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Have We Classified Ketamine All Wrong? Is It Actually an Opioid??

cryptix420

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Howdy,

I love ketamine, more than the average joe, and was pretty bummed to say the least when I heard recently it may have much more significant activity at the opioid receptors than has been believed since its invention.

Recently, a study was conducted where individuals were either given ketamine and a placebo, or ketamine and the opioid receptor antagonist naltrexone. The results demonstrated that when opiod receptors were blocked by naltrexone, the much-touted antidepressant properties of ketamine were virtually non-existent.

Sort of scares me, because I love the heck out of ketamine and thought it to be quite benign in a general sense (mind you I'm taking 1-200mg a day insufflated, not railing/IM'ing grams at a time).

What are your thoughts, peeps?

https://med.stanford.edu/news/all-news/2018/08/ketamines-antidepressive-effects-tied-to-opioid-system-in-brain.html
 

Vastness

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Why is it that you consider the fact that ketamine might have significant opioid activity to be concerning? Opiates are physiologically some of the safest drugs around (overdose dangers notwithstanding). Personally, I don't see that this information has much relevance whatsoever to how benign ketamine is. The primary physical dangers of ketamine relate to it's bladder and kidney toxicity, and whether or not it is in some sense an opioid really has zero relevance to this.
 

Shadowmeister

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Apparently a variety of drugs have downstream opiate activity (I was just reading something here today about that but I can't remember where), but by causing a reaction with the body's natural opioid system, which does not carry the risk of physical dependency or anything. Ketamine has no direct effect on opiate receptors.

Anyway, naltrexone supposedly causes dysphoria or perhaps anhedonia whether it's taken with ketamine or not, because it blocks opiate receptors which causes your body's endorphins to be less effective, so I don't think the findings suggest anything about ketamine, it's more that they show that naltrexone sucks.
 

dopamimetic

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Anyway, naltrexone supposedly causes dysphoria or perhaps anhedonia whether it's taken with ketamine or not, because it blocks opiate receptors which causes your body's endorphins to be less effective, so I don't think the findings suggest anything about ketamine, it's more that they show that naltrexone sucks.
This. Naltrextone (as well as naloxone) isn't just an opioid antagonist, but an inverse agonist - means it causes changes even in the absence of an opioid to deplace. One day Ive made the mistake to crush & snort a fraction of a tilidin/naloxone pill, and oh shit was this disgusting - even though I was more or less opioid-naive back then, and certainly had neither an active one in my system, nor tolerance. So yeah, it sucks.

Also, while it doesn't surprise me to see findings about dissociatives having opioidergic activity, I'd say they aren't potent mu agonists but maybe rather they cause an increase in endorphine / enkephaline release as NMDA antagonism appears to do with a handful of other transmitters ... because many people say that there aren't really so much similarities in how both chemical classes feel and last but not least NMDA antags reliably reduce mu tolerance. Ketamine might be a weak/medium opioid though, as is dextro(metho)rphan.

And I might be a real exception in this, but for me many of the dissociatives are more subjectively 'warm', mentally 'salvaging' etc. than even morphine in higher dosages is. I'd choose O-PCM over morphine any time, yet would I choose a combo of low-dose opioid & low-dose O-PCM over hi-dose morphine/heroin most of the times too.
 

psynce of sound

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In all of my trawling through research I have found the following to be what is the current theories behind ketamine:

The downstream opioid activity is theorized to be the result of 5htr agonism, I believe 5ht1a is what the current thinking lays upon. Also there is a competing theory related to GABAr.

The antidepressant properties are entirely independent of NMDA antagonism.

One hypothesis states that ketamine does have opioid receptor affinity but zero activity. I believe it is considered to act as a modifier of the activity of morphine sites on Mu receptors. It also modulates endorphin release/activity.

It also via a mechanism I would have to look up again create a patch/raft for uncoupled g protein bound receptors. Specifically opioid receptors hence why it has shown to cause decreased tolerance and cessation of withdrawl symptoms.

I have compiled this from a number of papers and theories. I also have some suspicion myself that potentially the 5ht/CB receptor diamer complex may also at a role, that though will have light shone upon it in the time with deeper understanding of this complex.
 

strange.light

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The antidepressant properties are entirely independent of NMDA antagonism.
So this would be an easy explanation why not all substances which act as NMDA antagonists have an antidepressant effect. But are there hypotheses what causes the antidepressant properties if not the NMDA antagonism?
 

psynce of sound

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So this would be an easy explanation why not all substances which act as NMDA antagonists have an antidepressant effect. But are there hypotheses what causes the antidepressant properties if not the NMDA antagonism?
From my reading the prime candidate is 5ht1a agonism, failing that it is the serotonin receptor affinity that ultimately triggers the cascade.
From there it is thought that it then either activates GABA signalling via downstream.
In the end the main aspect is the signalling cascade results in some very funny interaction with opioid receptors bound to g proteins.
 

Solipsis

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Am pretty sure the opioidergic system is closely related to or associated with the glutamatergic (NMDA) system to begin with (besides general connection and integration of all systems). I think the overlap in effects on noniception (pain transmission) / proprioception may be indicative of this.
Also of course the AD potential of K isn't its only effect and they are still elucidating the rather complicated, involved and 'unorthodox' pathways through which K exerts AD effects.

Trying to 'classify' a drug in only one way when it has multiple pharmacological actions and effects would be a mistake anyway as it would disregard those subtleties, complexities and ambiguities.

In any case, it would still seem too misleading to me to call K an opioid when it's main primary target is the NMDAr - if you'd try to classify drugs based on their relevant secondary and tertiary effects etc (so downstream, not with any direct binding and activation of the drug itself), it would quickly get crazy.

Also "opioid equals dangerously small therapeutic window" is not a good assumption even if there are a lot of opioids that are in fact dangerous.

Fact remains that ketamine does not significantly affect respiration etc, that's why it's used on children and elderly etc in surgery... so whatever downstream opioidergic effects it may have, they don't seem to significantly affect the autonomous nervous system which is what can make a lot of depressants inherently dangerous.

What is interesting to ask perhaps is whether this opioid effect (even if direct / like an allosteric modulator as hypothesized) has an interaction when opioids are also taken. I think from anaethesiology that there don't seem to be crazy dangerous interactions or they probably wouldn't use it... but who knows whether some opioids people use especially mixed agonist/antagonist may interfere with AD effect. But people who receive K therapy are not allowed to be on opioids anyway, or?..
 
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G_Chem

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I've always wondered this...

Back in the day I've shot/snorted Ketamine on a few occasions when I was completely out of my usual opiates to help and indeed it did give me some relief.

With that said I also believe it may be more of a "modulation" (right word?) than actual activity. I find my Suboxone is potentiated for 4-5 days after an experience followed by a few days of rebound. I've found despite the rebound, it's still possible to use Ketamine to lower ones dosage and then rough it through the few rebound days (which still aren't too bad.)

Whether it's got mu affinity or not, one things for sure.. The shit can be addictive. I've watched my brother and friends do sick amounts of the stuff, being a slave to K ain't no fun.

-GC
 

cryptix420

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True, true, ketamine definitely has a magnetic lull that draws you in powerfully but subtly. It's an absolutely fascinating substance. Love/hate doesn't nearly do justice to my relationship with this particular compound, but it's a start.

I have enjoyed reading about the ability ketamine has to increase BDNF levels (by increasing AMPA receptors), as well as stimulating neuronal growth in regions of the brain that have been affected by chronic stress. Something about the way the brain chews up ketamine is apparently very cleansing for those who have been through some sheit - although the process seems anything but comfortable.

I suppose the study regarding naltrexone was a bit overblown. Ketamine is indeed a magical thing. I have found that my life has improved substantially since using it somewhat regularly for the last month or two. I've spent a fair amount of time in Jamsyhd's threads, and found them very intriguing. I am not really a big fan of the k-hole, and have only gone there a handful of times in all the years I've used K. I find key bumps throughout the day a much preferable ROA.

I feel I am getting quite close to saying goodbye to K though, perhaps permanently. There are times when I really love it, and it gives me the most tranquil and spiritual intimacy I could possibly want...but there are also times it just makes me feel a bit crazy and delusional, yet somehow I keep going back to it.

I'll be transitioning to a different lifestyle quite soon, as well as an awesome job, and will finally be with my daughter again, and as such this sort of thing won't be an option. But wow, I do think ketamine deserves a spot next to LSD, psilocybin, MDMA, DMT, mescaline, and similar substances that can bring serious healing into peoples' lives. We live in magical, but trying times, and sometimes it takes something this strong to set someone straight.

Anyway, I suppose it's pretty obvious that it's not an opioid, especially during cessation. Although it can be a bummer to run out, it generally just feels like going back to life as usual - no real withdrawal. Although, I am simply insufflating bumps here and there. I can imagine long term IM use would cause quite a gnarly return to reality. But still, nothing like being dopesick.

Peace out
 

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Ketamine does help mitigate opiate withdrawal temporarily but I believe it's only because NMDA antagonism mutes physical sensations and feels comfortable. Essentially it's just masking it, not actually removing it.

Dissociatives can be extremely addictive to some people, but not physically. Stimulants can be extremely addictive too, as can GABAergics, or anything, really. Ketamine/dissociatives are great escapism drugs, hence for some, they're the most addictive class of drugs.
 

G_Chem

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@cryptix- I can agree with a lot of what you say.. I've found a tiny amount of Ketamine followed by a tiny amount of DMT does wonders for bringing me out of depression and lasts if I put in the work after the fact. (Neither alone work as well as the combination.)

@shadowmeister- I'm leaning towards agreeing with you, that said DXM and Nitrous have never had quite the same effect leading me to believe it's a bit more than NMDA antagonism. Even then, there were many much more effective substitutes, loperamide, tramadol and wild lettuce opium are super easy to access and work much better.

And while everything is addictive, Ketamine addiction can get pretty ugly and because of its place as an "antidepressant" and "prescribed pharmaceutical medication" while still having its foot in psychedelic/self growth door.. It gives people a false sense of security.

When you pick up that crack pipe or needle full of heroin your pretty aware of the nastiness that could follow, I feel we're still in the learning stages with Ketamine and as is evident already people are quickly seeing it ain't all roses.

I really like Ketamine but it can have a darker side than other substances that hang around in the same scenes.

-GC
 

Shadowmeister

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Loperamide is actually an opiate, and addictive itself, and really bad for your heart (some Bluelighters have died this way and others have had loved ones die or hospitalized). It messes with the QT interval of your heart and is cardiotoxic in dosages needed for opiate withdrawal relief. Tramadol is also an opiate and much safer than loperamide. Though I agree that both can be used very short-term to bypass the majority of classic opiate withdrawal and avoid the withdrawal of both (though it does prolong the withdrawal period in my experience). Wild lettuce is not an opiate though, I never tried that for opiate withdrawal.

DXM is an opioid, I'm not sure if it hits any opiate receptors though. But yeah it does work quite well for opiate withdrawal (and tolerance).
 

emkee_reinvented

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Tramadol is also an opiate
But also has dissociative action. It certainly has a weird feel about it, hard to determine the origin. It effects all kinda neurotransmitters, Norepinephrine, Serotonin and Gaba-a. but it seems like it has some dissociative aspects in there imo. Alhough the effects for me seemed to come in fazes. At 1.30 to 2 hours something seems to kik in a different effect, Most prob the effects on the mu receptor, the dissociative feel seems to precede this. But for all I know it's some other mixed response, all that pharmacologick action it's causing.

Never noticed the disso effects of Ketamine or Methoxetamine developing or being accompenied by anything like what Tramadol turns into after that 1 1/2 to 2 hours. Or turn into like a Codeine and to a lesser extent, as it is a odd opiod, Kratom experience.
And indeed, me personally I never suffered any withdrawal of repeated daily Methoxetamine dosing unlike Kratom which did cause it. Most probable caused by it's mu agonism. But Kratom is also pharmacologic complex so this is hypothetically speaking offcourse.

https://www.ncbi.nlm.nih.gov/pubmed/15845694
 
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Hexagon Sun

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Tons of high level and super interesting info in the thread. Nothing more to add. Cheers
 

G_Chem

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I know Im fully aware of the dangers of loperamide as well as the fact they are opiates, I was simply stating they are easy to get substitutes...

Also I said DXM "didn't" work as well as Ketamine despite the fact it is somewhat analogous to other opioids... (Nitrous was useless as well.) This would lead me to believe there is more than NMDA antagonism at play for the reduction of withdrawals.

Wild Lettuce Opium does work if used correctly. Most people use it incorrectly.. (Even things like droughts, single plants vs groups, etc affect the potency..) With that said it's infinitely better at potentiating other opioids than being one itself. I know it doesn't have direct activity on opioid receptors but does have a downstream type effect. I found it has an initial few hour opiate-like effect followed by a major increase in potency for other opioids in the few days that follow.

-GC
 

psynce of sound

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@cryptix- I can agree with a lot of what you say.. I've found a tiny amount of Ketamine followed by a tiny amount of DMT does wonders for bringing me out of depression and lasts if I put in the work after the fact. (Neither alone work as well as the combination.)

@shadowmeister- I'm leaning towards agreeing with you, that said DXM and Nitrous have never had quite the same effect leading me to believe it's a bit more than NMDA antagonism. Even then, there were many much more effective substitutes, loperamide, tramadol and wild lettuce opium are super easy to access and work much better.

And while everything is addictive, Ketamine addiction can get pretty ugly and because of its place as an "antidepressant" and "prescribed pharmaceutical medication" while still having its foot in psychedelic/self growth door.. It gives people a false sense of security.

When you pick up that crack pipe or needle full of heroin your pretty aware of the nastiness that could follow, I feel we're still in the learning stages with Ketamine and as is evident already people are quickly seeing it ain't all roses.

I really like Ketamine but it can have a darker side than other substances that hang around in the same scenes.

-GC
Again ketamine ability to affect the opioid system and those who abuse said system has been attributes to indirect downstream gaba activity due to serotonin agonism.
Also due to it patching the uncoupled g protein bound receptors. It is this activity that causes the reduction or absolute mitigation of withdrawl and tolerance reduction. That and the subjective effects which seperate body and mind will likely factor in.

The more you know.
 
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Transcendence

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Apparently a variety of drugs have downstream opiate activity (I was just reading something here today about that but I can't remember where), but by causing a reaction with the body's natural opioid system, which does not carry the risk of physical dependency or anything. Ketamine has no direct effect on opiate receptors.

Anyway, naltrexone supposedly causes dysphoria or perhaps anhedonia whether it's taken with ketamine or not, because it blocks opiate receptors which causes your body's endorphins to be less effective, so I don't think the findings suggest anything about ketamine, it's more that they show that naltrexone sucks.
Yes, high doses of naltrexone cause anxiety and dysphoria even in persons not opioid dependent. This suggests that ketamine might increase downstream production of endogenous opioids. This doesn't mean that it's an opioid. I don't even think it really explains the mechanism of action of ketamine therapy because ketamine and other dissociatives seem to be more effective than opioids. After ketamine therapy I felt like a lot of the neuroses and mental hangups had cleared rather than just whitewashed like with opioids.
 

psynce of sound

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Yes, high doses of naltrexone cause anxiety and dysphoria even in persons not opioid dependent. This suggests that ketamine might increase downstream production of endogenous opioids. This doesn't mean that it's an opioid. I don't even think it really explains the mechanism of action of ketamine therapy because ketamine and other dissociatives seem to be more effective than opioids. After ketamine therapy I felt like a lot of the neuroses and mental hangups had cleared rather than just whitewashed like with opioids.
It is believed that ketamine does the following things related to the opioid system:
Behaves as an allosteric modulator of the Mu opioid receptor,
Increases output of endorphins,
Patches (albeit temporary) uncoupled g protein bound receptors (specifically opioid receptors,
I have also read in a currently unpublished paper that it also causes the receptors to be "partially absorbed (for the lack of better terminology at this time of the day) by the g protein).
 

Dresden

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Ketamine is a dissociative AND an opiate agonist. But MAINLY a disso.
 
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