Opioids Tolerance destruction, holding on to hope by a thread

[Coralopiate]

Hi everyone,

I won’t go into my whole story here, but here are the most important parts:

Without opioids I am unable to function, essentially bedbound.

I made the biggest mistake of my life and binged on what I thought was heroin, and turned out to be fentanyl.

I got to the point where no amount of opiates do anything.

After a short break, my tolerance seemed to be reduced, I was nodding off, but there was no pain relief/pleasurable feelings whatsoever. It seems as though opioids no longer release dopamine in me for whatever reason. Sadly it seems this could be very connected to the analgesic effect, because both the euphoria and analgesia are both gone.

No matter what dose I take, the most I get is sedation, nodding and itching.

I overdose before I feel anything good.

Due to my situation, I qualify for euthanasia in certain countries, but that’s my real last resort. I’m trying everything I can before that.

Countless hours of research have led to me collecting a list of substances that can supposedly reduce opioid tolerance, as well as those that can help with dopaminergic recovery.

I am going to once again try detoxing, going off all opiates, and following this plan.

On day 6 I will start naltrexone. I’m not sure whether it’ll be low dose at 4.5mg or a regular 50mg. Seems the 50mg might be better for my purpose of lowering tolerance/healing opioid receptors.

During my period of abstinence, I will begin taking the following substances. I’ll be introducing one at a time, giving each one about a week to a week and a half to gauge side effects/etc.

Each of these has either research showing it can prevent and/or reverse opioid tolerance, showing it can heal/restore the dopaminergic system/receptors/etc. or has anecdotal evidence from multiple separate people affirming benefit in one of these areas.

I have most of these now, which are the ones I’m starting with:


Cerebrolysin
9-me-bc
bromantane
4-DMA-7,8-DHF
Corydalis
Theracumin
Metformin
Aniracetam
Oxytocin
Taurine
Ibudilast
Proglumide (cycled; 2 days on, 5 days off)
Megadose vitamin C (one dose/3 weeks)
Ketamine (one treatment every 1-2 months)
Mesenchymal stem cells, intrathecal and IV (one treatment every 1-2 months)
EGCG
Agmatine sulfate (cycled; 2 days on, 5 days off)
ALCAR
Probiotics
Ibogaine flood dose (maybe a month or so in)
Simvastatin
Pioglitazone
Resveratrol
Quercetin
Palmitoylethanolamide
Melatonin


Some others I will add after doing more research on them and ensuring I have a viable option:

Endothelin-A receptor antagonists (maybe ambrisentan)
CGRP antagonists
TLR4 antagonists
CaMKII inhibitor (maybe trifluoperazine)
PKA and PKC inhibitors
dasatinib
Glycine antagonists, nitric oxide synthase inhibitors
Spironolactone
Enkalphin Inhibitors
NK1 antagonists
Ceftriaxone
Disulfiram (Antabuse)
dehydroepiandrosterone sulfate
CRF-antagonists (maybe Antalarmine)
imatinib (PDGFR-β inhibitor)
FLT3 inhibitors (maybe Isoliquiritigenin)
EGFR inhibitors
Salvinorin A
Hsp90 inhibitors
Sigma Antagonists
EGFR inhibitors
PDGFR-β inhibitors

Many of these do have some scary potential side effects. The list includes chemotherapy drugs, certain antipsychotics, etc.

For me personally however the risk/benefit ratio is clear — considering I’ll either find a solution and be able to live/function, or I won’t.

This full process of abstinence and adding in the substances will likely take at least 3 months, if not longer.

I’ll be getting intrathecal and IV mesenchymal stem cell infusions likely around once a month.

I’ll also be getting ketamine infusions possibly at the same rate depending on my talk with the center.

Once I’m done and ready to try an opiate, I’ll be adding the following before consumption (along with everything else I’ve added in over the previous months):

Ultra low dose naltrexone, possibly around 10 micrograms but I need to do more research

DL-phenylalanine

magnesium L-threonate

I’ll likely do an infusion of ketamine and stem cells the day before.

I may add a microdose of ibogaine, but need to research this more.

At this point, all I can do is pray and take my prescription.

After a month, if I can stay stable on my dose and function again, it’ll be a huge success and would pretty much save my life.

This is going to be the hardest thing I’ve ever done, but hopefully it’ll be worth it.

 

[ChemicallyEnhanced]

Sorry to hear about your situation! I'm in a similar position and have been a few times before. I've been dependent on opioids since 2011. Started when I was VERY sick in hospital and they gave me IV morphine every 4 hours (6 times/day) for 11 weeks so I was probably dependant by the time I was discharged. Then I got a repeat oxy script.

I'm also basically bedridden when in withdrawal, too. The withdrawal is so bad I once used a hammer to break my wrist just to get pain meds.

I also messed up recently - or, rather, my pharmacy did. For my script, I normally get 4 boxes of 28 pills every 14 days, but a couple months ago my pharmacist fucked up and accidentally gave me 4 boxes of 100 pills. Now that I've blown through it on, my regular script no longer keeps me well.

Interesting (and potentially very helpful) list of things there. I'm definitely gonna try some. They seem very hard to come across, though! The only one of those I currently use is magnesium.

 

[Coralopiate]

Hey thank you! Sorry to hear you’re going through it as well.

A lot of them are definitely pretty hard to find, but some actually are very easy.

For example almost everything from the first list can be found on Amazon or nootropic sites.

Proglumide, simvastatin and pioglitazone are the only things I’m missing from the first list.

It does seem though that the potentially most effective are harder to find/more risky.

For example in my opinion some of the most promising are EGFR and
PDGFR-β inhibitors.

Apparently EGFR inhibitors like gefitinib can actually reverse established tolerance, which is exciting, but it is technically a chemo drug and accordingly “As gefitinib is a selective chemotherapeutic agent, its tolerability profile is better than previous cytotoxic agents. Adverse drug reactions (ADRs) are acceptable for a potentially fatal disease.”

For me though I’m definitely going to be working on getting it.


Opiate tolerance seems to work through a plethora of different mechanisms, and it’s my view that to really have a chance to reverse/prevent it, a multi pronged approach is needed, hitting it from all angles.

Something I never understood is why pain patients are not prescribed tolerance blocking medications with a good safety profile.

For example if a doctor is going to prescribe 10mg of oxycodone every 4-6 hours, they should also prescribe ultra low dose naltrexone and proglumide to be taken before each dose, while cycling the proglumide 5 days on 7 days off. An NMDA antagonist should be added as well, such as agmatine sulfate. This would not only prevent tolerance, increase potency and keep the medications effective, it would prevent opioid induced hyperalgesia and increase the effectiveness of the medication for neuropathic pain.

It blows my mind that this isn’t a common protocol considering those three things have a good safety profile, have been essentially proven to be effective in most cases, and are cheap and easy to manage. The benefits seem to far outweigh any potential detriment, which leaves me confused.

 

[Coralopiate]

I’m thinking about adding in the Mr. happy stack, however it seems that it can potentially reduce opioid euphoria; “In vivo microdialysis demonstrated that uridine reversed morphine-induced dopamine release in the dorsal striatum of morphine-sensitized mice” https://pubmed.ncbi.nlm.nih.gov/25088943/

Seems like this may be something that would be reversed by stopping uridine, but still concerning.

It does seem like it could help potentially repair my broken reward system, but I wish that study showed the opposite.

Looking further, it seems ibudilast also may reduce reward, making me hesitant to add it. Probably going to need much more research on both of these before I’ll feel comfortable taking them.

Very sadly, finding studies that show a certain substances increases DA release, conditioned place preference, or any other increase in reward is difficult because I’m theory it makes opiates more addictive, which is the opposite of what most of these researchers are looking for.

Some promising information though is that ultra low dose naltrexone apparently was shown to reduce reward in mice as well, however in humans it doesn’t seem to reduce euphoria or reward at all and may even potentiate it.


BPC-157 is another substance I’ve been looking at, but I’ve seen a few anecdotal reports of people experiencing a reduction in not just opioid euphoria but euphoria from many different substances.

It seems to get better after a few months, but it’s very concerning. Sad because it does seem like it has potential to heal.

For healing dopaminergic/reward system 9-me-be definitely seems to be the most interesting. It’s been shown to actually heal DA neurons after significant damage, and has a variety of other beneficial effects.

It’s being looked at as a treatment for Parkinson’s, and seems relatively safe.

There are some neurotoxicity issues I’ve seen brought up, but from what I can tell as long as it is synthesized correctly, and doses are kept moderate, there shouldn’t be a problem.

If this works I’m going to be so grateful to be alive.

 

[negrogesic]

Hi everyone,

I won’t go into my whole story here, but here are the most important parts:

Without opioids I am unable to function, essentially bedbound.

I made the biggest mistake of my life and binged on what I thought was heroin, and turned out to be fentanyl.

I got to the point where no amount of opiates do anything.

After a short break, my tolerance seemed to be reduced, I was nodding off, but there was no pain relief/pleasurable feelings whatsoever. It seems as though opioids no longer release dopamine in me for whatever reason. Sadly it seems this could be very connected to the analgesic effect, because both the euphoria and analgesia are both gone.

No matter what dose I take, the most I get is sedation, nodding and itching.

I overdose before I feel anything good.

Due to my situation, I qualify for euthanasia in certain countries, but that’s my real last resort. I’m trying everything I can before that.

Countless hours of research have led to me collecting a list of substances that can supposedly reduce opioid tolerance, as well as those that can help with dopaminergic recovery.

I am going to once again try detoxing, going off all opiates, and following this plan.

On day 6 I will start naltrexone. I’m not sure whether it’ll be low dose at 4.5mg or a regular 50mg. Seems the 50mg might be better for my purpose of lowering tolerance/healing opioid receptors.

During my period of abstinence, I will begin taking the following substances. I’ll be introducing one at a time, giving each one about a week to a week and a half to gauge side effects/etc.

Each of these has either research showing it can prevent and/or reverse opioid tolerance, showing it can heal/restore the dopaminergic system/receptors/etc. or has anecdotal evidence from multiple separate people affirming benefit in one of these areas.

I have most of these now, which are the ones I’m starting with:


Cerebrolysin
9-me-bc
bromantane
4-DMA-7,8-DHF
Corydalis
Theracumin
Metformin
Aniracetam
Oxytocin
Taurine
Ibudilast
Proglumide (cycled; 2 days on, 5 days off)
Megadose vitamin C (one dose/3 weeks)
Ketamine (one treatment every 1-2 months)
Mesenchymal stem cells, intrathecal and IV (one treatment every 1-2 months)
EGCG
Agmatine sulfate (cycled; 2 days on, 5 days off)
ALCAR
Probiotics
Ibogaine flood dose (maybe a month or so in)
Simvastatin
Pioglitazone
Resveratrol
Quercetin
Palmitoylethanolamide
Melatonin


Some others I will add after doing more research on them and ensuring I have a viable option:

Endothelin-A receptor antagonists (maybe ambrisentan)
CGRP antagonists
TLR4 antagonists
CaMKII inhibitor (maybe trifluoperazine)
PKA and PKC inhibitors
dasatinib
Glycine antagonists, nitric oxide synthase inhibitors
Spironolactone
Enkalphin Inhibitors
NK1 antagonists
Ceftriaxone
Disulfiram (Antabuse)
dehydroepiandrosterone sulfate
CRF-antagonists (maybe Antalarmine)
imatinib (PDGFR-β inhibitor)
FLT3 inhibitors (maybe Isoliquiritigenin)
EGFR inhibitors
Salvinorin A
Hsp90 inhibitors
Sigma Antagonists
EGFR inhibitors
PDGFR-β inhibitors

Many of these do have some scary potential side effects. The list includes chemotherapy drugs, certain antipsychotics, etc.

For me personally however the risk/benefit ratio is clear — considering I’ll either find a solution and be able to live/function, or I won’t.

This full process of abstinence and adding in the substances will likely take at least 3 months, if not longer.

I’ll be getting intrathecal and IV mesenchymal stem cell infusions likely around once a month.

I’ll also be getting ketamine infusions possibly at the same rate depending on my talk with the center.

Once I’m done and ready to try an opiate, I’ll be adding the following before consumption (along with everything else I’ve added in over the previous months):

Ultra low dose naltrexone, possibly around 10 micrograms but I need to do more research

DL-phenylalanine

magnesium L-threonate

I’ll likely do an infusion of ketamine and stem cells the day before.

I may add a microdose of ibogaine, but need to research this more.

At this point, all I can do is pray and take my prescription.

After a month, if I can stay stable on my dose and function again, it’ll be a huge success and would pretty much save my life.

This is going to be the hardest thing I’ve ever done, but hopefully it’ll be worth it.

I guess one question comes to mind: what specifically are you trying to restore through this exhaustive effort, the analgesic effects of opioid or the rewarding (euphoric) effects? They are intertwined of course, but also a bit different.

In any event, that is quite the list, with some of those substances carrying some heavy side-effects.

Perhaps while you're at it you might as well include testosterone to the list:

The role of testosterone in mu-opioid receptor expression in the trigeminal ganglia of opioid-tolerant rats - PubMed

Although tolerance serves as a major limitation in the long-term clinical use of opioids in patients with chronic severe pain, mechanisms of opioid tolerance are poorly understood. In this study, a morphine tolerance model was established by subcutaneously injecting male rats with morphine (10...

pubmed.ncbi.nlm.nih.gov

 

[Cult315]

I guess one question comes to mind: what specifically are you trying to restore through this exhaustive effort, the analgesic effects of opioid or the rewarding (euphoric) effects? They are intertwined of course, but also a bit different.

In any event, that is quite the list, with some of those substances carrying some heavy side-effects.

Perhaps while you're at it you might as well include testosterone to the list:

The role of testosterone in mu-opioid receptor expression in the trigeminal ganglia of opioid-tolerant rats - PubMed

Although tolerance serves as a major limitation in the long-term clinical use of opioids in patients with chronic severe pain, mechanisms of opioid tolerance are poorly understood. In this study, a morphine tolerance model was established by subcutaneously injecting male rats with morphine (10...

pubmed.ncbi.nlm.nih.gov

From the sounds of it both. What I’ve taken from the post is he’s very ill(and clearly in a ton of pain) leaving him bedridden which is likely also causing severe depression so he needs the meds to work for pain for one, and also make him feel good so he can actually function in life.

I can only imagine whatever ails him is very serious given the actual pharmacy worth of meds he’s trying to take, so I can see needing to feel good as well as pain management be a necessity.

 

[stom10]

With those lists as big as they are, you didn't consider memantine? Or did you consider and reject it?. I suppose the agmatine and ketamine might cover lots of the same ground...