Will a Dopamine Antagonist reduce the stimulating effects caused by Dissociatives?

[Ballz_Trippington]

(S)ketamine has no stimulant activity.

Studies on ketamine uncovered the fact that NMDA antagonists do produce a reward effect. Before then, it was presumed only dopamine (directly or indirectly) was the only mechanism for the reward system of the brain.

There are some selective NMDA antagonists like MK-801 (Dizocipline) that have no stimulant effects. I think their are trip reports online. But I warn you that their have been deaths associated with it's use. Not many, but then it isn't a common RC.

 

[Ballz_Trippington]

I'm beginning to think that most dissociative with exception of (S) Ketamine must have some secondary mode of action thst causes stimulation....does Dizocipline have DRI activity???
Because from anecdotal reports it seems to be very VERY stimulating...
From a trip report on Erowid:
"Due to its long lasting nature, I find it impossible to sleep the night of the day I take it, even when I take it around noon. It seriously makes insomnia from DXM or amphetamines look like a joke. Sodium oxybate (GHB’s sodium salt) plus melatonin took hours to actually let me sleep after a day I took 2.5mg of dizocilpine and was up until 5am. And even a combination of melatonin, kava tea and quetiapine (seroquel) also took hours to finally let me sleep after taking 1mg (I looked up potential interactions before mixing these, although I would be wary of combining other substances with dizocilpine due to it not having been used much in humans".
I wonder why only (S) Ketamine is extremely sedating????
I've also wondered this about LSA or morning glory seeds....it's the only Lysergamide that you have to fight to stay awake on....what could be the mechanism of action and why aren't pharmaceutical companies looking into the sedating effects of LSA???
Seems like the world would truly benefit from a non addictive sleep aid (besides Benadryl).

 

[Ballz_Trippington]

Hmmm I'm curious if Glaucine would be safe and effective to diminish the stimulating effects of Arylcycholhexelamines???
Glaucibe is a mild dissociative but tends to be relaxing....I've only ever used it as an antitussive which it's absolutely incredible for ceasing a bad cough.
But I just noticed that its a D1 inhibitor....not sure if it would be safe to take on the tail end of a disso trip???

 

[Xorkoth]

I'm beginning to think that most dissociative with exception of (S) Ketamine must have some secondary mode of action thst causes stimulation....does Dizocipline have DRI activity???
Because from anecdotal reports it seems to be very VERY stimulating...
From a trip report on Erowid:
"Due to its long lasting nature, I find it impossible to sleep the night of the day I take it, even when I take it around noon. It seriously makes insomnia from DXM or amphetamines look like a joke. Sodium oxybate (GHB’s sodium salt) plus melatonin took hours to actually let me sleep after a day I took 2.5mg of dizocilpine and was up until 5am. And even a combination of melatonin, kava tea and quetiapine (seroquel) also took hours to finally let me sleep after taking 1mg (I looked up potential interactions before mixing these, although I would be wary of combining other substances with dizocilpine due to it not having been used much in humans".
I wonder why only (S) Ketamine is extremely sedating????
I've also wondered this about LSA or morning glory seeds....it's the only Lysergamide that you have to fight to stay awake on....what could be the mechanism of action and why aren't pharmaceutical companies looking into the sedating effects of LSA???
Seems like the world would truly benefit from a non addictive sleep aid (besides Benadryl).

For me, the insomnia following dissociatives isn't always due to stimulation (though some certainly are), but just an inability to turn my brain off into sleep mode. Ketamine is an exception, though.

 

[Ballz_Trippington]

I really really wish thst there were more sedating dissociative out there....I've never had a solid and trustworthy connection for Ketamine.
Thing thing I hate the most about Dissos is the lingering stimulation.
I generally don't like stimulants whatsoever with a couple of exceptions.
I've had extremely bad insomnia for like 25 years so I tend to stay away from most stimulating drugs except on a rare occasion I might take sonething like white maeng da kratom (extremely stimulating), Isopropylphenidate, or something like 4f-Methylphenidate or MDA.
But I probably do any of those less than once a year.
I also strongly suspect there is a secondary mode of action causing that stimulation from dissos....it's just that pretty much all or at least most dissos are also DRI's so occam's razor should lead most to assume its from the DRI activity.
I'm so curious as to why (S) Ketamine lacks this stimulation and why there aren't a few other aryl's that share that quality.
I actually have a bad cough right now (though so far I keep swbbing covid negative).
I was thinking of taking a glaucine tablet ...which got me thinking about this thread and if glaucine might be beneficial to ramp down the end of an o-pce session.

 

[cdin]

Please forgive me if I'm being unintentionally ignorant but would this suggest that the stimulation from dissociative is not mostly due to DRI activity?
If so, what might be the mechanism thst causes such stimulation....I have really almost no experience with S-Ketamine so I'm not sure if it's stimulationg or hard to sleep after the sedating effects wear off??
It almost feels like MXE , O-PCE and 3-meo-pce are all initially very relaxing if administered rectally to the point thst I kust want to lay in bed and close my eyes listening to music but then leads to absolutely uncomfortable long lasting stimulation ....I would like to figure out how lesson the stimulating after effects ....even large doses of benzos won't do the trick for myself.

personally i think two things are at play - the DAT activity of the dissociatives, and a rebound of glutamate once the glut activity comes back online. I think the combo DAT/glut activity is nuerotoxic long term, and contributes a lot to poor mental/physical health outcomes for long term dissociative users (myself included). it's a shitty state to be in, while you could probably counteract it w seroquel/gaba PAM combo, I feel like the back and forth on all the systems is bound to be a recipe for disaster if done on a regular basis.

 

[Ballz_Trippington]

personally i think two things are at play - the DAT activity of the dissociatives, and a rebound of glutamate once the glut activity comes back online. I think the combo DAT/glut activity is nuerotoxic long term, and contributes a lot to poor mental/physical health outcomes for long term dissociative users (myself included). it's a shitty state to be in, while you could probably counteract it w seroquel/gaba PAM combo, I feel like the back and forth on all the systems is bound to be a recipe for disaster if done on a regular basis.

How does this explain the sedative effects of ketamine???

 

[cdin]

How does this explain the sedative effects of ketamine???

huh? we've been discussing the aftereffects this entire time. Clearly the primary clinical effect of ket is NMDA blockade which shuts down all sorts of electrical signalling. the mechanism of the sedative effects of ketamine is well known. https://en.wikipedia.org/wiki/Ketamine

 

[Ballz_Trippington]

and a rebound of glutamate once the glut activity comes back online.

Sorry....are you saying this is not true for S-Ket?

 

[cdin]

Sorry....are you saying this is not true for s ket?

Partially. The lack of dri effect will make it less shitty, but it still doesn’t solve the chronic glutamate issue. The only way to be doing s ket is to be using legit vials only. The street ket is all racemic at this point.

 

[Fertile]

Apparently not. Esketamine is available but only as injectable ampoules. I, for one, draw the line at injecting drugs.

 

[Ballz_Trippington]

Partially. The lack of dri effect will make it less shitty, but it still doesn’t solve the chronic glutamate issue. The only way to be doing s ket is to be using legit vials only. The street ket is all racemic at this point.

But how does this explain the lack of stimulation with S-Ket if it still employs the same glutamate issues as other dissos???

 

[cdin]

But how does this explain the lack of stimulation with S-Ket if it still employs the same glutamate issues as other dissos???

the glutamate issues are what cause some of the residual stimulation, anxiety and the lack of ability to fully hole anymore. fully holing requires glutamate channels being shut completely, over chronic usage of dissos glutamate receptors are upregulated and you can't hole even from large doses. it will still provide some of the effects, but not the full shutdown unless you are hit with surgical type doses.

 

[plumbus-nine]

But how does this explain the lack of stimulation with S-Ket if it still employs the same glutamate issues as other dissos???

For me all dissos so far including S-ket were more or less obviously stimulating. Afaik this is due to increased output of many transmitters besides glutamate, not because of that itself (?).

 

[Ballz_Trippington]

For me all dissos so far including S-ket were more or less obviously stimulating. Afaik this is due to increased output of many transmitters besides glutamate, not because of that itself (?).

Thank you!!!! THIS answered my question....I've never ever had access to ketamine so I've only heard anecdotal reports that S-Ket was the only disso thst had no lingering stimulation....I really truly appreciate a clear cut simple answer ❤

 

[G_Chem]

S-K is def more sedating than racemic but if you’re someone that gets energy from K then you’ll be fine on S too. I did S recently and was still able to go dance after but more often than not I get tired and want to sleep after.

Racemic is infinitely more energizing to me though, like I actually like dancing while ON it instead of just afterwards. I enjoy the after effects of S more but the acute effects of racemic more.

-GC

 

[ecstacylover]

The entire saga of whether ketamine and PCP are even D2 agonists to begin with involves some controversy.

It basically started when Seeman et al. reported in 2002 that ketamine and PCP bind with high affinity (higher even than their NMDA receptor affinity) to the high-affinity state of the D2 receptor. The high-affinity state of the D2 receptor is bound to its G protein, as it disappears in the presence of non-hydrolyzable GTP analogs.

In 2004, Svenningsson et al. called the claim of D2 affinity into question based on a single signaling pathway altered by both LSD and PCP, as well as behavioral experiments.

Then in 2006 Jordan et al. reported that ketamine and PCP completely lack efficacy at the D2 receptor.

Finally in 2008 Seeman et al. showed that at a concentration of 150mM NaCl (the conditions used by Jordan et al., 2006), PCP demonstrates no functional activity, but that at 120mM NaCl its functional activity is recovered. In other words, PCP's efficacy at the D2 receptor is a function of sodium ion concentration. Keep in mind that PCP was only a partial agonist in these assays (~20% or ~45% of the maximum response produced by dopamine when sodium concentration is held at 120mM or 5mM, respectively).

If the PCP is binding to the intracellular face of the D2 receptor (seems fairly reasonable given its lipophilicity) then its D2 activity would likely be extremely physiologically relevant given the low concentration of sodium intracellularly (~10-15 mM). Otherwise, its probably not relevant considering extracellular sodium concentrations (~145mM) would eliminate almost all of its D2 efficacy.

Oh and there's also one more study (Roth et al. 2013) which showed that PCP and ketamine lack binding affinity for D2, but this appears to be a consequence of using N-methylspiperone which, in contrast to domperidone, appears to obscure PCP and ketamine's affinity for the high-affinity D2 state.

All that said, its quite possible that NMDAr antagonists can increase dopamine release via disinhibition of dopaminergic neurons. This could explain the finding that MXE alters dopaminergic signaling, for example.

 

[ecstacylover]

Interesting that it's been suggested here that S-ketamine is less stimulating, because that was always the opposite of my experience. I guess without a polarimeter I can't even say that I had S-ketamine for certain, but I purchased a batch labeled as such and it seemed brighter, more colorful, and more stimulating than the racemic batch I purchased. Also, I had Anesket vials last summer which are racemic and those felt like the racemic batch I had previously—more sedating and just darker overtones on the whole compared to S isomer.

The scientific literature suggests that not only that S-isomer ketamine would be more stimulating (e.g. striatal D2 binding in nonhuman primates decreases after S-ketamine but not R-ketamine), but also that the stereospecificity of the stimulating effects is conserved within the ACH class. This is evidenced by a paper which found S-MXE increases locomotor activity, while R-MXE doesn't.

But to get back to the original point of this thread, it's definitely interesting to consider how D2 antagonists might combine with dissociatives. I did find a couple of papers suggesting that D2 antagonists block MK-801 increases in acute locomotor activity. I'm not sure if it was already mentioned in this thread, but the Seeman studies found that MK-801 was a D2 agonist as well.

The purpose of this study was to evaluate the role of endogenous dopamine in the hypermotility response to MK801. The administration of MK801 (0.1 mg/kg, SC) to rats produced an intense stimulation of coordinated locomotor activity, which was not associated with stereotyped behavior. This stimulatory response was inhibited by pretreatment with either reserpine (5 mg/kg, IP) or alpha-methyl-p-tyrosine (2 doses of 250 mg/kg, IP). Similarly, pretreatment with the D2 antagonist eticlopride (0.03 mg/kg, SC) or the D1 antagonist SCH23390 (0.1 mg/kg, SC) produced a marked inhibition of MK801-stimulated hypermotility, and the combination of eticlopride (0.03 mg/kg, SC) and SCH23390 (0.03 mg/kg, SC) produced a greater inhibition of MK801-stimulated locomotion than either agent alone. [ref]

Of course, whether you can dissociate D2 activation from the desirable effects of dissociatives is a concern in its own right. The subjective experience of "liking something" would appear to be quite important for producing drug induced euphoria, and this experience appears to mediated by the ventral pallidum. The ventral pallidum receives inputs from the nucleus accumbens (which is rife with D2 receptors) and in turn projects to the mediodorsal thalamic nucleus.

The most prominent MK-801-induced changes in glutamate release occur in the mediodorsal thalamic nucleus, while the D2 activation (whether direct or indirect) would be especially affecting the nucleus accumbens. As the ventral pallidum is sandwiched (from a connectivity standpoint) between these regions which appear to be strongly affected by NMDAR antagonists, I would guess that it's extremely important for mediating their euphoric effects.

Another point is that dopamine is an extremely important learning signal and codes for prediction errors, and altering its physiological function likely contributes to ketamine-induced perceptual disturbances.

Getting back to the the D2 antagonist blocking the MK-801 increases in locomotor activity, here's another one of those papers:

The effects of typical and atypical neuroleptics on MK-801-induced locomotor activity and stereotyped sniffing were tested. Pretreatment with the typical neuroleptic haloperidol (0.01, 0.05, 0.1, 0.5 mg/kg SC) and the dopamine D2 receptor selective antagonist eticlopride (0.005, 0.01, 0.05 mg/kg SC) each resulted in significant and dose-dependent reductions of locomotor activity and sniffing. The atypical neuroleptic clozapine (1.0, 5.0, 10.0 mg/kg SC) was somewhat unique in that all doses reduced locomotor activity, but only the highest dose (10.0 mg/kg) significantly reduced sniffing. [ref]

Also, if you're interested in how they quantified locomotor activity.

Fifteen minutes following the MK-801 administration, each rat was placed in the center of the open field and was observed for a 1rain period immediately and thereafter at 5min intervals for the remaining 60rain. Locomotor activity was quantified by counting the total number of crossovers a rat made from one of the twelve rectangular areas to another during each 1min observation period. All four paws must have crossed for a crossover to be scored.

And yeah, lots of atypical antipsychotics do block 5-HT2A as well, which is interesting since 5-HT2A antagonists can block locomotor sensitization to ketamine. My personal hunch is that locomotor sensitization contributes to the long-term tolerance that people observe with dissociatives. People generally desire the sedating effects of these substances which become more elusive over time, and all the while the effects become more stimulating. At least that meshes with my personal experience.

Although you probably can't completely dissociate the acute 5-HT2A activation from the desirable effects of dissociatives, I think it may be less of a contributor than other 5-HT receptors. Mainly this is because, from a purely somatosensory standpoint, I think the "5-HT-esque" effects of dissociatives have more in common with something like MDMA rather than psychedelics. Which is to say they are more cuddly and warm, as compared to the somatosensory effects of psychedelics which can be more cold and standoffish.

Mechanistically too, dissociatives would be expected to work on the 5-HT system in a fashion more similar to MDMA, since they would have to increase 5-HT release along endogenously defined pathways. This would be especially important in superficial cortex, where the vast majority of 5-HT synapses are located and signal through 5-HT3 receptors. In contrast, psychedelics activate deeper regions of the cortex which are exposed to lower concentrations of 5-HT due to the absence of 5-HT synapses there.

 

[Neuroborean]

I really really wish thst there were more sedating dissociative out there....I've never had a solid and trustworthy connection for Ketamine.
Thing thing I hate the most about Dissos is the lingering stimulation.
I generally don't like stimulants whatsoever with a couple of exceptions.
I've had extremely bad insomnia for like 25 years so I tend to stay away from most stimulating drugs except on a rare occasion I might take sonething like white maeng da kratom (extremely stimulating), Isopropylphenidate, or something like 4f-Methylphenidate or MDA.
But I probably do any of those less than once a year.
I also strongly suspect there is a secondary mode of action causing that stimulation from dissos....it's just that pretty much all or at least most dissos are also DRI's so occam's razor should lead most to assume its from the DRI activity.
I'm so curious as to why (S) Ketamine lacks this stimulation and why there aren't a few other aryl's that share that quality.
I actually have a bad cough right now (though so far I keep swbbing covid negative).
I was thinking of taking a glaucine tablet ...which got me thinking about this thread and if glaucine might be beneficial to ramp down the end of an o-pce session.

I think all this is quite interesting
I'm always at a certain point of doubt about kratom effects regarding sleep, both promoting or inhibiting.
Once you're dependent it seems to change and insomnia sets in due to withdrawal between doses or while tapering.
The thing is that sometimes I can sleep without a problem on them and other times is completely impossible, not sure why, it doesn't depend on the color, some reds are very sleep inducing for me but also some green kratom comedown can do it, and some reds are incredibly stimulating...

I don't know if you knew this but some studies (not all) claim that kratom could work as an antipsychotic due to D2 antagonism... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309668/#:~:text=While kratom is most commonly known for its affinity to,depression, anxiety, and psychosis.

Who knows, what I am sure is that kratom worked very well as a sleep aid when I started taking it, never slept so well than when in my kratom honeymoon.

I tend to stay away from stimulant stoo , a binge of whatever (even light substances) makes me extremely insomniac for almost a week... they kinda linger in my body.

Edit: Oh, I forgot. I'm now taking mitragyna javanica and while it causes strange light kind of stimulation (different than mitragynine I would say) it certainly is more sedating long-term, when using more than a week straight, I'm feeling much more sleepy than when using only kratom (but well, this could be some kind of light withdrawal too, I will tell for sure when the tapering finish.

 

[cdin]

I think all this is quite interesting
I'm always at a certain point of doubt about kratom effects regarding sleep, both promoting or inhibiting.
Once you're dependent it seems to change and insomnia sets in due to withdrawal between doses or while tapering.
The thing is that sometimes I can sleep without a problem on them and other times is completely impossible, not sure why, it doesn't depend on the color, some reds are very sleep inducing for me but also some green kratom comedown can do it, and some reds are incredibly stimulating...

I don't know if you knew this but some studies (not all) claim that kratom could work as an antipsychotic due to D2 antagonism... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309668/#:~:text=While kratom is most commonly known for its affinity to,depression, anxiety, and psychosis.

Who knows, what I am sure is that kratom worked very well as a sleep aid when I started taking it, never slept so well than when in my kratom honeymoon.

I tend to stay away from stimulant stoo , a binge of whatever (even light substances) makes me extremely insomniac for almost a week... they kinda linger in my body.

Edit: Oh, I forgot. I'm now taking mitragyna javanica and while it causes strange light kind of stimulation (different than mitragynine I would say) it certainly is more sedating long-term, when using more than a week straight, I'm feeling much more sleepy than when using only kratom (but well, this could be some kind of light withdrawal too, I will tell for sure when the tapering finish.

im in a couple kratom groups, one of which has been ordering and gc/ms testing every available sample of hirsuta and javinica. so far 0 have come up correct, one sample was indeterminate and all of the others were positive for mytraginine etc. vendors are just repackaging shite kratom and selling it as "hirsuta or javinica" probably to circumvent local bans as well