
 
It is never wrong to keep this in mind as a safety measure of course. With the interactions, it´s really playing with fire unless we have more solid data. But I feel it´s more like handling high current voltage, if it is done right one gets shining results..

I have become reckless recently with opioids after I got away twice with only minor discomfort. And ... I can´t believe it myself ... it´s now day 4 with no H. I am back to normal again. It feels just great to be out of the sedation and feel all the body´s precious dopamine again.. A very light kratom tea works again like I never had done opioids before. And it was totally, completely painless. Some mild sweating and gastric disturbances in the first night - that was all and over. Okay, the fear of what might come was too high so I sedated myself with clonidine (3x 150mcg/d) but I think it would not have been necessary. Not even loperamide was needed! After some hours of rumbly stomach I could almost feel how my body began to produce endorphins again ...

Sorry for the short posting, I´ll write more accurately later. But it really fuckin works. 40mg/d of memantine allow me to use opioids sans addiction. Have to see what´s about the cravings, but ... this is more than game changing (if you happen to have the right genetics, maybe). Everyone dealing with opioids should read up about this topic ... I can´t believe this is general knowledge (publically available on the net) and no one cares.
 
Taking NMDA antagonists every day can't be good for you in the long run. I'm sure I'd rather withdraw from heroin and slowly get back to normal than to suffer from chronic cognitive problems. Memantine is prescribed for cognitive diseases like dementia but the assumption here is that over-active NMDA channels cause excitotoxicity, I don't think a very young or mid-aged person who is generally healthy in this respect could benefit from long-term memantine despite some reports here on BL.

It's one thing to use an NMDA antagonist to alleviate opioid withdrawal for a short period of time, and it's different when you continue using it along with opioids to slow down or eliminate tolerance.
 
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The points in the thread are very valid. Myself and others have tried nmda antagonists for opiates and stimulants to some avail, my experiences have shown that constant dose dependent tolerance maintenance occurs moreso in the euphoric effects with constant dose consistency (once daily max) . I utilized delsyum. Likewise I have used ultra low naltrexone, delsyum and gabapentin to kick/stave withdrawals.

The bottom line is staying tolerance is a BAD IDEA. These are physiological mechanisms for handling xenobiotic substances and we can use examples from endocytotic recycling of gpcrs (protein maintenance/turnover), drugs and their effects on protein transcription cascades through the reverse cascade (affecting translated proteins which affects transcription factors, shifting new transcription ratios of proteins, think rnas, lsd is infamous in its causal shift in transcriptive protein synthesis). Lastly one can argue constant adjustment of the cell conductivity of neurons affects the cell conductivity of other neurons thst are coupled with the receptor of choice (I. E gaba and opioid receptors), therefore the thermodynamic limits are applied by proteins to maintain cell conductance overall.

So many rational examples why tolerance is an excellent evolutionary system persay. However no one appreciates this because we wish drugs can be fun forever, many do not realize euphoria is blinding, narrow minded, and biologically dangerous. Thinking you are on top of the world can lead to dangerous outcomes (the drunk driver example notoriously).

Many wish stimulant drugs to maintain euphoria but the bottom line is after the euphoria has faded alongside psychomotor stimulation, in adaptation periods, the mental focus remains unbeknownst to many who are not very meta cognitive, the medication continues working. They do not question it.

Considerations..
Zedz
 
Magnesium (1000mg per day) and Dextromethorphan 100mg per day is what SWIM uses to try to keep tolerance low. Too bad SWIM cannot get Memantine prescribed and SWIM's pain doctor does not have any ultra low-dose naltrexone preparations, but SWIM's previous doctor made ultra-low dose naltrexone preparations on his own and they worked because SWIM tapered off 75mg oxycodone within 1 week and only felt slight WD's, BUT SWIM did have a prescription for Lyrica 600mg per day, which is known to reduce WD's, especially in high doses.
 
I've been using just straight NMDA pills for perhaps a month to try and lower my tolerance. It has worked to be honest. It works a lot more when I'm on it and using K but I was able to hole from maybe 50-60mg IM S-Ket which would have been nigh impossible beforehand (or ever!). It's the only NMDA agonist I could get and using more NMDA antagonists (like Memantine) would only increase tolerance.
 
NMDA doesn't readily partition into the CNS (it is 8000-fold more potent icv vs. im), which is a good thing because it is an excitotoxin.

The reason why NMDA would potentiate ketamine is that the binding of ligands to the PCP site is use-dependent, and a larger % of binding sites are occupied by ketamine in the presence of NMDA.
 
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Huh...so in a sense I was right to do so but just not /that/ right! Still though, it really potentiates ACH's and essentially that's what we really want at the end of the day. My tolerance prevents me from even using ketamine any more because it's just a waste of money. Before using NMDA I got a gram of K and finished it within two hours with only mild effects and it was supposed to be really good K too. I would finish a 10g bag of MXE in under a week, it was an absolute nightmare as dissos are my DoC but NMDA really did help, it was like a godsend but I'll try Memantine and things like that too for the long run. Thanks!
 
blueberries said:
Huh...so in a sense I was right to do so but just not /that/ right! Still though, it really potentiates ACH's and essentially that's what we really want at the end of the day. My tolerance prevents me from even using ketamine any more because it's just a waste of money. Before using NMDA I got a gram of K and finished it within two hours with only mild effects and it was supposed to be really good K too. I would finish a 10g bag of MXE in under a week, it was an absolute nightmare as dissos are my DoC but NMDA really did help, it was like a godsend but I'll try Memantine and things like that too for the long run. Thanks!
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I don't think the NMDA you are taking is getting into the brain. If it is then you shouldn't be taking it because NMDA is an excitotoxin. When people ingest excitotoxic amino acids over long periods they often cause motor neurons to degenerate. BMAA is one example, but there are many others.
 
adder said:
Taking NMDA antagonists every day can't be good for you in the long run.
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This is an important question of course, and I must admit that taking something daily where nobody knows what the long-term consequences could be or how to help with withdrawal sometimes scares me.
After abrupt (forced) cessation of 40mg/d together with an opiate (antagonized by naloxone btw), cocaine, clonidine and venlafaxine I felt very tense, anxious and overexcited with intense headaches, it felt like being on the borderline to seizures but fortunately nothing happened and the next day I was put on low-dose lorazepam. Regarding the bunch of substances I was taking before it was no surprise to have a bad week of course and probably the long half life of memantine saved me from experiencing opiate w/d.

The over-excitation feeling did not fade even after ten days and the venlafaxine-related brain zaps on top of this made the fear of seizures very real. The over-excitation was real too since even with mirtazapine I just slept for 5 hours. So after I was discharged with all the substances seized and nothing seemed to help I got a prescription of memantine again. Within hours I felt huge relief. This made me fear of being dependent of memantine of course..

Now some months later I´m down on 20mg/d with no negatives. Also memantine has a relatively low affinity to the NMDA receptor which does not block it completely. Cognitive-wise I feel ambivalent. It might slow down some thought processes but overall it´s much lighter than many psychiatric medicines.

I think about tapering down to zero, while on the other side it has its solid positives on stabilizing mood and is synergetic with methylphenidate so I´d like to stay on a low dose. Also I felt really no cravings for opioids which I attribute to a large part to the memantine. Doctors throw around neuroleptics all day and they are known to be toxic on the long run, for example.

But any information about the long-term consequences of memantine is very welcome! Could the D2 agonism (possibly causing dopamine agonist related PAWS) be more problematic than the slight NMDA blockade in the end?
 
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