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Chronic downregulation

Zephyn

Zephyn

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Oct 31, 2020
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Could chronic downregulation of receptors from regular binge user over extended periods of time (say years to decades) cause symptoms akin to withdrawal, but not to the extent that it is classified as withdrawal?
 
ibtisam midlet said:
no dependence will not be developed so no withdrawal, if you did not exceeded kindling effect ration which is 2 days of continuous taking in some substances , but tolerance will
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Kindling effect ration? 2 days? I have never heard of any drug causing any issues with even around the clock use from just 2 days. What about 2 days, every 3 days, for drugs with a short half-life anyway?
 
ibtisam midlet said:

Kindling - Wikipedia

en.wikipedia.org en.wikipedia.org
i think with short half-life drugs its way more then 2 days but with pre-existing chronic opiate use, its 2 days for long acting opiates
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Yeah I am thinking there might be some possibility of establishing the brain of someone of "chronic opiate use" or alcohol or benzos etc or whatever, without actually getting acutely dependent though..
 
ibtisam midlet said:
its okay to take it every other day, just make sure your body is free from any clinically relevant dose of the drug in the day that you not take it
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From what I've experienced with even intermittent use over a long time span. I wouldn't dare take any addictive drugs every other day.
 
I guess to suffer from this - chronic downregulation of some transporters(?) or receptors. First serotonin, from a decade of SSRI use, sometimes reckless combinations with other drugs which work on serotonin too. Since I started antidepressants I didn't get any more real visuals from drugs besides LSD (5-ht2a problem?). And more than a year of heaviest dissociative abuse (interestingly this seemed to be impressively forgiving unless I got some bad batches which caused first a transient physical toxicity - stuttering and similar stuff for months, but of course addicted me continued use-as when high, the symptoms faded a bit and then came back full force.. and after something psychosis-like, which resolved too slowly but remains to be easily triggerable with some psychoactives, not all, not always, but it made me finally stop and didn't touch anything dissociative for 2.5 years now with one exception, which confirmed me that I need to stay clear of them)

It's not that I need overly high doses of thingies to work, but I am just so fucking lethargic and somewhat out of it all the time. High dose pregabalin which apparently inhibits glutamate reuptake resolves all but as known this stuff has an ungodly tolerance curve so guess it's no option. When used as directly it's the opposite, anxiolytic but somewhat dulling.

As the dissos increase glutamate levels, I suspect a permanently altered glutamate reuptake or somewhat alike. Anything known to reverse this? It sucks and is disabling.
 
It's not that I need overly high doses of thingies to work, but I am just so fucking lethargic and somewhat out of it all the time [...] As the dissos increase glutamate levels, I suspect a permanently altered glutamate reuptake or somewhat alike
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given you have no actual hard evidence "permanent downregulation" is occuring, why not treat the problem from first principles instead? i.e. don't worry about the "low level" "hardware", focus on the lethargy from a more holistic perspective. this is kind of like worrying about the levels of certain neurotransmitters. You can't measure them easily, so why focus on that?

as someone who has recklessly abused psychedelics and dissociatives, I can say with confidence I don't feel like my nervous system is broken in any way. (and I was doing 100mg+ PCP doses multiple times a day sometimes)
 
Is there any evidence of permanent receptor downregulation?
 
Just had a similar question - why for example does opioid rotation work? How can you become highly tolerated to one certain agonist but (much? somewhat?) less to another?

Like, I am tolerant to morphine from long term use. I built down the last time but a) once a higher amount, tolerance AND w/d would be back in an instant, b) I probably lied to myself somewhat, etc.. c) additional misery from venlafaxine w/d which is nastily coupled with opioid receptors, same set of withdrawal - just subjectively / acutely worse! (

At least I would tolerate 60mg morphine to get w/d (mostly) away and 120mg to have an OK day. No euphoria to speak of. Now acquired kratom, known as a weak or partial agonist - maybe 6g red vein just blew me away, made me fade in and out of dreams for 4h straight - something morphine never was able to do ever since I abused dissos along with it... It's still lingering, not feeling good but opioid euphoria in its max. From not oxy etc. but random online kratom.

HOOH said:
Is there any evidence of permanent receptor downregulation?
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We have for example brorphine (not bromadol! which is pretty) that is said (can't link cause of vendor related but see cite below) to irreversibly destroy opioid receptors / neurons which firstly mimicks heavy tolerance but would never completely build down, thus lose endorphin functionality forever. Nasty. Made me reconsider said vendor, at least they warn off but still was a favorite in past, had hoped better.

Brorphine also shows binding to other ORL-1 like targets ie the three canonical opioid receptors encouraging phosphorylation of the ORL-1 and desensitisation. Furthermore activation of Phospholipase A2 activity can be agonistic towards apoptotic pathways indicating a mechanism of neurotoxicity and degeneration mediated by A2 activity from ORL-1 activity. One can indeed lose MOR expressing neurons, not something that will grow back once use of the drug has ceased, this can be highly worrying as it can induce a tolerance to opioid drugs that cannot be reversed by abstinence as the neuroplasticity of repair will not always produce new neurons that express the MOR and in some cases will result in net loss of neurons, neurotoxic brain damage, one may not lose function due to neuroplasticity but one can lose MOR sensitivity in the parts of the brain that matter for opioid induced sedation and euphoria and analgesia, a goal we all share. Also continued activation of ORL-1 not only causes it’s own downregualtion but also downregualtion of the MOR and KOR, a partially unwanted effect if euphoria is the goal."
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plumbus-nine said:
Here. I have acquired semi permatolerance to dissociatives.
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Same. I don't think I've gone over a year, but did at least a year break with no noticeable difference. I wouldn't expect 3 to be very different. And my use is nothing compared to a few people I've met.

Gabapentinoids and cannabinoids are the same although for the cannabinoids I've only given 90 days break maximum.

I also struggle with a lot of drug induced mental AND physical health symptoms that are long lasting though I can't pinpoint on anything in particular. (Others don't seem to have the same reaction)
 
Kindling is very real.

Chronic gabaergic abuse really does screw up your brain. I can certainly attest to that.

Even if I take 1 benzo pill 12 hours later my anxiety is significantly increased. 15 years ago I could abuse the shit out of alcohol with very little consequences other than a hangover.

After so many years of benzo and alcohol abuse my brain is ultra sensitive.

Now, instead of a hangover it is accompanied by rather bad anxiety and what feels like an acute alcohol withdrawal making me want to constantly drink and binge.

"Brain damage" may be the wrong word... But long term use really does change your brain for the worse.
 
SnafuInTheVoid said:
Kindling is very real.

Chronic gabaergic abuse really does screw up your brain. I can certainly attest to that.

Even if I take 1 benzo pill 12 hours later my anxiety is significantly increased. 15 years ago I could abuse the shit out of alcohol with very little consequences other than a hangover.

After so many years of benzo and alcohol abuse my brain is ultra sensitive.

Now, instead of a hangover it is accompanied by rather bad anxiety and what feels like an acute alcohol withdrawal.

"Brain damage" may be the wrong word... But it long term use really does change your brain for the worse.
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Yeah but what about someone who doesn't abuse daily or regularly but regular enough over 10 or 15 years? That's the big question
 
I am the same with benzos now, one or two days isn't bad but anymore and the rebound is horrible. I'm wondering about "chronic" rebound turning into a sort of "'prolonga(ted)'" withdrawal if that makes sense
 
Zephyn said:
Yeah but what about someone who doesn't abuse daily or regularly but regular enough over 10 or 15 years? That's the big question
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That's me 100%

I mean alcohol daily for 9 years but on benzos maybe 3 months out of each year

But even daily alcohol I mostly was not the type of guy to wake up and immediately hit the bottle
 
SnafuInTheVoid said:
That's me 100%

I mean alcohol daily for 9 years but on benzos maybe 3 months out of each year

But even daily alcohol I mostly was not the type of guy to wake up and immediately hit the bottle
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Yeah never been able to do that but did get to the point of cravings at 12-1pm. Anytime I drink earlier, its because I missed a night or two of sleep.
 
HOOH said:
That's not receptor downregulation, that's just glutamate excitotoxicity (I believe).

Antagonists (like dissos) don't even cause temporary downregulation.
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Not sure about this. It was a theory but shouldn't then anesthetic doses be even more toxic (afaik they are not). These lesions in K users scared the shit out of me but one year later I am nothing but fucking lethargic and overweight due to my eternal mistake of switching from dissos to opioids to both to opioids (hint: former are easier to handle even if they are mentally more powerful and you're able to skip most of opioid w/d) but of course would be interesting to do further testing. You can't use an irreversibly toxic compound for years and get away with it.

Also with me it's not truly permanent but the memory of tolerance became permanent like with opiates, e.g. after a withdrawal you are sensitive again but soon your habit will be worse than before - just that the withdrawal with dissociatives takes months to years and has little other symptoms than temporary depression, irritability, anxiety. Some lucky individuals even get none. It might be kindling too, getting worse the more often one abruptly stops after several holes (thus highly varying glutamate levels - if sub-anesthetic doses actually do increase glutamate as supposed).

Still, tried to google about but didn't find a thing now.

Oh, venlafaxine (all SSRIs maybe) also undergo kindling shit.
 
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i had never heard of this kindling shit until a few years ago
 
plumbus-nine said:
It was a theory but shouldn't then anesthetic doses be even more toxic (afaik they are not).
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No since it's a one-time experience, as opposed to something that's used regularily.

Glutamate excitotoxicity is real, and results form an INCREASE in NMDA activity, not less, again, antagonists don't cause tolerance.
 
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