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Opioids that have NMDA antagonist effects
- Thread starter The Holy Quadruplty
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fastandbulbous
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Definitely, just like oxymorphone...
Yea couple years back I got a chance to try dihydromorphine and it definitely had a different feel to it that somewhat resembled oxycodone but I haven’t tried oxymorphone so maybe it’s closer like you say.
-GC
plumbus-nine
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Opioids + dissociatives can make a lovely combination if you're not like me in whom the dissociative fairy wanted to get me off opioids. I got acoustic hallucinations from opioids alone, exponentially more when dosing both but none from dissociatives alone. So much about the claim NMDA antagonists would induce schizophrenia like symptoms. But besides these disturbances (which you are likely not to get), the combination shines and somewhat cancels off each other's side effects. Also heavily abolishes the opioid's addictiveness, I was able to jump from 4mg of buprenorphine and 120mg morphine respectively with the aid of deschloroketamine (against bupe) and memantine (against morphine). Wonder why methadone doesn't feel more like a dissociative, and guess it's just that the potency of l-metha is much higher than that of d-metha and one would have to get isolated isomers and dose a multiple of d-metha vs. l-metha.
I want to try methorphanol, the racemic dextrorphan. But levorphanol is scheduled, so we won't see that one available. Maybe allorphanol? Dextrallorphan must be one hell of a hallucinogen/dissociative.
fastandbulbous
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Sadly, with our stupid (and rabid) Psychoactive Substances Act, everything is technically illegal.
One more reason to hate tories...
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I was first introduced to butorphanol when I was working as a vet tech. I would "aquire" the near empty bottles that were destined for the trash. It is it the mostly widely used opioid in veterinary medicine by far.
Later I began to drive down to Mexico to buy more veterinary grade butorphanol, same name brand stuff (torbugesic), sold in large 50ml bottles
Used it exclusively IV, definitely weird stuff. It does have dissociative effects but these subjectively feel more like the KOR agonist variety than the dissociation one experiences from NMDA agonists.
I remember butorphanol making lights seem dimmer than normal, also making colors appear to be desaturated (which is a similar effect I get from salvia). Certainly not the most enjoyable opioid but it had a rush to it and was available fairly inexpensively from Mexico. Attempts to inject larger doses were met with open eyed hallucinations that had a sinister nature to them. It was best in single doses of 10 to 20mg.
Fertile
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On Opiophile a few people kept a supply (for their horses) of butorphanol as their last resort. It sounds like dysphoria is a serious problem, but then withdrawal is likely to cause even more dysphoria.
It would be a reasonable precursor if it wasn't so costly ($48,999/Kg).
Their is a convenient 2-step method for the N-dealkylation and then one can introduce an N-substituent that results in a potent agonist. If memory serves, one analogue is active at something like 0.010mg/Kg i.e. x70 the potency of the N-methyl i.e. x700 M.
I can mention this because it is utterly impractical unless one is prepared to invest in a real organic chemistry laboratory and as we have seen in recent footage, the cornerstone of clandestine drug production is one or two guys using a metal bucket as a reaction vessel with a larger plastic container for the purposes of cooling,
In short - interesting, but of no use.
Although I DO have one question. If the tertiary amine of an opioid is converted to, say, it's quaternary salt with methyl iodide or 2-phenylethyl iodide (to give 2 extreme examples) can one of the alkyl or alkylaryl moieties be removed AS the appropriate alkyl(aryl) halide? If so, is their a rule that defines which group is removed? Phenyl trimethylammonium iodide (PhMe3NI) will donate a methyl iodide to a secondary amide in almost quantitative yield.
Above is an extreme example, but I cannot find the appropriate rule.
The Holy Quadruplty
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Isn't magnesium a NMDA antagonist too, and isn't it in some Subutex pills as a binder. I'm pretty sure the ones I get do, but not 100% sure.
BourbonMac
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Yeah magnesium binds to NMDA. Some people use it to potentiate kratom in particular or help reduce tolerance (also good in withdrawal). I'm not sure about other opiates. Magnesium never potentiated for me per se but it did add a nice feeling, magnesium glycinate is great for muscle relaxation and anxiety.
The Holy Quadruplty
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It looks like there is Magnesium Stearate in the Subutex pills I take. I wonder if it's enough to have effects. I also wish I knew how strong of a NMDA antagonist Buprenorphine is, and if I actually get any NMDA antagonist effects from Subutex, or not?
The Holy Quadruplty
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Nice! I've heard Ketamine is an opioid antagonist, but probably isn't a strong enough one to displace the Oxycodone that I know of.
The Holy Quadruplty
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Btw I was reading this, and it says Diphenhydramine is a NMDA receptor antagonist. I wonder if it really is, or not?
Diphenhydramine selectively inhibits NMDA receptors.
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There is no competition of the drug with the glutamate- or the glycine-binding-site.
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Due to the lack of a tricyclic structure diphenhydramine is able to interact with the Mg2+ binding site.
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Results provide a possible explanation for the analgesic, amnestic, and sedatative effects of diphenhydramine.
Abstract
Background and purpose
Diphenhydramine is a well known H1-receptor antagonist that plays a major role in clinical practice. Nowadays, diphenhydramine is primarily applied to prevent nausea but also its sedative and analgesic effects are of clinical importance. As other drugs mediating sedative and analgesic properties partly operate via the inhibition of glutamate receptors, we tested the hypothesis that diphenhydramine, as well interacts with excitatory ionotropic glutamate receptors.
Experimental approach
Electrophysiological patch-clamp experiments were performed on glutamate receptors which were heterologously expressed in human TsA cells.
Key results
Diphenhydramine inhibits NMDA-mediated membrane currents in a reversible and concentration-dependent manner at clinically relevant concentrations. The inhibition occurred in a noncompetitive manner. Diphenhydramine did not compete with NMDA or glycine for their binding sites and half-maximal inhibition was obtained around 25 μM diphenhydramine, independent of the subunit composition. The inhibition was caused by a classical open channel blocking mechanism and varied strongly with the membrane potential. Our results suggest that diphenhydramine most probably interacts with the Mg2+ binding site or a very closely related area of the channel pore.
Conclusion and implications
The data presented here provide evidence that the NMDA receptor antagonism of diphenhydramine contribute to its sedative and potentially LTP-related effects like analgesia and amnesia.
LucidSDreamr
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Anyone with pharmacological expertise can answer...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.
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
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
This was an amazing read and calcium has no effect on NMDA
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
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.
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
[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
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
Is the nmda antagonism of methadone significant at standard doses?
Like I guess what are the relative IC50s at each target (NMDA receptor or mu opioid receptor) for methadone or whatever other metric used to quantitatively compare the Two activities?
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it's not an opioid antagonist. but naloxone does negate the anti-depressant effects, so if anything, ket downstream activates mu in some way that is part of the anti-depressant effect. i have used them together a lot. it's fine assuming your tolerance/everything is in line.
Opioid Receptor Antagonism Attenuates Antidepressant Effects of Ketamine
In addition to N-methyl D-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of the study was to determine if opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant ...
www.ncbi.nlm.nih.gov
plumbus-nine
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I think if then it will be a weak one, or we'd see people dissociating on DPH instead of entering delirium. It might contribute to euphoria though but I guess like e.g. d-methadone that the affinity for NMDA will be orders of magnitude below that to the other targets.
But in general, a dissociative plus delirant in a single drug would make an addictive intoxicant from hell.
The Holy Quadruplty
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Promethazine that I take, but am out right now, has anticholinergic, and NMDA effects forsure. It gives strong deliriant, and dissociative effects, but doesn't work on AMPA receptors tho.
