Dissociatives DXM & Ketamine Tolerance Survey & Management Thread (your experience is needed!)

[KetTolerance]

Hello everyone. As many knows - ketamine can induce long term and almost permanent tolerance.
I was not aware about it until it happened.

My goal is to learn all about this condition and collect any cases that can change this tolerance.
I will be glad to see your experience and insights about it.
Please share any experience about tolerance to dissociatives (Ketamine, DXM, 2-FDCK, etc)!
If you have high tolerance to cannabis (especially have no anxiety and thought loops, can smoke a lot of concentrates) - what is you tolerance to dissociatives?
How it's different from your first times?

My story:

Spoiler: My short story

I'm 27 year old male and had long journey with dissociatives.
At school ages i tried DXM many times and there was no tolerance. Effects was "sharp", "clean" and good.
At 20 years old i tried many dissos like ketamine and MXE. It was two binges by 1 month everyday use and 6 months not using dissociatives between.
First binge i can't remember tolerance build up, but remember depression 2 months after i stopped.
But i did many drugs like mephedrone, so maybe it's not related.
I notice depression as possible first signs of temporary changes in glutamate system because glutamate action not feels like exact emotions and feelings, it's easily can mask to something other. Like tiredness and lack of motivation from other addictions. Because many things goes to that pathways.

I want to map every change in all stages of permanent tolerance development.
It's actually gradually builds up and you can notice exact signs. I will write it below.

Second time i remember 4 things: reduced effects, irritability and mental tiredness, feeling like brain "hot" from hyperactivation with ketamine (when tolerance got me first time and i tried to use it again), and about few months of unconscious depression after.
But after that, i had good high for long time. Years after being sober.
(That depression feels like hopeless, lack of motivation, like you can't be happy and lack this healthy pleasant cognitive euphoria vibes from good activities like walking, conversation, music and sleep.)

And this time, i've done ketamine for a year and a half and it suddenly stopped working.

When i started after years of being sober, effects was good, strong, k holes, doses like 80-300mg by few times per session.
I used too much, maybe every 1-3 days.
Permanent tolerance came was like a day before it was ok, and next day effects suddenly disappeared!
I remember i desperately tried to boost the dose and had some weak visuals like from that rotating optic illusion, but the deepness of the effect was failing like demolition of old tower!

Like in an hour effects just deflated to about 10% of something regular.

What i got:

Spoiler: How it feels and what i got

1.Tolerance starts as a plateau - you can't break through this level of effects. And it tend to weaken to zero in few times.
It's possible to feel something stronger with large doses, but it barely works non linearly and doses are dangerous.
Some times i tried and got only dim effect. Not deep, not strong. Like not much receptors now involved.
Maybe like stronger affinity dissos will do more effects, but weaker may be lack of time to do any effects because it "washed" out of receptor too fast.
NMDA receptors also consists of 4 subunits and it naturally can have different affinities and responses to ketamine-like drugs.
Maybe different binding site still working - i don't know and don't want to test right now.
That big doses felt like brain reduce effects very fast, like if have less or more receptors and can't got necessary concentration to block transmission or induce glutamate.
And effects despite being stronger was not "deep and sparkling" like normal. It was more muffeled and blunt. Like a buzz but not that sharp crystallized feelings and thoughts.
Binding affinity, ion channels (and GPCR ) receptors depends on concentration of ligand, but permanent tolerance to ketamine may (or may not) respond to stronger dissos (like o-PCE vs ketamine, or PCP, or MK-801).
2.Being sober for 1 month vs 1 other month is not the same.
Time not really helps in predictively manner. I even got much more results after 1 week than after 1 month - details below.
3.Before when i had strong dissociation, i also had sleepy feeling after end of action.
With tolerance this sleepiness became weaker and went away. No effect no sleepiness, at least for me.
4.Slurry speech and ataxia went away about 9 months before permanent tolerance.
5.Face numbing and pleasant buzz started to disappear 3 months before permanent tolerance.
6.Time loops and disorientation went away about 9 to 6 months too.
This timeline could help figure out what brain areas depend on this changes and concentration distribution in brain (where more or less it was and how strong it changed neurons).
7.There was motivation, will and happiness decline every time i tried to use ketamine again to test tolerance - it's just not working.
And it lasts for week, but later i probably adapted to this and depression is not severe like first time permanent tolerance kicked in.
By the way - i had depression even when i had strong effects, so it might be glutamate depletion/reduction or something like this, not really related to tolerance. I even had suicidal thoughts after massive abuse. Effects was strong, but my brain was like really messed by so much action.
I'm was like i'm losing myself and want to stop abuse and that wasted state.
8.I can't get high from weed, alcohol, tobacco - effects just dim too! If you know this sparkling flowing feeling - i have not this all.
BUT i've got it again after my tolerance was reduced for some time.

9.After day tolerance kicked me or when i try use ketamine to test it - i have some king of distracted from reality feeling. Not dissociation, but like i'm not "in the moment".
Like perception feels "cold" and less detailed, like less feeling about something you see, less associations.
And racetams can give that feeling back. And it does something with tolerance too.
10. One month ago i had successfully temporary change in my tolerance - i was able to get high, but only once.
BUT week ago i was unable to feel anything!
First week for 5 days i used aniracetam and started to feel jittery. And when i stopped and used ketamine 2 days after - i had no effects.
I was mentally tired and started to use magnesium citrate to calm down. Like 400mg per day, for 5 days on second week.
My conclusion was: if aniracetam is not working, maybe magnesium will work.
And guess what? When i tried ketamine again - i was able to feel effects from small doses and was able to dissociate like i haven't for few months before, even after 1 months breaks!
I used magnesium before ketamine too, but next times it not help.
And just magnesium after not restored tolerance.
11.When i started magnesium, i started to feel more "in the moment", more this calm aesthetic feel of perception when you looking at something.
Before successful dissociation i was sure that it will be ok! Actually, i was falsely sure before too. But this time a lot of things changed and i was almost normal again - much more deep emotions, feeling, sleep, thoughts, cognition.
12.And i got pleasant feelings from weed and tobacco what i haven't for long time too after tolerance drop recently, but it went away.
13.I still enjoy orgasm even when i can't enjoy cannabis. And i was unable to finish when i was dissociated and even when i just tried to test tolerance with small dose of ketamine and had no dissociation.
But it definitely stronger when tolerance less. But not many times, maybe 1.5 or less.
Ability to finish goes back after two hours.
14.Before permanent tolerance, even small doses got me that headspace and feeling of energy, probably because of rise of glutamate after blocking of gabaergic interneurons. Like better speed without side effects.
15.I had reduction of tolerance to cannabis after using opioids for two months too. Long time ago.
16.Once i had no effects but still raised the dose untill it started to appear like before, like some kind of concentration was needed to block enough receptors.
17.Cannabis with ketamine gave me synergistic effects (before permanent tolerance).
18.With opioids it was like i'm going to lose consciousness without any additional pleasant effects or buzz, just passing out not even dreams (before permanent tolerance).
19.Magnesium before tolerance drop (recently) gave me some very subtle feels of deja vu too.
20.Before permanent tolerance i had subtle deja vu feel from aniracetam every time.
21.Feels like i'm less overwhelming excited by something in my life, like can't feel overwhelming strong anger, euphoria - and this changes my will.
I learned to control it, but at first if felt like i lobotomy. Now i'm active and motivated, but still less than before.
Aniracetam really helps and probably not needed every time, it's just goes better after 1 week after using any ketamine.
When i had no tolerance, i had probably same decline for 1 week or so after binge, but now it feels like less energy.

Unfortunately, reduced tolerance effects went away after 1 day of use - but effects like was 70% of normal level!
This is really promising with that problem.

I want to fix my nervous system back, i'm concerned about it.
I miss the high, but i concerned by that serious consequences.
Thanks God that i'm pretty functional and can live my life almost like before.
I have almost normal memory and mental abilities - not dumb, not shaking, not something like that.
So, cognition works "almost normal" (maybe 10-15% difference from baseline), but i can't get high at all (maybe 1/10th or less of baseline) - pretty interesting how it's possible.
Because any other drugs leave you more predictable compensation like sleepiness from stimulants, lack of sleep and appetite from cannabis, and withdrawals from opioids.

Please don't abuse dissociatives if you feel reduction of effects - permanent tolerance is not a joke. It alters personality and you can't be sedated for surgery.

Please share your expreience how and what changed your response to ketamine on permanent tolerance.
Can you get high on cannabis? Can you feel tobacco if you're using it?
Have you tried racetams and magnesium and how it affected your permanent tolerance?
Does stimulants like amphetamine does something for permanent tolerance?
Or caffeine, or any other medication - if you noticed something or know exact timeline and dosage, please share.

Let's beat this thing and find reliable way how to reverse this changes.

Later i'll write about what i found. About gabaergic interneurons, calmodulin, magnesium block, internalization, AMPA and NMDA.
Ketamine is possibly works by reducing "brakes" of gabaergic interneurons and boost glutamate, calcium influx and depolarization.
With permanent tolerance you probably can't get that surge because of upregulation and/or downregulation of nmda receptors (at different locations) and/or different subunits, and changes in other pathways (like different GABA influx to pyramid neurons - not depend on NMDA blocking anymore like before).
Also there may be epigenetic mechanism of receptors and enzymes synthesis, like that control glutamine synthesis, internalization and subunits.

Alcohol and cannabis "loss of magic" is probably mediated by same pathways, because i can't get high from cannabis.

 

[KetTolerance]

How to calculate receptor count and concentration to figure out is there any receptors at all or it have different subunits, or maybe it's internalized?
Like somebody use huge doses of grams - i think it's impossible to have that much receptors not covered by that dose.
Or possible?
It looks like it's doesnt matter how large dose - you don't have binding sites.
Interneurons have AMPA receptors too, so they still can fire at natural glutamate and relase GABA after depolarization.
It's a very complex system with a lot of interactions and feedbacks.

I need to understand what we possibly have on gabaergic interneurons: upregulation or downregulation.
Because it seems like when receptor count is less, we have less calcium influx = less gaba by design.
So receptor is possible have reduced "range".
Very strong glutamate surge can induce receptor internalization. Maybe if you have strong conflicts and worries in your life and long term effects after this, like you're not feel anything - it may be mediated trough this pathway too.

JCI - GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

This article suggests that knocking out of GluN2B on gabaergic interneurons leads to no antidepressant effects of ketamine.

Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons.

 

[KetTolerance]

Poor tolerance reverse is might be related to long term potentiation and amout of calcium flux through NMDA.
So it looks like you need to keep some exact level of NMDA function, but not much and not small.
Magnesium probably helps with that. This subject is related to calmodulin and CaMKII.
Like new equilibrium is set and it's supported by our own brains. Neurons just don't want to change back receptors and gene expression because new feedback loops keep it in place.

Less and more glutamate in synapse can turn to same upregulation of AMPA receptors and subsequent more depolarization in future.
This is pretty difficult puzzle. That stuff have nonlinear dependence.

To reduce tolerance we need to change this equilibrium.
We need to understand some feedbacks and dependencies.

 

[Esperighanto]

Please share your expreience how and what changed your response to ketamine on permanent tolerance.
Can you get high on cannabis? Can you feel tobacco if you're using it?
Have you tried racetams and magnesium and how it affected your permanent tolerance?
Does stimulants like amphetamine does something for permanent tolerance?
Or caffeine, or any other medication - if you noticed something or know exact timeline and dosage, please share.

So, this is one of these things I'm going to preface by saying the thing I always say, I have a very quirky brain and metabolism, and am a notorious dosedemon who tends to be able to body massive doses of things. Smoking 125mg of 3-MeO-PCP after insufflating 25mg of 2C-B, 25mg of DOM, and 40-45mg of miprocin (4-HO-MiPT) changed my life for the better, permanently. I take long breaks in between periods of NDMA antagonist use, and my tolerance always resets back to where it was. The synergy with cannabis (and my separate cannabis tolerance) are completely unaffected by dissociative tolerance, but I cannot comment on if tobacco still hits as nicotine has never had any effect on me tbh, maybe something from patches but I can't tell if it's just super mild or simply a placebo effect.

Racetams (and noopept) as well as magnesium are things I frequently consume, and have for long before I ever touched any dissociatives. Maybe this is why I don't seem to form permatolerance at all? I have no clue tbh.

Amphetamines/cathinones, phenylmorpholines, phenidates, xanthines, any stimulants I can recall using have also seemingly never affected my disso tolerance, that seems to just go back down when given enough time. I've consumed a sum total of ~31 grams of NMDA antagonists between 11 different substances so far in my life. I was just gifted 20 grams of memantine though and it's twice as potent as my last batch, so I'm going to be exploring this shit wildly. In fact, I'm on 45mg of it right now and it's exceptionally, unexpectedly potent so I apologize about run-on sentences, grammatical/spelling issues, things like that in this comment. I promise I'm doing my best hahaha.

I suspect that racetam/noopept usage may help tolerance but I've never actually experimented to see if it does, though I have experimented to see if noopept can undo dissociation from arylcyclohexylamines and it sure as hell can. Cannabis tolerance has never related to it for me though, is that a common thing?

 

[Didgital]

Please share your expreience how and what changed your response to ketamine on permanent tolerance.

After having been around heavy ketamine users for years, there does not seem to be a way to truly permanently reset tolerance. What I have heard (prolly hundreds of times at this point) is once one achieves permatolerance, you can take a break for weeks/months and when you go back to doing ketamine, that first initial dose, you get high just like everyone else. But then your tolerance immediately comes back.

I've literally had friends get mad at me, because I can almost hole from 100mg or I at least get very wonky. They see this and try to get where I'm at by snorting bombers, but they never can.

But hey if you figure out some magic reset solution, I'm sure tens of thousands of people would love to hear about it.

 

[Innerpeace]

It seems the only way is don't abuse it like anything.

Some people like myself have taken a six month break then did dissos twice a week for a couple weeks , then once a week....after that initial frequent use, every two weeks

In medical settings it says by the six treatment to tenth treatment if your not getting relief , then it may not be for you. I know medical s note everything ,I do think there some value in it

Of course this can't go on forever and once every three weeks, every month, every two months or you can go for six months if you have that type of mental discipline. Running out and not buying any was how I did six month break.

 

[Didgital]

It seems the only way is don't abuse it like anything.

Some people like myself have taken a six month break then did dissos twice a week for a couple weeks , then once a week....after that initial frequent use, every two weeks

In medical settings it says by the six treatment to tenth treatment if your not getting relief , then it may not be for you. I know medical s note everything ,I do think there some value in it

Of course this can't go on forever and once every three weeks, every month, every two months or you can go for six months if you have that type of mental discipline. Running out and not buying any was how I did six month break.

100%

 

[Featherfall]

I've literally had friends get mad at me, because I can almost hole from 100mg or I at least get very wonky. They see this and try to get where I'm at by snorting bombers, but they never can.

really just nothing around you can do every day, people hate that

 

[Didgital]

I just wanna say too, the only people I've known to develop bladder issues were people that had achieved permatolerance but keep trying to stay high. I've seen people unable to walk because of K cramps and still do more K.
Sad shit.

 

[mr peabody]

Thread 'KETAMINE | +50 articles' https://www.bluelight.org/community/threads/ketamine-50-articles.895160/

 

[KetTolerance]

Any ideas what kind of enzymes and pathways could stop fast tolerance return after long breaks (even year long)?
Maybe it's gene overexpression and altered calcium influx (and some other less significant consequences). This prevents receptor downregulation and promote synthesis after long breaks.
Basically, our neurons may hold this altered receptor production because of maladaptive positive feedback (gene expression, enzymes and calcium flow).
I had no effects after one of 1 month break attempt and taking of Aniracetam for 1 week before test. It feels like Aniracetam can prevent tolerance going away and keep altered NMDA receptor upregulation by depolarizing effects of soidum influx through AMPA channels (which is displace magnesium from NMDA and rise calcium influx).

Let's find therapy to turn back this condition!
I have some success with Magnesium - it worked stronger after 1 week taking magnesium every day (stronger than 1 month break!), but only once.
Please share your experience how cannabis effects has changed after you got permanent tolerance to DXM or Ketamine.
If you have high tolerance to alcohol and feel missing something due to long term consumption - please say something about what's changed.

 

[Esperighanto]

I used 125mg of ketamine daily for 10 months, then stopped for a while and found no tolerance formed. I later put down 7 grams in about 10 weeks (roughly as fast as I physically could manage, suicidal depression type shit) and I have yet to find tolerance form. I do regularly use memantine, noopept, bupropion, buspirone, caffeine, THC/HHC, and amphetamines though all of which may absolutely be confounding factors. I also use serotonergics like my life depends on it, so maybe that's related too, I'm not sure. I've kept track of my total arylcyclohexylamine consumption throughout my life though, I'm just over 36 grams right now.

Sorry I'm typing somewhat poorly rn, just bumped 15mg of 2C-B since it's its 51st birthday today.

 

[Khacorrat]

I don't have much to say, but I'm curious about the way tolerance builds up and the famous "permatolerance" which seems unavoidable if you do dissociatives too often.

I tried ketamine (my only disso so far) almost 15 years ago and really like it, especially in combination with LSD! At this time we used to buy 1g and consume it through the night (4-5 people). At this time no tolerance were build because I consumed like once every 2-3 months.

Fast forward, I didn't consume during like 10 years. At the end of last year, my wife and I got some and we retried it. So to stay on the topic, I have to say that we got a bigger stash (5g) from which I consume like 3g in 3 months (twice a week, sometimes two day in a row, max 200mg/session).

At the end of those three months, I had the feeling that I needed more to be at the same level of dissociation. This was especially true when I did ket two days in a row but way less when I stick to once or twice a week (reminder, max 200mg). Then I took a 3 months break and tolerance goes back to baseline.

I don't know if it was only a potential tolerance buildup of if set/setting could play a (huge) role in the experience.

Also, I don't know if some encounter the same, but it works way better if I took it in one time (example 80mg) than if I take it in two times.

Disso are a "weird" class of drugs, but so interesting when you use it as a tool

 

[KetTolerance]

I used 125mg of ketamine daily for 10 months, then stopped for a while and found no tolerance formed. I later put down 7 grams in about 10 weeks (roughly as fast as I physically could manage, suicidal depression type shit) and I have yet to find tolerance form. I do regularly use memantine, noopept, bupropion, buspirone, caffeine, THC/HHC, and amphetamines though all of which may absolutely be confounding factors. I also use serotonergics like my life depends on it, so maybe that's related too, I'm not sure. I've kept track of my total arylcyclohexylamine consumption throughout my life though, I'm just over 36 grams right now.

Sorry I'm typing somewhat poorly rn, just bumped 15mg of 2C-B since it's its 51st birthday today.

Have a nice trip!
Can you say what changed between your first time with Ketamine and now? Maybe a subtle but persistent difference.

I don't have much to say, but I'm curious about the way tolerance builds up and the famous "permatolerance" which seems unavoidable if you do dissociatives too often.

I tried ketamine (my only disso so far) almost 15 years ago and really like it, especially in combination with LSD! At this time we used to buy 1g and consume it through the night (4-5 people). At this time no tolerance were build because I consumed like once every 2-3 months.

Fast forward, I didn't consume during like 10 years. At the end of last year, my wife and I got some and we retried it. So to stay on the topic, I have to say that we got a bigger stash (5g) from which I consume like 3g in 3 months (twice a week, sometimes two day in a row, max 200mg/session).

At the end of those three months, I had the feeling that I needed more to be at the same level of dissociation. This was especially true when I did ket two days in a row but way less when I stick to once or twice a week (reminder, max 200mg). Then I took a 3 months break and tolerance goes back to baseline.

I don't know if it was only a potential tolerance buildup of if set/setting could play a (huge) role in the experience.

Also, I don't know if some encounter the same, but it works way better if I took it in one time (example 80mg) than if I take it in two times.

Disso are a "weird" class of drugs, but so interesting when you use it as a tool

I think, tolerance builds exponentially. For some time it's almost nonexistent and goes back to baseline. Although, many people says about "50 trips rule" with DXM.
I rely on this anecdotes where recovery speed is probably depend on current glutamate system state (fast recovery for rare use).

Can you track changes how it felt at first times and now, after break?
I think, there will be difference anyway. I had satisfying trips before, but even then already lost some numbness, ataxia and slurry speech.
I want to make a tests for evaluating current state of tolerance. Because you may feel like it's ok, but have weak effects and vice versa.
Cannabis probably have small cross tolerance with dissociatives, but "magic" depends on NMDA - so it can reveal current state.
I have no anxiety, altered sense of time and thought loops from cannabis. And sense of music and environment perception was less "spacy".
When it goes back, then i have stronger dissos or cannabis effects. But after dissos my senses became blunt again and dissos doesn't work.
This may be because of "concentration floor" - when affinity is not enough to bind to all receptors and properly block it. I think hard stuff like MK-801 and PCE can break through tolerance, but this is very harmful - they have longer binding and stronger affinity. If Magnesium works, then it may be upregulation of NMDA receptors (on gabaergic interneurons, at least).
I will wait for 1 year, try some ideas and test with cannabis every month or so. I hope this not an obstacle.

 

[Esperighanto]

Can you say what changed between your first time with Ketamine and now? Maybe a subtle but persistent difference.

Yeah, ketamine used to reliably induce dysphoria, "drunken spins", and vomiting for any dose over 15mg very specifically until I used MDMA for the first time. My relationship to existing in a physical form was fundamentally reconstructed as a result of that initial exposure to an empathogen, I had not realized that I was a rubber band ball of trauma and tension but that one experience released all of the tension permanently, and since then ketamine and other NMDA antagonists suddenly flipped from universally dysphoric and terrible to being quite fascinating.

Over time of using arylcyclohexylamines specifically, I have an easier time "steering" the experience towards or away from holing, and I have a significantly easier time integrating the experiences into something meaningful. If my tolerance allows for it to function, I am almost guaranteed to be on a serotonergic of some variety, so dissos are all very kaleidoscopically "stained" now, if that makes sense. The way that using a lot of acid makes cannabis feel more serotonergic, the same happens with dissos for me.

I want to make a tests for evaluating current state of tolerance. Because you may feel like it's ok, but have weak effects and vice versa.

For me it's usually juggling, skateboarding, calisthenics, reading/writing, conversation and verbal capacities in languages other than my native language, retaining information from studying, if I can successfully whip up a grilled cheese, writing code, the normal shit I get up to when not using drugs. Over time the familiarity I gained with things like serotonergics, dissociatives, stimulants, sedatives, etc. of many varieties makes it easier to do any of these things, but that familiarity is separate from tolerance as tolerance resets to zero after a period of abstinence, yet I do not forget the lessons learned which accumulate into forming familiarity.

I think, tolerance builds exponentially. For some time it's almost nonexistent and goes back to baseline. Although, many people says about "50 trips rule" with DXM.

Yeah I mean, I suspect that when it comes down to it that subjective variances in neurotypology and neurochemistry are going to remain so nuanced that there's likely no consistent enough patterns for a rule of thumb like "50 DXM trips" or whatever. I've used DXM at least a couple hundred times, I'd be shocked if it's fewer than 300 total. It hits exactly the same as it always has. I've used amphetamine, methamphetamine, MDA, MDMA, various benzofurans and N-benzylated phenethylamines, DXM, arylcyclohexylamines, etc. pretty extensively and in dense/high dose ways at times, but with an adequate tolerance break I've yet to notice any sort of "permatolerance", I do instead recognize a minute degree of familiarity.

Cannabis probably have small cross tolerance with dissociatives, but "magic" depends on NMDA - so it can reveal current state.
I have no anxiety, altered sense of time and thought loops from cannabis. And sense of music and environment perception was less "spacy".
When it goes back, then i have stronger dissos or cannabis effects. But after dissos my senses became blunt again and dissos doesn't work.
This may be because of "concentration floor" - when affinity is not enough to bind to all receptors and properly block it. I think hard stuff like MK-801 and PCE can break through tolerance, but this is very harmful - they have longer binding and stronger affinity. If Magnesium works, then it may be upregulation of NMDA receptors (on gabaergic interneurons, at least).
I will wait for 1 year, try some ideas and test with cannabis every month or so. I hope this not an obstacle.

People who are super drawn to dissos as escapist tools and not instruments of inner work are destined to be the types desperate to reset their tolerances, to continue trying to escape even harder, when in reality they've wasted their chance to utilize one of the most fascinating tools for self work I've ever even so much as heard of, let alone been so fortunate as to become familiar with.

My personal stance on this is that the concept of "magic" even being a word used in the conversation surrounding drugs is some goofy shit that reflects an inherently unscientific form of what anthropologists refer to as "magical thought", a cargo cult-ish style of erroneous pattern recognition that occurs to try to explain things we cannot make sense of. The ancient Nords having a strong hunch that thunder was the hammer of Thor striking upon metals, the idea that there is "magic" within pharmacology, and as if the entirety of emergence (as defined by cognitive scientists) is not the magic itself, the whole damn thing, not just NMDA antagonism, not just this or that, but the entire system where somehow reality managed to manifest a computer so it can experience itself.

As far as I am aware, there is no reason to suspect that there's any overlap between cannabinergic and NMDA/AMPA reception in the brain, afaik cannabinergic reception occurs on a subsite of GABA and acts as a sort of reuptake modulator, it's detailed pretty well here but I'd love to see this study repeated with other similar (though different) methodologies to try to make it more concrete: https://pubmed.ncbi.nlm.nih.gov/24646614/
I can see how cannabinoids can induce experientially dissociative colorations upon cognition, but it seems to be much more impactful on internal metacognition shit than it is on qualia. I'm not sure why, it reminds me of salvia in that way though. I would consider both salvia and cannabis to be two examples of what might be best referred to as an "atypical dissociative" for the sake of this conversation, really there's probably a solid nomenclature for all of this out there somewhere I've yet to read through.

When you say you have no anxiety, altered sense of time, or thought loops from cannabis, are you saying that you think that's the result of NMDA antagonist tolerance? I've never experienced anxiety or thought loops from cannabinoids, not a single time in my entire life. Eating an eighth of an ounce of decarboxylated THCa crystal doesn't even do shit like that to me, but time dilation can certainly occur. When you say "But after dissos my senses became blunt again", that is a really important thing here imo. I've had this happen from pretty large scale PCP binges, and I'm unsure if it's the result of some sort of toxicity, or some sort of neurogenic coloration that occurs as a result of these, but LSD has its own sort of "afterflavor", harmaline does, etizolam does, most psychoactives do for me at least. Time heals them all.

I couldn't find any definitions of the term concentration floor in pharmacology literature just bopping around on Google Scholar real quick, but I'm puzzled by the concept of "binding to all receptors". Few things outside of like, full agonist nitrogen mustard chemical weapon type shit that you have likely never even heard of can achieve something akin to this degree of receptor hypersaturation, at least as far as I'm personally aware. I think that whole concept is not studied much because generally it's undesirable to carpet bomb any biochemical circuit like this, neurotransmitters or not. I've not tried dizocilpine (MK-801) but I have used a handful of arylcyclohexylamines, so far the list is DCK, ketamine, 3-HO-PCP, 3-MeO-PCP, 3-HO-PCE, 3-MeO-2'-Oxo-PCP (MXPCP), 2F-O-PCE (aka 2-FXE or CanKet) and 2-Fluorodeschloroketamine, maybe I'm missing one? I don't think so, pretty stoned rn though ngl.

Of those drugs, I would absolutely love to know why a PCE derivative (which is almost guaranteed to be of higher potency) would be more harmful than PCP. Arylcyclohexylamine toxicity is essentially a direct function of dose, the amount of ketamine you need to get to an equal experience compared to 3-HO-PCE or CanKet would tell me that ketamine is significantly more toxic than both. Despite having not used it, I checked around on unsubstituted PCE's dose range and it's ~3-12mg, whereas 3-HO-PCE is ~5-25mg, and CanKet is ~15-75mg. Ketamine for most people is going to be in a 30-150mg range, saying that that's even in the same ballpark of toxicity is unfounded imo. There is also the unique toxicity of 3-hydroxyphenyl groups though which I suspect may be hepatotoxicity, though I am far from certain. I recently found a case study that pointed towards a 3-phenylpiperidine with the hydroxyl group lined up in the same exact carbon configuration relative to the compound's nitrogen as you'd see in 3-HO-PCP/PCE, I need to find that DOI so I can link it here. Like I said earlier, the weed I snagged today figuratively broke a steel chair over my head.

The magnesium thing is interesting, I administer it sublingually when I need it since I absorb none (missing all large and most of my small intestines), and I am quite a fan of racetams/noopept which can definitely act like a tripkiller for NMDA antagonists. I've specifically railed the doses of 3-HO-PCP which land me in M. C. Escher's "Impossible Staircase", then hit a fat line of noopept and experienced a significant attenuation in the dissociative (though not the stimulant) effects of 3-HO-PCP. Same worked for 3-HO-PCE, CanKet and 3-MeO-PCP, never tested it on MXPCP. Maybe this relates? Idk. It's all super fucking nuanced and I doubt any of us will genuinely meaningfully understand this as a completely surveillable biochemical circuit that we've mapped out at any point in our mortal lifetimes tbh, it's a BIG challenge to figure out. The curiosity towards learning more about this seemingly recursively infinite well of questions though is why I'm passionate about pharmacology and the exploration of structure-activity relationships in the first place.

I'm not going into all of these points to try to like, dunk on you or some shit, I'm just trying to point out how maintaining at least a meaningful attempt towards scientific rigor is necessary for generating scientifically valid answers to questions like "how do I alter my tolerance to NMDA antagonists".

 

[placebonaut]

(twice a week, sometimes two day in a row, max 200mg/session).

I'm a bit fucked up but IIRC ~9 times a month risks bladder damage, I assume that's dose related as well. Be careful, you may be pushing the limit, worth checking safe levels.

Can you track changes how it felt at first times and now, after break?

I log every trip with dose and effect, very useful tool to use to compare progression of drugs and helps flag over use/growing tolerance, but needs a little discipline to keep doing it

thought loops from cannabinoids

it's dose dependent for me, I need a very high dose where I need to go lay down in bed! I don't ever do this intentionally, but sometimes get a hot spot in edible chocolate bar which will knock me out - yes I've stopped buying them

 

[Esperighanto]

it's dose dependent for me, I need a very high dose where I need to go lay down in bed! I don't ever do this intentionally, but sometimes get a hot spot in edible chocolate bar which will knock me out - yes I've stopped buying them

I mean, buying edible chocolate bars is really just a great reason to homogenize a bunch together and boil the shit out of it, recasting it into whatever shape you want but then hopefully homogenizing your way past improperly mixed ingredients in the first place. I am always fascinated by thought loops though. Sometimes I can get on one from LSD or DOM or whatever where it has me reading about some random shit to another to another and I'll have like fifty tabs open within an hour, but I never find myself thinking "I am even 0.1% stuck in a cycle of thought I cannot simply change at will".

I log very trip with dose and effect, very useful tool to use to compare progression of drugs and helps flag over use/growing tolerance, but needs a little discipline to keep doing it

I'm always super glad to hear of folks out there with good data gathering skills surrounding drug use. I speak a lot on the more goofy shit that I get up to when I'm posting on BL, but in reality it's only useful to research things with a relatively clean metabolism and good data over time.

 

[iom]

This thread touches on an important issue that concerns a lot more than ketamine, at least if "perma-tolerance" and kindling-like phenomena are similar between different drugs.

After having been around heavy ketamine users for years, there does not seem to be a way to truly permanently reset tolerance. What I have heard (prolly hundreds of times at this point) is once one achieves permatolerance, you can take a break for weeks/months and when you go back to doing ketamine, that first initial dose, you get high just like everyone else. But then your tolerance immediately comes back.

This is an important observation which looks a lot like kindling reactions to other drugs like benzos, SSRI/SNRIs, etc. With the latter drugs, the kindling can also rapidly reintroduce dependency which must be addressed by slow tapering to avoid causing serious or even life-threatening symptoms.

One straightforward way to look at this response is that some habitual users may not ever fully return to baseline after ceasing use of the substance. This could be because their systems have shifted to a different phase or state and/or because of "learning" which might (only guessing here) involve the nervous system (not necessarily the brain itself).

Is there a general solution to this problem? I rather doubt it. I suspect many of these phenomena are highly variable between individuals, and what might cure one person might be useless to another. To the extent that these reactions involve "learning" either by one's nerves or by other types of cells (which absolutely do have the capability to form memories, if you will), it may be very difficult to undo these "lessons" unless there is some way to reset things.

For example, many people report that iboga/ibogaine seems to induce a "system reset", helping the body to forget past history of dependency and essentially equilibrate to a more healthy baseline state. Plenty of anecdotal information backs up these claims with regards to opioid dependence and tolerance, but very little formal research has yet been done with these compounds to confirm these anecdotes much less to investigate potential utility in "resetting" other aspects of the nervous system.

I also wonder if serotonergic psychedelics might, under certain circumstances, help the nervous system to "forget" past history which could include other perma-tolerances. I don't think the anecdotal record for psychedelics versus opioids is nearly as strong as for iboga/ibogaine, but classic psychedelics are a lot easier and safer to use in general so maybe worth pursuing.

Lastly, in the case of benzos and SSRI/SNRIs, at least some anecdotal reports suggest that kindling is much more likely to occur after sudden or cold turkey withdrawals. Slow tapering is therefore recommended as a way to avoid causing such kindling reactions in the future. It's also possible that people who have "survived" overly-aggressive tapers or cold turkey withdrawals from benzos and SSRI/SNRIs and who have prolonged post-acute withdrawal symptoms might benefit from careful (!!) reintroduction at a low level (ideally the lowest level sufficient to control the post-acute symptoms---too sudden or too high can cause more kindling) followed by a long smooth taper (years long if necessary) to zero. Hypothetically, this could help the biological system, which got "stuck" in a dependent state, to smoothly transition back to a non-dependent baseline.

Unfortunately I don't know that this last approach would be at all helpful for ketamine/DXM "perma-tolerance"because these dissos aren't necessarily being taken continuously like benzos or SSRIs. It's entirely possible it would just make things worse, but I guess if one is desperate enough to try anything... Just don't blame me if it goes wrong! And report back so others can hopefully benefit from whatever insight is found.

 

[placebonaut]

I mean, buying edible chocolate bars is really just a great reason to homogenize a bunch together and boil the shit out of it, recasting it into whatever shape you want but then hopefully homogenizing your way past improperly mixed ingredients in the first place.

Too much of a ball ache to fix what should just be basics for the vendor. I suspect it's just bad production technique on their part, but they are 1 of the biggest vendors on the UK market, I've had 3 bars from them and all have had the same problem, fool me once....

I could try gummies or something from someone else but think instead I'm going to give making infused oil myself from bud, that way I can pick the strain I want as well.

I am always fascinated by thought loops though. Sometimes I can get on one from LSD or DOM or whatever where it has me reading about some random shit to another to another and I'll have like fifty tabs open within an hour, but I never find myself thinking "I am even 0.1% stuck in a cycle of thought I cannot simply change at will".

they can be pretty crippling with high dose weed, thankfully I've never dosed so high that the duration has been more than 30-60 mins, but it's very much a lay down in a dark room and ride it out type thing. Could be quite unpleasant for some people I suspect if the thought loop is a bad one.

I'm always super glad to hear of folks out there with good data gathering skills surrounding drug use. I speak a lot on the more goofy shit that I get up to when I'm posting on BL, but in reality it's only useful to research things with a relatively clean metabolism and good data over time.

It's the best thing I've done with my drug use, really helps me see what's actually going on, it's part log, part journal, and part a dumping ground for research.

I have targets and warning for maximum usage levels that I want to stick to

a very useful tool!

main thing is to be honest with yourself about things, log accurately.

 

[Skorpio]

another. To the extent that these reactions involve "learning" either by one's nerves or by other types of cells (which absolutely do have the capability to form memories, if you will), it may be very difficult to undo these "lessons" unless there is some way to reset things.

I think this agrees with my take on things.

Protein localization (ie receptor internalization) doesn’t really square with how long the tolerance to arylcyclohexylamines lasts.

Epigenetic and transcriptional changes would be longer lasting, and encompass targets beyond the NMDA receptor, but the time scale still feels longer than something that is driven solely by epigenetic changes.

Circuit level changes (both including neurons and glia) make more sense to the paradigm of a slow-building tolerance that drops even more slowly with extended abstinence, but will rapidly return upon resumption of use.

Given the NMDA receptor’s central role in long term potentiation/Hebbian learning and the fact that living organisms at our core are simply homeostasis machines, it does make sense that tolerance is more persistent than with other classes of drugs.

Another aspect is that most drugs of abuse are agonists at various receptors (and the majority work on GPCRs), where receptor downregulation can maintain homeostasis.

One other thing to note is that the NMDA receptors are quite unique structurally, even for ion channels. Also to my knowledge, there aren’t endogenous pore blocking ligands for NMDA channels. I would expect that this would again drive a unique etiology of tolerance development compared to other compounds.