N&PD Moderators: Skorpio
Anyone know how to increase NMDA receptor density?
Speculosity
Greenlighter
Hi everyone, I was wondering if anyone know of ways to increase NMDA receptor density?
So far, I only know that piracetam does it.
http://www.ncbi.nlm.nih.gov/pubmed/8234409
Anamo7tram
Bluelighter
An NMDA antagonist? Like ketamine for example.
Perhaps an AMPA agonist as well, since down regulating AMPA should upregulate NMDA as a compensation mechanism, but this is highly speculative.
serotonin2A
Bluelighter
^Agreed. Excessive NMDA activation produces neurotoxic effects.
To the earlier poster that suggested an AMPA agonist, that is also a bad idea. AMPA agonists tend to be even more neurotoxic than NMDA agonists. For example, domoic acid.
sekio
Bluelight Crew
Off topic- what is it with people wanting to increase density of certian receptors in their brain? Is this some sort of a miracle cure?
endotropic
Bluelight Crew
I'm assuming in most cases it comes from a desire to reverse drug tolerance. It seems like a logical solution unless you have a pretty solid understanding of neurobiology.
I've seen people on another forum seriously attempting to obtain telomerase expressing lentivirus so they can infect themselves and "live forever". Taking supplements to reset drug tolerance seems pretty tame compared to some of the crazy out there.
Anamo7tram
Bluelighter
I can't find info on the claims your making in your post.
neurotic
Bluelighter
^ What? Google excitotoxicity
Anamo7tram
Bluelighter
I didn't ask about exciotoxcity, i asked about the claims he was making , which are not supported.
Just becouse you activate glutemate recptors, dosent mean you will have exciotoxcity, if that was the case, we wouldn't have nootropics acting as postive altorisitc modulators for ampa recptors nor ampakines.
Also, the poster misread my post, I said NMDA ANTagonist.
serotonin2A
Bluelighter
My post WAS about excitotoxicity. You suggested taking an AMPA agonist and those compounds produce excitotoxicity. Look up domoic acid, kainic acid, ibotenic acid. These are not things that you want to expose your brain to.
Nootropics that act as AMPA PAMs (or reduce desensitization) are not agonists. They do not directly activate the receptor.
nAON
Bluelight Crew
I once had an idea for a scifi story, where a virus that selectively integrates into GRIN2 gene regions causes an epidemic of transmissible psych disorders 
In answer to the thread - NMDA receptors are expressed horrendously widely in the brain and are necessary for pretty much every form of neurotransmission to an extent. What, specifically, are you trying to achieve, beyond giving yourself epilepsy?
Anamo7tram
Bluelighter
dopamimetic
Bluelighter
I'm really perplexed by that topic. It's a hard fact that dissociatives cause tolerance of a kind that builds slowly (maybe not even totally dependent upon the pattern of usage?) and tends to last forever. I've read contradictory statements about whether NMDA receptors do down/upregulate with sustained antagonism or no, to what extent, and what the consequences would be.
Obviously they are deeply involved in many thought and emotional processes.
For me (and others), low-moderate NMDA antagonism shows many great benefits like anxiolysis, reduced overexcitability / abolished ADHD symptoms, emotional stability / protection, and even overall antidepressant effects and better sleep. I first realized this whilst tripping on DXM. MXE has been the best mood-lifting 'treatment' ever since. Then I found memantine, which is well researched, reasonably safe and available by prescription. It's not the same as MXE, but it exhibits robust mood-stabilizing, anxiolytic / anti-fear (and stimulant tolerance halting) effects for me personally.
Because of this, I got a prescription for it and have been taking it at varying doses between 20-40mg for around the last three years. After all, it's not a wonder drug, but it does a solid job and has a much better tolerability than other psychopharms with related effects (anti epileptics, neuroleptics).
The tolerance thing is hard to grasp. I have been very sensible to dissociatives before, getting into the K-Hole with just 80mg of intranasal ketamine or 40mg methoxetamine. Today 80mg of K won't do all that much. But memantine and traditional dissociatives seem to have only partial cross-tolerance. Hard to describe. Some days they potentiate or at least add to each other, on other days not. Tolerance is not totally through the roof, but it's difficult to achieve a hole these days.
--
Now the problem: Due to an unfortunate incident, I will probably be forced to go through 'detox' and drug therapy in anywhere between 2-12+ months. So I have some time left to act before I'll have to kick my autonomy.
I wouldn't consider myself 'addicted' to the memantine (as drug counseling stated, omg). It's not different than anyone being on lithium or valproate. When I go off the memantine, after some days (due to its long half-life) I will become somewhat thin-skinned and sensible to stimuli, positive as negative. I have had previous incidents (long before the memantine) where I acted wrong in public due to over excitation and fear, leading to hospital admission and police records.
This is definitely to avoid. I also don't want to go through that emotional rollercoaster in a drug detox setting. If there was nothing to worry about for me, it probably wouldn't be that afford to just taper down at home.
But unfortunately, it's a very stressful situation for me, I don't know if I will have to go to jail actually (because of some now-prohibited RCs.) and all that.
I know that I respond in a very bad way to neuroleptics, even before the memantine. I know that administering neuroleptics while emotionally over-aroused will lead to psychosis as it has before more than once (but every time NLs were involved. It's just how my brain is wired.)
Unfortunately this is the standard treatment these days, and docs in a drug detox setting probably won't listen to me.
So I am looking now for ways to aid the normalization of my glutamatergic / NMDA system / to avoid rebound effects from going off the memantine. (Will stop my [low-dose] IPPD use of course.)
I've read about sarcosine being possibly helpful, or piracetam of course (but I've reacted with tension and negative emotions to even aniracetam before) - but what and how much might help, or exacerbate the condition?
- Might adding sarcosine / piracetam to the memantine for some weeks be worth a try, or will that just cancel out each other?
- Would it speed up the process to switch the memantine to either of these (or another drug) in combination with something calming / sedating like clonidine?
- Or the other way round with agmatine or acamprosate to taper down?
- Can benzodiazepines be used or will they slow the NMDA adaption process?
- How strong or weak is the D2 agonism of memantine? (When they took me off the memantine/clonidine a year or so ago, the doc said my condition resembled meth withdrawal^^ this was greatly exacerbated by emotional distress and neuroleptics, but still)
Many thanks for any reply! (And sorry if this is the wrong place to ask, I know it should be in a good doctor's hand, but I know also that I won't be able to find such a doc really knowing about this...)
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serotonin2A
Bluelighter
You can't assume that the tolerance is due to NMDA receptor upregulation. Drugs can cause behavioral tolerance, which is probably caused by circuit-based changes that compensates for the presence of the drug. Basically your brain just adapts to being chronically intoxicated.
atara
Bluelighter
Speculosity said:
Step 1: ask for help with what you're really trying to do. Nobody -- not me, not Hamilton Morris or Nick Bostrom or whatever science journalist you've been reading, not even Dr. Oz (lmao) -- nobody knows what "increasing NMDA receptor density" will accomplish on its own. The brain always adjusts multiple things at a time.
dopamimetic said:
This doesn't make any sense. What kind of insane rehab clinic is going to make you stop taking a prescription medication?
dopamimetic said:
"Neuroleptic" isn't a well-defined class of medications. Neither is "mood stabilizer", "antipsychotic", "atypical antipsychotic", "antidepressant", "anticonvulsant", or "anxiolytic". What drugs you have had a problem with constitutes useful medical information; if you're claiming that anything that comes in a translucent orange bottle gives you psychosis, of course the doctors won't believe you (and they shouldn't!).
Are you saying you have a problem with the drugs of the class (olanzapine (Zyprexa)/quetiapine (Seroquel)/ziprasidone (Geodon)/risperidone (Risperdal)), or those of the class (carbamazepine (Tegretol)/valproate (Depakote)/oxcarbazepine (Trileptal)), or (haloperidol (Haldol)/fluphenazine (Prolixin)), or..?
dopamimetic
Bluelighter
I'm open to any corrections / other implications etc. - I know that I know just about nothing, but I need to do what I can and this includes to try to put these things in words that I am able to understand and build theories upon, to see if they are wrong or might be on the right way etc..... thanks for your time and answers of course, it's much appreciated!
serotonin2A said:
This is standard procedure here in part of Germany.
atara said:
I couldn't have imagined the conditions of reality until I was confronted with them. Really. I could easily have died in the emergency care of the university-associated psychiatry of Jena (Thüringen), I was there because of suspected RC opioid OD, that I reversed with naloxone..... and they just locked me into a bright room w/o surveillance. Not knowing anything about the concerned substances at all. (Had I knew that earlier, I'd have been just staying at home, and that'd have saved me all of the current bullshit.)
Once you have the sign 'addicted' (at least in combination with drug law offense), then every potentially psychoactive substance is considered an 'addictive toxin' that has to be withdrawn and covered in therapy, to achieve abstinence. It's ridiculous. Well-established regimen get stopped suddenly at once, and replaced by whatever the chief doc thinks to be needed. Usually something out of a small set of currently-marketed psychopharms.
Ok, here you're right. Sorry. I need to become less emotional and more specific.
atara said:
Well, I've not exactly meant to say that. But my English skills are limited and maybe prone to misconceptions.
atara said:
With 'neuroleptic' I refer to dopamine antagonists. I am somewhat sensible to their (side)effects, and while I tolerate low doses of low-potency ones like 25-50mg of quetiapine that are mostly sedating, at only slightly higher doses like just 150mg of quetiapine / 250mg of amisulpride, serious side effects like akathisia, extreme restlessness together with dysphoria, anxiety that can increase to a feeling of impending doom, tachycardia and weakness arise.
The stronger ones, like risperidal and olanzapine, but also 200mg chlorprothixen, have lead in all five times or so to more or less pronounced psychotic episodes. They were transient, but full-blown with amnesia, acting strangely, inability to understand / think normally, saying nonsense etc. and even aggressive outbursts. Just read that 'paradoxical reactions' to olanzapine are well known to occur in a small part of the population. I seem to be one of these. Haloperidol was one hell of side effects nightmare, fortunately only given once in a smaller dose.
This is why I just wrote 'neuroleptics' - everything that antagonizes dopamine (besides the anti-emetics like MCP / domperidone) is at least uncomfortable to me.
Because of chronic frustration with the therapists and disputes over treatment targets etc. I unfortunately began to experiment a bit on my own.. but that's all some years back.
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Indeed, it may not beneficial in every part of the brain.
http://www.ncbi.nlm.nih.gov/pubmed/15531111
However:
I have a feeling this mechanism may ultimately be related to reduced activity of glutamate decarboxylase in schizophrenics. So "normal" individuals don't have to worry so much about this. And piracetam is not limited to increasing NMDA receptor density on certain sites. It is hard to find studies where only piracetam was used for the treatment of schizophrenia without the addition of an antipsychotic.
http://www.ncbi.nlm.nih.gov/pubmed/22367838
Some other nmda receptor density promoters.
http://www.sciencedirect.com/science/article/pii/S2211383514001038
sekio
Bluelight Crew
Me personally, i never found dissociatives/NMDA antagonists to require any sort of post-medication when I discontinue them. And I go pretty hard.... The only negative effect is wanting to do more dissociatives withing ~6 months.
dopamimetic
Bluelighter
Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,[55] and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists. (referring to: -->)
Group II Metabotropic Glutamate Receptor Agonist Ameliorates MK801-Induced Dysfunction of NMDA Receptors via the Akt/GSK-3β Pathway in Adult Rat Prefrontal Cortex
So there is receptor alteration caused by antagonism. Ouch, ok. Is there anything special to MK-801 that does not apply to K/MXE/memantine, and/or did they use the usual supra therapeutic dosages for that effect to emerge? Finally, are the rat's NMDA receptors / glutamate pathways any different from the human's ?
Interesting is that there is conflicting data about the reactions. Low doses of MK-801 increased NMDAR density while high doses decreased it. Sounds just too easy that one could restore his receptors by tripping hard for some days 
but there might actually be something. I didn't make any notes and it's too long past, but I remember that I couldn't grasp the 'tolerance' / after effects of DXM, and repeatedly had the feeling that it's somewhat 'inverted'. Kind of one high dose could revert several low doses.
Well, somehow it is not really surprising that an agonist alleviates the effects of an antagonist. I guess they mean not only 'prevents impaired receptor expression' but more 'prevents the effects of NMDA antagonists'...?
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