• N&PD Moderators: Skorpio | thegreenhand

Reversing opioid Tolerance through compounds

im also curious to get something to reverse tolerance both to opiates and alcohol as well. it will be amazing find!
 
Is there any diagrams that show whats on a opioid postsynaptic cell
A lot of opioid's desirable effects are mediated through activation of mu-opioid receptors located on pre-synaptic cells, rather than post synaptic

The pre-synaptic cell in question is often GABAergic in nature, and mu-opioid receptors tend to turn off such cells. As do NMDA antagonists, which have effects on opioid tolerance and such and are used by some to that effect. Caution is advised, as long term NMDA antagonist use is not without side effects.
 
I wasn't too amazed when I discovered withdrawal, myself. ;-P

i have had breaks from drinking and opiatizing and i still have tolerance. withdrawal sucks and it doesnt fix anything really
 
^On that note, "losing the magic" with MDMA is something of an enigma. For some people it seems largely irreversible given even large amounts of time
 
i have had breaks from drinking and opiatizing and i still have tolerance. withdrawal sucks and it doesnt fix anything really

Same happened with me, got through the wds, waited a week and still felt nothing from a high dose. takes ages and is horrible once youre used to getting high. 120mg oxycodone now feels like what 10mg felt like a year ago

I wish the weissman method was cheap or could be done on the nhs, this would probably work without any pain and agonists could be used to speed it up :)
 
A lot of opioid's desirable effects are mediated through activation of mu-opioid receptors located on pre-synaptic cells, rather than post synaptic

The pre-synaptic cell in question is often GABAergic in nature, and mu-opioid receptors tend to turn off such cells. As do NMDA antagonists, which have effects on opioid tolerance and such and are used by some to that effect. Caution is advised, as long term NMDA antagonist use is not without side effects.

this is something i've been wondering about lately since I've noticed that lyrica totally substitutes for an opioid when mildly dependent on opioids. Haven't been able to test this substitution with a heavy opioid habit yet (and hope I never have to).

One moderator on these forums with a heavy opioid dependency of 240mg oxy per day, said lyrica is the onlything that allowed him to sleep (not even benzos) during opioid withdrawal.
 
At an overview level, opioid withdrawal related insomnia is largely due to activation of sympathetic nervous system (hence helped by clonidine) and the Reticular Activating System (RAS), the latter of which essentially controls/filters projections from the brainstem out to the higher brain (resulting in wakefulness/pain perception etc depending on if it passes along a stimulus).

The commonality between opioids and lyrica in terms of the effects on sleep I would bet are largely due to effects on the RAS, there are various neurotransmitters in the RAS that lyrica could be affecting to help with the insomnia, including Substance P (which normally contributes to pain/glutamate release).
 
Interesting. So whilst clonidine and tizanidine help with the physical side of withdrawal, although don't, unless at high enough doses to knock someone out cold, allow sleep, perhaps the effects on the RAS of gabapentinoids could help with getting the person withdrawing to sleep?

I might have to try that, since I have a fuckton of gabapentin, and as far as antiglutamatergic drugs go, I always found that more than anything else bar more opioid, NMDA antagonists with clonidine+tizanidine helped actually get me to sleep. Whilst clonidine/tizanidine/both alone, hypotension aside just helped alleviate the misery, and not allow one to enter into a more restful state, but not actually sleep. But with the addition of say, MXE, 3-OH-PCP, 4-MeO-PCP, diphenidine, methoxphenidine etc. Or at a pinch, even dextromethorphan, such as last night, I was in opioid WD thanks to a pharmacy bollocksup and my lacking my last dose of morphine prior to a refill in the morning, I'd gone through a fair few mg of clonidine and some couple of hundred mg of tizanidine, but still couldn't actually sleep, even after adding 2.5mg nitrazepam (all I had) and a couple of cyclizine pills, only sleep I got was after throwing in a bottle of DXM syrup. That did allow me to drift off to sleep for long enough both to cut out some infernally slow waiting time for the rx refill and actually sleep enough to feel rested after the DXM wore off and me just resting, with an occasional top-up of the alpha2 agonists (note-this would be an EXTREMELY large dose of tizanidine, don't take this as advice, in fact don't even think about it! I'm used to it, I respond well to it, and even for me thats a bloody lot, especially combined with clonidine. And even I have no choice but to make sure I piss and shit first, because the hypotension is enough to make sure I couldn't possibly stand without orthostatic hypotension knocking me out within seconds until I return to a horizontal position. DON'T FUCKING DO THIS! I MEAN IT! 4mg to 8mg tizanidine, orally will make someone unused to it unable to sit up not uncommonly, and if plugged then thats enough to leave someone on their ass, so don't even think of three-figure dose ranges. Just a couple of plugged tablets if not in opioid WD is enough to knock me out in the right/wrong circumstances (the 4mg ones). So when I say don't, I fucking well MEAN don't.

Either/both drugs however really do help with the overactivation of sympathetic activity, the restlessness, tearing (the latter can be helped by antimuscarinic antihistamines like cyclizine too), akathisia and overheating, clonidine or tizanidine work wonders. IIRC theres another drug acting as an alpha2 drug, lofexidine developed for opioid withdrawal although I've never had it. But I'm scripted high doses of tizanidine for a permanent muscle spasm caused by nerve damage, and also rx'd clonidine to help prevent and treat autie overloading if/when it happens. And tizanidine also happens to work alright as a breakthrough med for that too.

I've often wondered about xylazine and dexmedetomidine; IIRC some places xylazine, an alpha2 agonist used in tranq darts for large animals like rhino, is fairly popular in some countries. But so far I've not had the chance to try either. Guanfacine is another one I'd love to try, since of the ones I've tried, I love these alpha2 agonist sympatholytics, and its the polar opposite with even tiny degrees of alpha2 antagonism, its a living, breathing personal hell made flesh to me.
 
And Asecin, you could try memantine. It is one hell of an effective assist for opioid detoxing. At high doses (50-100mg BD, or even TDS if you take to it, especially with a little alpha2 agonist, such as clonidine, a few hundred mikes a few times a day, or the shorter acting tizanidine (less hypotensive, shorter acting than clonidine, but far more myorelaxant) can work wonders.

I got nicked once, and the fucking filthy bastard pigs tried to use opioid withdrawal as a method of coercion to get information out of me and a false confession. But that particular time, I'd taken a couple of hundred mg of memantine the previous day, along with my opioid dose. I'd had no opiates (being on 110-120mg morphine IM BD min. and 80mg oxy daily minimum (the oxy used to be lower, but was increased after I burnt my eye, courtesy of the filth interfering with the labels on certain bottles containing things that need not be mentioned specifically but were all of them alkaline, some damn strong bases and none of them anything you want close to your eyes, that resulted in a pressurized, ammonia propelled jet of boiling hot basic, salts-laden slops that punched through a bottlecap and hit at an upward angle hard enough to knock the protective goggles up off my eyes and allow the rest of that stream of searing hot, highly basic corrosive shite to belt me one right in the eye, resulting in an emergency hospital trip, a fuckton of absolute screaming agony the likes of which I barely thought possible to exist, and that makes a white phosphorus burn on a kid, look and feel like paradise, along with a HClO4 burn (relatively mild considering what could have happened) plus a SOCl2-induced degloving of 3/4 of one hand, down to the bare raw, acid-soaked smoking muscle, whilst having your testicles slowly burst in a red-hot vice coated in fuming sulfuric acid (albeit I've never had the experience of the bit with the testicles, but the rest of it put together wasn't anywhere near that nasty and painful)

So at the time, I'd developed an even larger tolerance to opiates, and was sometimes using street H or H/fent or fent derivative type strong-ass but short duration opioid mixture, and the memantine plus clonidine even helped take away some of the horrendous pain (was still wearing an eyepatch at that point, it should be noted, because exposure to light was still causing me great pain), and the filth tried to use that, and forced withdrawal (I HAD my meds with me, taken to the station, and they were holding them over me, threatening to force me to wait for many hours until I ever got to see a doctor), and I managed to hold out, giving them an entirely 'no comment' statement, aside from the mandatory name, address and D.O.B.

I am pretty sure I'd have cracked, eventually, if it hadn't been for having that hefty dose last taken of memantine in me, and its long duration of effect. I even SLEPT in the holding cell. (not before urinating all over the meat-wagon mind you, walking around it slowly with my knob out and making sure to take extra time to piss under and on the door-handles of the driver-side and front left side door, whilst making sure they kept their distance until I'd finished, telling them if they came in range, the target would switch from cop van to porkers themselves=D)

(yes, the pricks have it in for me, have done for a long time, and I was dying for a piss by the time I'd been taken to a pig shop a long, long way from the one that is minutes driving from where I was), so I'd really had it with the fuckers, and decided it was time for some payback to begin, although I've launched legal action too, aside from getting the personal satisfaction of pissing all over a cop car and making sure extra attention was given to the door handles of the twunts)
 
perhaps the effects on the RAS of gabapentinoids could help with getting the person withdrawing to sleep?
I suppose 2 scenarios are -

1. Gabapentinoids may lead to decreased glutamate release in cortex by direct effects on alpha2delta receptors brainstem/RAS
2. Gabapentinoids may lead to decreased glutamate release in cortex by a direct effect on alpta2delta receptors in cortex

NMDA antagonists may be causing some of their dissociative effects by decreasing NMDAr driven communication between cortical regions, and the dissolution of such communication may allow for easier entrance into sleep (or anesthetic-like states, but a decrease in consciousness and reduction in brain metabolism is generally going to be more restorative than wakefulness either way)

There could also be the aspect of NMDA antagonist mediated relief of opioid withdrawal via coincident effects on the limbic system.

Dynorphin release mediates a fair bit of opioid withdrawal symptoms, and dynorphin (mostly) seems to augment NMDA receptor transmission

You may be interested in dynorphin's apparent binding to the NMDA receptor as well as Dynorphin as a therapeutic target for chronic pain

CY
 
so, lyrica and memantine for opioid dependence? i havent seen this before. ive tried memantine for alcohol withdrawal long time ago but it didnt work. do you think lyrica might actually help with alcohol withdrawal too??
 
so, lyrica and memantine for opioid dependence? i havent seen this before. ive tried memantine for alcohol withdrawal long time ago but it didnt work. do you think lyrica might actually help with alcohol withdrawal too??

Can you comment on the antidepressant effects of memantine? Does it have the same immediate effect like standard dissos. Is it recreational at all? Is it euphoric? Is the high lucid or functional? Thanks
 
In general the reports on memantine seem to be that it is "colder" than other dissos and tends to lack euphoria relative to other dissos, whereas "high trapping" NMDA antagonists with DRI properties (PCP) seem to be much more enjoyable.

"Low trapping" NMDA antagonists like memantine still have some antidepressant potential I'm sure and some are being investigated as such. I've found memantine to have interesting effects on the internal monologue/ego/headspace and such, especially when combined with meditation, but it may not be as good at producing euphoria as other dissos.

I would say the high is fairly lucid/functional, especially given that one titrates up the dose, giving some of the effects (nicotinic acetylcholine receptor antagonism) time to desensitize. It can take some time for compensatory nicotinic receptor upregulation, in the case of memantine.

As always, YMMV, everybody is unique.
 
I've always found memantine-induced dissociation quite enjoyable. It does have some prodopaminergic effects of it own does it not? What is the typical timespan frame for nicotinic receptor upregulation as a response to memantine antagonism?
 
I think its supposed to be mainly a week or two on the nicotinic receptor upregulation, dose dependent I'm sure.

I think there were trip reports reporting typical euphoria off of memantine (especially with heroic doses) but a lot of the others described it as "cold/mechanical" IIRC, I'll bet there's a lot of individual variation there.

Long term antidepressant potential seems largely separate from the short term effects of drugs however, rapid acting ketamine being the exception I suppose.
 
it gives me some dissociation but probably not as much as i can get from small dose cough syrup, but this one is more difficult to explain. there is no high, no need to do it daily, just doesnt push you toward it for any serious reason. i just kept taking it in the hopes for tolerance reset towards various drugs including alcohol and it didnt do any of that. on the other hand, it does have some obscure dissociative effect and antidepressant effect and i think its pretty interesting to try by everyone at least once. being that its quite safe, non-addictive or toxic in any level, i think everyone should try it and see how they react. i know ive reacted differently each time ive done it for few days a time in a year difference of taking a break and im pretty sure its going to affect me even more different next time i do it which i plan on doing.
 
Memantine's dissociative effect is quite dose related, it doesn't start getting really dissociative until you're pushing into the hundreds of milligrams.

That said it is still very much bioactive at the 10-50mg range and presumably acts just as well as other NMDA antagonists for dissociative-induced antidepressant effects.
 
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