NMDA receptor antagonist Puns

I was just googling 2-FDCK (a legal Ketamine analog) for my own attempted use of it in antidepressant treatment. Someone said something like "at low doses it's like alcohol", and I'm like, "hm... well alcohol is also a dissociative basically, sure feels like that", and I googled "alcohol NMDA" and voila, it seems that that is the main action of alcohol.

Come on people, how come noone thought of this earlier! :)

Disclaimer: I don't claim I've figured it all out, I just think this must play a role. I mean, NMDA antagonists are new antidepressant drugs.

This post is meant to help anyone who finds themselves in the same situation I've been.

I'd like to preface by saying out of all the substances I've used over the years, NMDA receptor antagonists have treated me the best, and I think in some circumstances, ingesting them is actually the correct thing to do. However, I've honed in on how the addiction seems to manifest, and after repeated hospitalizations/lapses in harm reduction, I've decided to turn away from them.

Approximately 2-3 weeks ago, I died for 2-3 minutes (thankfully revived with CPR and noopept by a close friend who was watching me), after intravenously injecting 80 milligrams of 3-HO-PCP (tested via GC-MS). Before stating that 80 milligrams is an absurd dose, especially for IV administration, please understand I've gone through around 100 grams of a variety of arylcyclohexylamines (mainly 3-MEO-PCP) in the past 4 years. My tolerance is INCREDIBLY high, and has only been growing for duration I've been playing with these carbons. I've taken grams of 3-MEO-PCP and 3-HO-PCP IV in one night before, and still made it in to work the following Monday completely fine.

Despite using harm reduction practices, micron filters for injection, weighing my dose, being confident that 80mgs of 3-HO-PCP would result in a light dissociation, my heart still ended up stopping momentarily. After being rushed to the hospital (10th time in 4 years for dissociative use), a blood analysis indicated that I was completely healthy besides a dangerously low blood potassium level (hypokalemia), which would explain the momentary death as potassium channels are incredibly important in the electrical architecture of the heart. This led me to check my health records for each time I came into the hospital on a large amount of dissociatives, and every single blood test I had indicated hypokalemia. The interesting thing is I regularly see a physician, and when I'm sober, hypokalemia isn't present.

I'm at a stage of my dissociative use where I binge quite infrequently (every 2-3 months), however when I get my hands on them, it feels like I enter a new dimension (quite in line for what they're supposed to do), and I experience a momentary hint of relief from depression, then it's straight back to monotonous living. In the beginning of my use (and to reference John C Lily), I was coincidently happening upon tons of these compounds, one time literally finding my first sealed ketamine vial in a forest, and "accidentally" receivi

Thoughts on this? I find this interesting. Anyone have any more information/experience with this?

PATENT PUBLISHED - LETS ROCK A method for treating Alzheimer's disease (AD) by administering to an AD patient a PKC activator, such as a bryostatin-1, without administering a NMDA receptor antagonist, such as memantine.

https://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/11045447

I’ve searched around for this question but can’t find an answer. Dissociates have a specific site on the nmda receptor, and I don’t know of any endogenous substances that bind to it. Wouldn’t this mean that there must be something if a specific site exists?

They don’t just bind to the site glutamate binds and stop it from binding, they bind to the PCP site, their own specific site that’s in the channel. As far as I’ve seen, only synthetic substances have been talked about when it comes to binding to it.

OK I've done a lot of research and experimentation on this as I'm coming off a bad 2-FDCK daily habit. So far hanging tight but been dealing with a lot of physical and mental withdrawal symptoms, the physical being quite surprising as many will tell you there should be none. In my case they are wrong. The physical are pretty bad and have persisted for many days.

For this guy it was so bad he had to go into the ICU using Ketamine (although a pretty large amount):

http://www.jnsci.org/files/html/2017/e450.htm

The issue you have to deal with is the rebound hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Quoted from the article:

'Given that ketamine is an NMDA receptor antagonist, it is plausible that discontinuation could result in a glutamate rebound, leading to hyperexcitation and agitation.'

Yup - got that going on. Kind of like trying to kick a daily alcohol habit. Been there.

This case is one of the very few that talks about the very real physical withdrawal symptoms that emerge.

Now how to deal with this in the most natural way possible. First let's look at the list of NMDA receptor antagonists:

https://en.wikipedia.org/wiki/NMDA_receptor_antagonist

OK so I've got a few of those and ordered the ones I do not have. I won't go into why each of these is important but read the wikipedia article for more information.

Recommended:

Legal and OTC:

1. Agmatine - Blocks NMDA receptors and other cation ligand-gated channels. Can also potentiate opioid analgesia.
2. Magnesium - https://www.psychologytoday.com/us/blog/evolutionary-psychiatry/201410/magnesium-and-the-ketamine-connection
3. L-Phenylalanine - a naturally occurring amino acid (equilibrium dissociation constant (KB) from Schild regression is 573 μM[62]).
4. Huperzine-A - https://en.wikipedia.org/wiki/Huperzine_A
5. Black Seed Oil (Thymoquinone) - https://www.frontiersin.org/articles/10.3389/fneur.2018.00236/full

Perscription

1. Gabapentin - It's unscheduled - should be very easy to get a script - look for

http://nervewing.blogspot.com/2020/10/obscure-and-unknown-heterocyclic.html

I have been neglecting this series for a bit due to life turmoil and working on various drug design projects. Nonetheless, I'm back again, with more dissociatives!

Today's post deals with two obscure dissociatives with unique properties (one of which I learned about from some enterprising explorers on r/researchchemicals. They are HA-966 and Selfotel. Both of these compounds are heterocyclic amines- a single heterocyclic amine ring is a unique structure as far as dissociatives go, not fitting into any of the other known categories. This yields unique pharmacological properties! Both of these compounds are competitive antagonists of the NMDA receptor. What does this mean?

Well, most of our familiar NMDA antagonists like PCP or ketamine work as uncompetitive ion channel blockers- this means that after the NMDA receptor has been switched to its open configuration by being bound to NMDA/glutamate and glycine, which act as "keys" to open its channel up, these drugs come in and wedge themselves in the channel and block anything from getting through. A competitive antagonist however, like HA-966 or Selfotel, will rush in and block those "keyholes" that NMDA/glutamate and glycine normally bind to, akin to gluing the keyholes shut. This has the effect of preventing the NMDA receptor channel from opening in the first place. This can be extrapolated to display unique affects in the subjective experience, though this has only been explored a little, and only very recently!

HA-966 in its racemic form is also a GABAergic depressant, it is sold on the nootropics market.

Selfotel meanwhile is a failed pharmaceutical, initially studied for its anti-ischemic, anticonvulsant, anxiolytic, and neuroprotective properties. It turns out, in what it was to be indicated for (stroke), it may actually increase mortality. Oh well.

https://pubmed.ncbi.nlm.nih.gov/11803444/

In short: GABAergics, alpha 2 adrenergic agonists (like clonidine, lofexidine), antimuscarinic agents can all mitigate the neurotoxic effects of (high doses or prolonged use of NMDAr antagonists).

From Wikipedia I found: "HA-966 or (±) 3-Amino-1-hydroxy-pyrrolidin-2-one is a molecule used in scientific research as a glycine receptor and NMDA receptor antagonist / low efficacy partial agonist. It has neuroprotective and anticonvulsant,[1] anxiolytic,[2] antinociceptive[3] and sedative / hypnotic[4] effects in animal models. Pilot human clinical trials in the early 1960s showed that HA-966 appeared to benefit patients with tremors of extrapyramidal origin.[4]

The two enantiomers of HA-966 have differing pharmacological activity. The glycine/N-methyl-D-aspartate receptor antagonist activity is specific to the R-(+) enantiomer, whereas the sedative and ataxic effects are specific to the S-(-) enantiomer.[5]

R-(+)-HA-966 did not induce drug-appropriate responding in animals trained to discriminate phencyclidine (PCP) from saline, suggesting that the glycine receptor ligand R-(+)-HA-966 has a significantly different behavioral profile than drugs affecting the ion channel of the NMDA receptor complex.[6]

S-(−)-HA-966 has been described as a "γ-hydroxybutyric acid (GHB)-like agent"[7] and a "potent y-butyrolactone-like sedative",[5] but it shows no affinity for the GABAB receptor (GABABR)"

Studies I found:

https://www.ncbi.nlm.nih.gov/pubmed/1838797 "Different stereoselectivity of the enantiomers of HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) for neuroprotective and anticonvulsant actions in vivo."

-HA-966 is an antagonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA) receptors. Neuroprotective effects of HA-966 were determined in postnatal day (PND) 7 rats that received intrastriatal injections of NMDA (15 nmol) and then were administered either racemic HA-966, or the purified (R) or (S) enantiomer 15 min later. The (R)-enantiomer dose-dependently attenuated NMDA-induced brain injury, whereas the (S)-enantiomer was ineffective. When given intravenously to mice, racemic HA-966 and the (S)-enantiomer prevented tonic extensor seizures from low-intensity electroshock (ED50 = 13.2 and 8.8 mg/kg, respectively). Anticonvulsant effects of the (R)-enantiomer were much less potent (ED50 = 105.9 mg/kg). Ataxia measured by inverted screen fall-off was 17 times more potent with the (S)-enantiomer than with the (R)-enantiomer. Since previous published work indicates that glycine-site NMDA antagonist activity is primarily due to the (R)-enantiomer, our results suggest neuroprotective action for the (R)-enantiomer and anticonvulsant action, not re

Has anybody every consumed this cannabanoid (also known as HU-211)? It has been shown to behave as NMDA receptor antagonist, on the dizocilpine site, which means it should be in the same ball park as most other recreational dissos. I'm just wondering if its out there, if anybody has tried it, or if I need to go hunting and be the first.

https://en.wikipedia.org/wiki/Dexanabinol

So the 3 that I know of having a notable effect on NMDA antagonism are Ketamine, Dextrorphan (DXM Metabolite; I’m pretty sure of that), and Magnesium. What are some other substances that have a measurable antagonistic effect on NMDA receptors? -Also, if there are any numbers showing just how effective a given substance is I’d much appreciate if you’d link and/or state those numbers.

Edit: I should make it known that I’m asking because of an Amphetamine tolerance and how effective some substances may or may not be to reduce an Amphetamine tolerance. I’m on about 60-90mg of DXM Polistirex right now, along with 200mg of Magnesium Citrate & Glycerate, and hope this will show some efficacy in lowering my tolerance.

https://youtu.be/HM8WDZIhs3M

At an hour and 52 minuets Hamilton mentions an endogenous nmda receptor antagonist. I tried looking it up off the names he gave but couldn’t find anything. Anyone know anything about this protein or endogenous nmda antagonists?

I'm interested to hear what people have to say about Olney's Lesions and his greater research in general. Wherever I look people seem to have fierce opinions on the subject, either its real and happens to any disso-user or its false and doesn't happen.

My brief understanding is his research may be potentially outdated now and inaccurate since while rats can show this damage, larger more developed primates with slower metabolisms fair better (i.e humans).

Additionally John Olney seemed to have had some pretty controversial views on simple food additives like MSG and aspartame. So is he/his research respected around here or largely disputed?

Glutamate receptors and their roles are very complex, but my understanding is that one property of NMDA receptor antagonism is protection against excitotoxicity in some circumstances.

As NMDA receptor antagonism seems to be a fairly common mechanism of action for some nootropics (e.g. memantine and agmatine) and other commonly used drugs (Ketamine, DXM) and supplements (Magnesium), I am curious if there is any potential or evidence for increased excitotoxicity following withdrawal of NMDA receptor antagonists, particularly after extended use, maybe due to some sort of glutamate/glutamate receptor dysregulation.

I know there is a lot of pharmacodynamic variability between the various antagonists so I'm sure it's not a clear cut situation, but I'm just curious if anyone here knows anything about this subject.

Hi, I'm looking for information on what supplements and/or med act as antagonists on the NMDA Receptor Subtypes NR2A and NR2B. Also what agonists can be avoided?

So it is my understanding that withdrawal of GABAergic substances like alcohol is largely due to a "glutamate storm" that overactivates NMDA receptors. Does this mean that drugs which inhibit NMDA receptor activity could treat the symptoms of acute alcohol withdrawal? Or is there some mechanism by which they could actually make the symptoms worse? (I've heard this before but I don't understand how this would occur pharmacologically).

So I'm prescribed gabapentin. I don't take it daily as prescribed though. I usually just take high doses a couple nights a week.

Last night I took about 2400 mg. Earlier in the day I had also taken 15 mg of DXM. Then this morning I took kratom, and god damn it was a lot stronger than kratom has been in a long time.

I know that NMDA antagonists reduce opioid tolerance, but I can't really find any strong evidence that gabapentin is one. I found one study saying that "there is strong evidence of gabapentin being an NMDA antagonist", but other than that one paper there isn't really anything else I could find. Gabapentin has never done this before, and DXM hasn't done this before either.

So I'm wondering if there's anyone that might be know of some other studies on gabapentin being an NMDA antagonist or if anyone knows why else kratom might have been a lot stronger today.

Just learned this from Wikipedia.

https://en.m.wikipedia.org/wiki/Guaifenesin#Mechanism_of_action

It should synergize really well with DXM. Does anyone feel more high taking DXM with guaifenesin? I

I found this study

https://link.springer.com/article/10.1007/s12640-017-9810-1

The major findings of our present experiments is that the inhibition of the NMDA receptor complex with memantine and ketamine suppressed the development of diazepam withdrawal sensitization

-- is that a positive or negative result?

And heard that glycine has helped people which helps to down-regulate glutamate

It's become a well-established fact that NMDA antagonists have a significant role in preventing the development of G-protein coupled receptor internalization and therefore, preventing tolerance to drugs that act on those receptors. NMDA is essentially the channel through which the excitatory transmitter, glutamate, makes its way to the receptor cell to signal the internalization process within. This is one of the earlier studies, though there are many confirming the same thing now: (https://www.ncbi.nlm.nih.gov/pubmed/8137155)

Does glutamate also signal the resensitization process as well, or is this done via another mechanism?

Something I've begun to wonder is whether or not NMDA antagonists can also prevent the resensitization process if active during the abstinence of the ligand in question. I suppose the real question is, in addition to causing receptor internalization, is glutamate also the transmitter responsible for signaling resensitization as well? If so, then wouldn't continuing to block the glutamate channel with an NMDA antagonist prevent the reversal of tolerance to a drug?

Consider the following scenario: a patient has established tolerance to morphine, with an obvious degree of mu-opioid receptor internalization. If they discontinue morphine, they will experience physical symptoms of an abstinence syndrome (can be precipitated with naloxone). Under normal circumstances, in the continued absence of morphine, the mu-opioid receptors would begin the process of resensitization and their tolerance to morphine would begin to reverse, as would the withdrawal symptoms. Consider this: If they are administered an NMDA antagonist throughout the period of morphine abstinence, would this prevent the reversal of morphine tolerance as well?

I bring this up because many people claim that using NMDA antagonists during opioid withdrawal help reduce some of the symptoms. Could doing this actually be preventing the resensitization process and just prolonging the ordeal?

Drugs that act as antagonists at the NMDA receptor always seem to improve my depression very quickly. Such drugs include Amitriptyline, Dextromethorphan (DXM), Minocycline, Memantine and Ketamine. I have only tried the first three and they have all been extremely effective. Drugs that act as agonists (directly or indirectly) at the NMDA receptor always make my depression far worse. Theanine and Topiramate both made me quite depressed when I tried them.

I would really like to try memantine as it is not too difficult to access, but ketamine is another story. I’m not sure how you go about getting ketamine infusions in Australia but it’s something I feel I should look into.

While I would consider using Amitriptyline long term as a last ditch treatment before begging for MAOIs, the side effects are currently preventing me from using Amitriptyline as a long-term antidepressant. I have managed quite well this year with a combination of Lexapro, Mirtazapine, Armodafinil and occasional use of Dextroamphetamine.

However, my physical health has taken a beating despite the improvements in my mental health. I’m currently switching antidepressants and trialling Agomelatine (so expensive, mixed reports on efficacy, scary rare side effects) as I need to get off the Mirtazapine if I want to have any hope of losing the weight I need to lose and lowering my cholesterol. When I was an alcoholic and wanted to kill myself 24/7, my blood tests showed that my liver was healthy and I had normal cholesterol. I also weighed 10 kilos (22 pounds) less than I do now, 9 months later.

How could I have been so physically healthy when I felt so terrible and treated my body so badly? It’s a cruel world, isn’t it? None of it makes sense. I don’t like having to balance between crippling depression and diabetes/heart/disease. Even though my physical activity was way less and my diet far worse when I was severely depressed earlier in the year, I was still far healthier on paper.

Anyway, I will continue cycling through the drugs and trying to live my best life. I’ve never been a New Year’s Resolutions type of person as I know how frequently they fail, but I really need to get back into exercise and lose weight. Weight loss aside, I know it’s great for depression and anxiety, assuming you can actually get out of bed in the morning and do anything at all.

I already eat mostly healthy food but I just eat way too much. No excuses and all that, but I’m still going to blame the Mirtazapine for

I’m an 18 year old boy and I started using Phenibut 4 years ago. I found Phenibut on the internet after rolling on MDMA for my first time. MDMA healed a condition I didn’t know I had: social anxiety. I was also searching for something to combat the crash. I began using Phenibut at 500 mg doses and later on took some days 5 grams daily. In the beginning I had huge motivation improvements and was talking a lot, compare it to the effects of taking amphetamines and benzos at the same time, without the crash and effects lasting the whole day. After some weeks of use, the only effects I got were anxiety reduction. Eventually I could find a pattern: after 2 hours of taking Phenibut I would get very tired, after 5 hours I got a huge dopamine rebound. Then after that still very tired.

To conclude: the effect that stays is the anti-anxiety effect. The effect that was forever gone was the motivational (dopamine) effect I got the whole day. This left me with a carless attitude all day.

I tried various substances to get the magic of Phenibut back.

• Magnesium (weak NMDA antagonist): did nothing
• Fasoracetam (GABA-B upregulator): took 10 grams of this for a period of 3 months (~100 mg a day). Definitely brought the motivational effects bad, although this costs a lot and got problems with customs and got a fine, because I had to import it from the USA to the EU.
• Tianeptine (opioid agonist): caused a warm feeling and euphoria. Didn’t get the magic of Phenibut back. I couldn’t take it without Phenibut or I would get jitters because of the dopamine/stimulating effects.

I already wanted to an NMDA antagonist because they seem to reduce tolerance for dopamine agonists like amphetamines and also: Phenibut. They have anti-anxiety effects on there own because they block overactive neurons in the brain. Options were:

• memantine (super long lasting NMDA antagonist, serotonergic, cholinergic, dopaminergic, sigmaergic)
• ketamine (short acting NMDA antagonist, dopaminergic, opioid)
• methoxetamine (research chemical and cheaper analog for ketamine: long lasting NMDA antagonist, serotonin and dopamine reuptake inhibitor, opioid)
• 3-MEO-PCP (research chemical and super cheap analog for ketamine: long lasting NMDA antagonist, opioid agonist, dopamine reuptake inhibitor)
• DXM (short acting NMDA antagonist, serotonin and dopamine reuptake inhibitor, sigmaergic)

I went through 1 gram of methoxetamine in 1 week and this is lik