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Pharmacology - Opioid Tolerance: Reversing Receptor Sensitivity

Discussion in 'Opiates & Opioids' started by fiveleggedrat, Oct 11, 2008.

  1. fiveleggedrat

    fiveleggedrat Palladium Member

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    So Swim's been hitting the books lately, and studying lots of medical papers that he'll get to uploading later. He is trying to find a way to reduce the permanent tolerance he has gained, even after taking breaks for months from opioids. He no longer gets ANY euphoria from opioids, and tramadol just completely stopped working.

    This all focuses strongly on the Mu receptor. Not interested in playing with K or Delta or any other receptors, since euphoria is tied mostly to the Mu receptor.

    So I have 3 theories so far:

    1) 50mg naltrexone daily regiment (While sober, obviously!) for 1-2 weeks. This in theory would sensitize receptors. Most papers I read say that people often OD when coming off an antagonist, although that could be just from lack of physical tolerance. I am very certain of this theory and that blasting the brain the naltrexone for a while would make it sensitive again to endorphins, and therefore, opioids. Cheap to test.

    Edit: This idea centers on the use of an antagonist in general. Naltrexone seems like the best choice so far. Also, the 50mg dose is speculation based on what I have read.

    2) iNOS inducible inhibition. (inducible nitric oxide synthase inhibition). Not even going to attempt to explain this, it's complicated. I'll go in-depth into all 3 of these options later, explaing why I think they would work. More or less, sounds to prevent regulation of the mu receptor. This one sounds good on paper, but would be very expensive to test.

    3) Using NMDA antagonists to temporarily or perm. reduce tolerance. Learned about this one studying receptors and neurotransmitters. Cheap to test common ones like DXM and n2o but Swim wants to test this with MK-801. Too bad it's rare and expensive.

    Anyone have any opinions/thoughts?
     
    Last edited: Oct 13, 2008
  2. W!SE

    W!SE Newbie

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    I would like to know WHERE he could get some naltrexone + the other 2 You mentioned above .. as well as HOW (what to say, etc.)

    gracias
     
  3. chillinwill

    chillinwill Newbie

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    well naltrexone is commonly prescribed for both alcohol and opiate dependency so incorporating that fact with a doctor might be a problem if you don't want them to know about you using
     
  4. W!SE

    W!SE Newbie

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    what..the fuck

    anything else that's over the counter ? my friend isnt that desperate .he will start exercising daily today
     
  5. biggpri

    biggpri Silver Member

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    swim may be wrong here, but isn't nitric oxide potentially toxic to people. it's used for industrial purposes, and is not the same thing as nitrous oxide. I was under the impression that it should rarely, if ever, be used by humans. again, swim may be wrong here, but thought a warning would be helpful.
     
  6. fiveleggedrat

    fiveleggedrat Palladium Member

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    Nitric oxide is produced in the brain naturally and is involved in signal transmission, or something along those lines.

    Yes, I do believe nitric oxide is not safe to put into the body, but what I mention is something to interact with nitric oxide in the brain that's already there.
     
  7. RoboCodeine7610

    RoboCodeine7610 Silver Member

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    I like the natreloxone idea, since hes always wandered the same thing:If one were to take an opioid antagonist for a while and develop a tolerance to it, wouldn't that make an opioid agonist much stronger?
    Nice research fiveleggedrat.
    Robo
     
  8. fiveleggedrat

    fiveleggedrat Palladium Member

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    Swim ended up looking all this up mad as hell that opioids don't cause euphoria anymore, and his doses have gone 2x-4x what they used to be. No one can really explain Swim's mental tolerance. I use 1-2 times monthly, and usually misses at least one of those times due to lack of opioids, so when Swim gets them and they don't do much besides a mild buzz and mild CNS depression, Swim wants answers.

    Besides, many others stand to benefit from this. Can we imagine if those who are actually in pain and suffering and taking opioids for pain, and stuck on insane dose regiments could renew their tolerance like a opioid naive? That would be some amazing information.

    I am amazed by the idea of taking someone on 240mg oxycodone daily and getting them back on 20mg and having it work, only having to do some type of "tolerance therapy" every now and then to get tolerance down.

    I know such a concept is certainly farfetched, but I really am calling for more research on the actual mechanisms of tolerance and interacting with brain chemistry, as opposed to "potentiators", which have been a joke for Swim.

    fiveleggedrat added 5 Minutes and 49 Seconds later...

    Oh yeah, Swim combined 50mg DXM with a 10mg hydromorphone rectal dose a few days ago. Of course, the DXM was oral. Combined 20 minutes in advance.

    Result: No change. I got a considerable buzz from that 50mg, actually, and significant pupil dilation for about 10 minutes. Went back to normal quickly. Swim hesitated to add more, and ruin his hydromorphone by being too "spaced out" from the DXM, a substance Swim never has a good experience with.

    And lastly, for reference, check this out: Swim used hydromorphone 1 week, and dose was 8mg rectal. Pretty darn good, even with no euphoria. Swim used ONE WEEK LATER, exactly. Result? I did 8 and got a buzz. Swim dropped another 8, and still, lame. I wasted 16mg rectal with the same exact conditions. Swim even added 25mg promethazine. How can swim do 8 one week and be good, and next week, 16 feels like 4, maybe 6? Why?

    This is the insane Mental tolerance Swim bitches about all day.
     
    Last edited: Oct 14, 2008
  9. medievil

    medievil Silver Member

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    Ultra low dose naltrexone looks most promosing, regular doses of naltrexone arent neceserry and would probebly make You feel bad
     
  10. fiveleggedrat

    fiveleggedrat Palladium Member

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    Swim certainly does not expect a naltrexone regiment to be pleasant. Swim expects at least some unpleasant side effects.

    I do not, and will not, have the ability to do ULD anything. ULD requires super precise equipment, at least from my understanding. Besides, ULD does not seem to answer the problem. I believe I have read ULD only prolongs the inevitable. I believe ULD is also largely unproven. Any studies here would be great, I'm almost too busy at the moment to find any on my own.

    I'd love for anyone else with theories or ideas on inducing receptor sensitivity to share or speculate.

    Swim even considered MAOIs, and clearly, nothing in common between Swim's goal and combining an MAOI + opioid.

    I know it's laughable, but I am trying to find a believable method that would run under $100 for experimentation. Hence, the leaning towards naltrexone. Only brand name and chem supply is expensive. Generic is much cheaper. About 1/10 as cheaper vs. other suppliers.
     
  11. Psych0naut

    Psych0naut Platinum Member

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    Using an antagonist certainly helps to reset the receptor sensitivity to certain drugs. The Benzodiazepine antagonist Flumazenil is being used in research regarding protracted withdrawl syndrome. The Benzodiazepine protractred withdrawl syndrome is a syndrome where the Benzodiazepine receptors in the brain have been inverted, making them permanently useless, or for the duration of most of one's life. These inverted receptors can't be activated during normal brain situations either, because of them being inverted. This is where the Benzodiazepine antagonist Flumazenil comes into action. It's being used for just a single administration in it's normal dosage to these patients, and like magic, all the Benzodiazepines receptors return to their natural position, making the inverted situation undone, so they can be activated again. So in this situation, the specific antagonist can help to reduce permanent tolerance to a certain drug by a full hundred procent. I assume it would work the same for opioids, with Naloxone or maybe Naltrexone.
     
  12. fiveleggedrat

    fiveleggedrat Palladium Member

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    Excellent information. Perhaps that is Swim's problem, inversion is taking place. Very fascinating, and I have had much difficulty finding information about all this in medical literature. It seems like this phenomenon is not common. Swim's friends certainly cannot understand.

    I am also noticing marijuana having less effects on him as time passes. Could the same be taking place? This is, once again, not a tolerance thing. Also, could the same concept be used? CB antagonists? Or whatever the proper inverse of THC and similar is.

    I am afraid to use ANY drugs anymore, worried his receptors will become tolerant and he will lose effects to everything.

    I chose naltrexone primarily for the long halflife. Naloxone is active for, what, 2 hours? And I don't believe it works orally. I do not needle too. Naltrexone works orally, I know. Swim figures the long activity would be better, comparing it to methadone for building a tolerance quicker than a short acting opioid.

    fiveleggedrat added 1309 Minutes and 8 Seconds later...

    Little question if anyone sees this thread anytime soon: Naltrexone or naloxone? Opinions, please :) Due to a poor researcher (that's Swim), might not be able to do naltrexone for a bit longer, and I am anxious to test this. Considering Naloxone, for cheapness and for the higher Mu affinity. Guess I would have to use a needle for the first time ever :eek:
     
    Last edited: Oct 16, 2008
  13. Matt The Funk

    Matt The Funk Silver Member

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    How easy would it be for SWIM to obtain this in a medical setting? He feels as though his GABA receptors (or something of the sort) may be highly "out of whack" from benzo addiction and prescription use and would like to know if he should simply ask his psychiatrist about this?
    (sorry if this is too off-topic)
     
  14. fiveleggedrat

    fiveleggedrat Palladium Member

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    Not an issue. In a medical setting, it sounds likely difficult. In a self admin setting, from a chem supply company, possible. Then again, I do not know about the drug SwiPsychonaut mentioned; not much information seems to be out there on it.

    My suggest getting the chem name and checking some supply houses. It's likely uncontrolled. Also, I am NOT encouraging illegal behavior or law breaking. Only consider self work if legal in one's area.

    I am very gracious to SwiPsychonaut for that information; it has come in handy for Swim several times already. I have more ideas now and more info to back them up.
     
  15. Cakes

    Cakes Palladium Member

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    this is saying that using an exact antagonist eliminates all withdrawl symptoms?

    In light of Psychonaut's post, it sounds like it might be a very good idea.

    if this part is true then it rather sounds as if SWIM may have answered his own question.

    amazing. absolutely.
     
  16. fiveleggedrat

    fiveleggedrat Palladium Member

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    I have thought intently lately, and decided on naloxone, due to higher Mu receptor affinity and reduced price, and it should be easier to obtain.
     
  17. Cakes

    Cakes Palladium Member

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    If he does, then keep us appraised by all means.
     
  18. fiveleggedrat

    fiveleggedrat Palladium Member

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    Swim just spent about the past several days on the net looking for both naloxone and naltrexone, in both pharm form and pure chemical form; Swim can find a supplier of neither (Swim must either A) have a script B) Chem licenses or C) Have assorted medical licenses)

    Looks like Swim can't even do this study now. Fuck this stupid fucking nonsense on a substance that saves lives on it's own.

    I do not have money to see some bloated fucking doctor for a prescription, and what's the chance a doctor would script anyways :mad:

    I'm so furious. I've done so much research, and once again, the law is the only thing stopping it's completion.

    And, I can't even ask for help finding a source. Lovely.

    I hate this country. /endrant
     
  19. Psych0naut

    Psych0naut Platinum Member

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    Protracted withdrawl syndrome isn't very common among former Benzodiazepine users, but it certainly isn't unique either, it happens with 10-15% who are withdrawing from Benzodiazepines. For more info about Flumazenil's use in treating the Benzodiazepine protracted withdrawal syndrome, have a look at this article. There are several CBD agonists which are used pharmaceutically, and available for retail. It might be possible obtaining those, although I doubt about it's use in resetting tolerance to cannabis. Tolerance to cannabis is created through a different mechanism.

    By the way, for some reason, I was certainly able to find plenty of info on these subjects, just take a peek in the medical archives of sites like pubmed and medline, and you'll come up with dozens of documents. Having a pharmaceutical background does help though, as acces to most of these archives can only be bought. However, I found an abstract which was free to view. This is exactly what you're looking for, an abstract with a detailed experiment where Naloxone was used to reset opioid tolerance in opioid tolerance patients.

    Flumazenil is only available in ampoule form, for injection, and in ambulant settings. As far as I know, only hospitals have it in stock, doctors certainly don't, and I don't even know if ambulances have. Also, it's only been used experimentally for undoing invertion of the GABA-bz receptors, so asking your psychiatrist about this probaply won't have any use. It might be possible that talking to a sleep specialist in the hospital would yield something though.

    You're welcome, it was my pleasure helping out! :thumbsup:

    Yes, it eliminates all protracted withdrawl symptoms, as well as normal withdrawl symptoms after having stopped taking them. However, it should only be taken after having quit taking benzodiazepines, after having slowly tapered one's dose to nearly zero befores stopping completely. If Flumazenil is used to reduce tolerance to benzodiazepines when still using Benzodiazepines without having tapered, as well as being physically addicted to them, it will cause instant withdrawl.
     
  20. fiveleggedrat

    fiveleggedrat Palladium Member

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    Yeah, Swim's biggest problem is that he often searches with the wrong terms and words. I love pubmed, and sites like that. I use the type of papers there as my main research; most people don't even peruse those types of things for info, so I often find things in them that aren't on here or erowid and such.

    I came up with another theory regarding tolerance; I'll share the raw info on the substance/method here:

    Check that shit out! Haha. Yeah, I probably won't explore this method, at least not first.

    Thanks for that paper SwiyPsych0naut. You rock! It's a darn shame no one else even bothers helping me out with this. You'd think this would be of importance to someone other than Swim with his goofy broken receptors.
     
    Last edited: Oct 18, 2008