High doses of dextromethorphan.. produce effects similar to classical hallucinogens

[Nagelfar]

Sigma binding may very well add ... co localizing gcprs such as the cb1 receptor to the nmda receptor. This could cause additive behavioral effects and be part of the reason that DXM has the unique feel (other nmda antagonists are sris too you know).
https://www.ncbi.nlm.nih.gov/pubmed/26461475

The commonality seems to be drugs of abuse. I've noticed those studies claiming that glutamate and NMDAr drugs are related to subconscious "memory" of liking a drug and disruption of that pathway is what makes drugs like ibogaine work.

Which would lead me to think that an NMDAr antagonist would be very much non-addictive. Perhaps it is sigma agonism that makes it so (and 'morish' drugs like cocaine so very much so, but very similar drugs like Ritalin not so much addictive in comparison at all)

 

[serotonin2A]

The commonality seems to be drugs of abuse. I've noticed those studies claiming that glutamate and NMDAr drugs are related to subconscious "memory" of liking a drug and disruption of that pathway is what makes drugs like ibogaine work.

Which would lead me to think that an NMDAr antagonist would be very much non-addictive. Perhaps it is sigma agonism that makes it so (and 'morish' drugs like cocaine so very much so, but very similar drugs like Ritalin not so much addictive in comparison at all)

To play devils advocate here -- based on the types of drugs that bind to sigma-1, I don't see any evidence that sigma-1 is specifically linked to reinforcement. Although some drugs that bind to sigma-1 are reinforcing (cocaine, PCP, methamphetamine, dextromethorphan, MDMA), most sigma-1 ligands are not abused (citalopram, fluvoxamine, sertraline, progesterone, DHEA, citalopram, harmaline, clorgyline, N-allylnormetazocine, haloperidol). In general, it seems like sigma-1 receptors are highly promiscuous and many different structural classes can bind to it.

BTW, methylphenidate is a sigma-1 ligand: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051910

 

[Cotcha Yankinov]

Interesting study I thought I'd throw out there, maybe sigma 1 doesn't have too much to do with acute effects but could be mediating some addiction related neurological changes

https://www.ncbi.nlm.nih.gov/m/pubmed/27735948/ - "Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons"

 

[Skorpio]

@serotonin2a: Can you send me documentation of the pharmacology of noscapine (other than tubulin inhibition). I can't find anything on it that isn't Russian (the paper by sukihinina)

Also haloperidol is an antagonist at sigma. I don't think sigma is central to any of the effects of the drugs that you have listed, but I do have a hunch that they would be less "liked" (in terms of the drugs of abuse) or effective (in terms of the anti depressants or haloperidol). I also think sigma is implicated in mu opioid tolerance development, via the same co localization method mentioned.
Could be putting two and two together to get five.

 

[X11400]

Dissociatives are classified as a separate class of psychedelics. The visuals aren't psychedelic in a classical sense, but it's definitely hallucinogenic. different types of hallucinogens share similar pathways and affect similar chemicals in the brain, though. DXM isn't a good way to qualify dissociatives because it's a very dirty drug with prominent pharmacological mechanisms other than its NMDA antagonism. I always found dxm very introspective, until hitting a certain dose and getting sucked into a hole, of course.

Most recreational dissociatives (particularly of the arylcyclohexlamine class) Bind to other receptors other than the NMDAr. To say Dextromethorphan isn't a dissociative really doesn't give any credit to the hundreds of positive dissociative experiences reported on the net.

 

[MoFo_S]

I love NMDA antagonists because they're great antidepressents, and the trip can be quite interesting in its own right. I started using DXM when I was 15. Once MXE became available, I switched to that, because it doesn't induce vomiting like DXM almost always does for me - chematoreceptor trigger zone or whatever it's called. MXE, PCP, Ketamine and others have never induced nausea for me. One good thing about DXM use is that it tends to be more self-regulating, with the heaviness of the trip, the unpleasantness of chugging cough syrup.