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Opioids that have NMDA antagonist effects

The Holy Quadruplty

The Holy Quadruplty

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Feb 9, 2022
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Can you name some opioids that're also NMDA antagonist? I'm pretty sure Buprenorphine is one right? I know Methadone, and Tramadol are as well.
 
Lydol(Pethidin,Dolargan,Demerol) i think(but not sure).Alwful opioid for me....good combo(but dangerous)with meth.Cholinomimetic for sure along with opioid activity ...there's other too,but don't remember.Bupe is not NMDA antagonist,vut methadone is.DXM is with such properties also
 
Nas47 said:
Lydol(Pethidin,Dolargan,Demerol) i think(but not sure).Alwful opioid for me....good combo(but dangerous)with meth.Cholinomimetic for sure along with opioid activity ...there's other too,but don't remember.Bupe is not NMDA antagonist,vut methadone is.DXM is with such properties also
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Are you sure that Buprenorphine doesn't, because I've heard different? That's one of the main reasons I made this thread to get all of everybody's thoughts on it. So thank you for your answer, and yes I heard Demerol has NMDA antagonist effects as well.
 
About bupre,not fully sure,but i think so.just check it out.Opioids with NMDA antagonist properties tend to have lowing tolerance influence....u not used to up ur tolerance so easy,which is a good thing
 
Methadone. Which I find to be quite interesting. Much be to help people regulate calcium and glutamate revisions from downregulation of opiate withdrawal
 
DXM isn't a real opioid, well it itself is one with low affinities to mu but its major metabolite, dextrorphan (DXO), happens to be a mu antagonist. I think both have affinities too low to be relevant but I remember one report of somebody being addicted to DXM who eventually showed symptoms of opioid withdrawal even while on the drug but this individual was using more than 1g every day.

I know that d-methadone is a NMDA antagonist and wondered why it still is one of the most addictive opioids (of its league, potency-wise, at least). NMDA antagonists usually potentiate opioids and/or reduce dependence to them.

The Holy Quadruplty said:
Doesn't calcium have something to do with recreational feelings, or something like that?
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Calcium is involved in many things in biology but yeah, I think NMDA receptors, among others, modulate calcium influx into neurons.
 
The Holy Quadruplty said:
Was taking Promethazine which has NMDA antagonist effects with my bup. I also took, and take Chlorpheniramine, Xanax, and smoke weed with my Subutex. I need to see my doctor for my next refill since I got a new doctor, but when waking up at nighttime so haven't been able to reschedule a new appointment yet so out of promethazine till then.
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Why u take promethazine?Bupe itself got the ability to work better in low doses and tolerance developes slowly.(at least for me)....u got Xanax for boost.....less different substances u take better.....'cause the probability of cross reactions is less
 
Yeah if the kratom is good there should be an alright amount, but the bunk brown stuff is so useless. Sun dried kratom just gets the alkaloids destroyed, I always go for the greenest I can. I never had any potentiation from magnesium personally but some people have.
 
When i used to drink Kratom always preferred dark green stuff labeled as Red Borneo(or Green Malay)...never tried brown Kratom,but i know,that they sale such thing.
 
Methadone, levorphanol, ketobemidone - or at those are the 3 that are given because the NMDA activity gives more analgesia.
 
Nas47 said:
When i used to drink Kratom always preferred dark green stuff labeled as Red Borneo(or Green Malay)...never tried brown Kratom,but i know,that they sale such thing.
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Yeah if they let it dry in the sun for too long it turns straight up brown. Supposedly increases one specific alkaloid by a small amount making it better for pain but hardly any psychoactive effect. The whole thing about "strains" is basically a myth though, the same plant can produce leafs with red or green veins. Vendors just try to make it sound more like cannabis with a variety of effects when really kratom is just kratom, it's either good or bad. And some vendors I feel purposely make bad strains like these browns, which might work alright for a newbie but any veteran will get no effect from them.

THC is just THC but there are other cannabanoids and terpenes that can make things slightly different. White vein at least is known to be slightly more stimulated because the veins or "bones" of the leaf themselves are mixed in, but I can't say I've ever noticed, and whites have seemed weaker to me in general maybe because this mild stimulant effect overpowers the sedative effect I prefer.
 
The Holy Quadruplty said:
Doesn't calcium have something to do with recreational feelings, or something like that?
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During withdrawals either benzo or opiate the NMDA receptor is flooding our brain with excitatory cells. GABA being inhibitory and calcium and glutamate being excitatory. Calcium and glutamate is very important for us, but while we’re withdrawing. They kinda suck lol. Gabapentin and Pregabalin are actually calcium channel blockers and that’s why they are reported to be helpful during a withdrawal.
Methadone does have NMDA antagonism. I’m not sure if that’s on purpose and that’s why it’s used for opiate withdrawals or if it’s Because of its super long half life that makes it a perfect maintenance drug. I can say having gone thru many withdrawals from opiates and just a couple from benzos anything with Nmda blocking abilities. Gabapentin. Pregabalin. Ketamine. FXE. Methadone. All are super insanely helpful. Gabapentin being slightly helpful, but pregabalin being extremely helpful. Many ex heroin addicts become addicted to ketamine possibly to battle the PAWs. I haven’t seen good ketamine in over 10 years.
However for me I started methadone treatment after failing over 6 different times trying to quit blues. I eventually quit because methadone over powered the blues. I couldn’t feel fentynal no matter what I tried. At 140mg of methadone. I still had to take 100mg for three days to battle the acute withdrawals which I felt non. But if I didn’t take that 100mg at night time I would wake up nauseated in the mornings. It was very interesting to me to find out methadone is an Nmda antagonist then learning about Nmda roles. Also learning about Excitatory and inhibitory system of the brain.

So from personal experience and not really understand psychopharmacology to that grand of a scale. I’ll say that calcium seems like it sucks when battling an addiction lol. But awesome for a classroom setting when I need to learn something new.

Some sources about Nmda and withdrawals.

pubmed.ncbi.nlm.nih.gov

Opioid dependence and NMDA receptors - PubMed

Opioids can induce dependence and elicit a withdrawal syndrome in users after the cessation of drug action. Opioid withdrawal is characterized by aversive symptoms that can elicit distress-relieving drug-seeking behavior and that thus contribute to the development and persistence of addiction...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov

The role of the NMDA receptor in ethanol withdrawal - PubMed

The function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is very sensitive to acute inhibition by ethanol. Because of the role of this receptor in processes such as synaptic plasticity and neuronal development, it may contribute to the acute cognitive deficits caused by...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov


This was an amazing read and calcium has no effect on NMDA

www.verywellhealth.com

What Are NMDA Receptors & What Is Their Role in Disease?

Learn about NMDA receptors, what they do in your brain, what illnesses they're involved with, and what treatments target them.
www.verywellhealth.com www.verywellhealth.com

Another thread with some interesting info



I’m gonna look up Pregabalin and calcium blocker withdrawals. Let’s see?

Some scientists believe that pregabalin helps with opiate withdrawal due to it modulating monoamine release in “hyper-excited” neurons and because it binds to certain voltage-gated calcium channels.

opiateaddictionsupport.com

Pregabalin For Opiate Withdrawal: Here's What You Should Know - Opiate Addiction Support

Pregabalin For Opiate Withdrawal benefits and precautions - Pregabalin has been shown to be effective at reducing Opiate Withdrawal Symptoms.
opiateaddictionsupport.com opiateaddictionsupport.com

pubmed.ncbi.nlm.nih.gov

[Pregabalin for the reduction of opiate withdrawal symptoms] - PubMed

Pregabalin is a substance which modulates monoamine release in "hyper-excited" neurons. It binds potently to the α2-δ subunit of calcium channels. Pilotstudies on alcohol- and benzodiazepine dependent patients reported a reduction of withdrawal symptoms through Pregabalin. To our knowledge, no...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov


Simply said for me. I went thru hell and back during opiate withdrawals. I never had Pregabalin during an acute opiate WD but I did have gabapentin and benzos. Both of which helped immensely.

I started to use pregab for post acute withdrawal symptoms like sleep disorders. And it’s been a life saver in this regard. But thru my experience of ‘em withdrawals and all that I know analog them they cause a down regulation in opioid receptors or gaba receptors and that downregulation is counter acted by an up regulation of excitatory cells. It sucks so bad

Soooo no don’t give the dude who’s overdosing some milk. 😂. Or shit. Maybe yeah. Maybe yeah. Maybe that milk will wake the mofucka up. I’m just joking and smoking way too much FXE right now
 
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I'm sure it's possible to find some kind of connection to NMDA activity for All opioids. The fact remains only 3 opioids are given because their NMDA activity is sufficient for them to provide NMDA mediated analgesia.

Methadone, levorphanol and ketobemidone.

A trial of morphine + DXM was undertaken a few years ago - it failed.

I think Gabapentin & pregabalin showed success simply because they have a sedative action. People read in vast amounts of detail that the researchers didn't consider.

It's possible to assert all manner of interaction that was not part of the original experiment. Don't forget - all of those animal models were 'sacrificed' either during or after the study. You wouldn't thank me for knowing HOW the animals are sacrificed. It is not pretty; or ethnical, in my opinion. I'm 100% behind the research team being the first animal models. I bet, if that were the case, we would see a lot more in vitro experiments.
 
Fertile said:
Methadone, levorphanol, ketobemidone - or at those are the 3 that are given because the NMDA activity gives more analgesia.
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Docs can take the piss and big up tramadol's NMDA antagonism (it is shite at both, mu opiate and nmda antagonist). Dihydrocodeine (in fact any opiate with the double bond reduced to saturated has some NMDA antagonism).
Only 4 are available on the NHS: methadone, oxycodone, dihydrocodeine and tramadol. DHC is the only one I'm happy having a repeat prescription for. Pethedine (demerol) isn't really an option as to get decent antagonism means taking a dose near the convulsive threshold.
IMO, the best one is ketobemidone, although lots of pharmacology textbooks state ketobemidone is more addictive than heroin.
 
I guess hydromorphone is also covered? What I maybe SHOULD have said is that the BNF, PDR or given nations version of same only list those 4 as having improved analgesic activity due to NMDA antagonism. I'm not sure if methadone is listed as such, but the PDR lists levorphanol, BNF lists dipipanone & Scandinavian reference lists ketobemidone as being of value in cases where pain is described as 'refractive'.

I meant to say that their is an interesting class that can have various N-substitutions, is legal and unwatched and chemically unlike other opioids, to whit:

https://ibb.co/2KmTpRJ

I read that various N substitutions will confer agonist, partial agonist, silent agonist, inverse agonist and antagonist properties. If the N substitution is an arylalkyl, I don't know if it needs 2 or 3 methylene spacers, but I HAVE found various examples on PubChem. I also don't know if the scaffold is simply unknown OR if it's synthetic complexity makes itunattractive.
 
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