recyclethepandas
Greenlighter
- Joined
- Aug 11, 2013
- Messages
- 40
there are plenty of these studies if you search ncib, but here's a good and simple pdf source: http://www.paintrials.com/publications/capasso8.pdf
as a recovering and previously broke heroin addict, for a long time i was interested in potentiation of opiates. i was also interested in mitigating my withdrawal symptoms. for the first time in history, scientists have found a method of potentiation whose mechanism involves decreasing tolerance, rather than inhibiting the function of cytochrome enzymes or using other drugs unrelated to opiates to compound the high with their own effects. this method involves using opioid antagonists. for many years, scientists have known that opioid antagonists can precipitate withdrawal in opiate dependent individuals. in fact, large doses of naloxone can even precipitate withdrawal from endogenous peptides and endogenous morphine (yes, morphine has been discovered to be produced in the human brain) in users who have never even touched exogenous opioids. basically, we've always known that withdrawal decreases tolerance. anyone who's ever kicked opes knows that after a 30 day period of abstinence, much less drug is required to attain the same high that one used to get from large doses. however, no studies were ever attempted with ultra-low doses of antagonists. the scientists assumed that antagonists followed the same kind of dose-response curve that agonists do. that is, an ultra-low dose of an antagonist will produce an ultra-low, or nonexistent, incidence of antagonism. but recent studies have highlighted the mechanisms by which tolerance can be reduced without precipitating massive withdrawal with regular doses of an antagonist. they also highlight the mechanism by which the human brain moderates tolerance to its own opioid peptides.
essentially, releases of µ opioid receptor agonists, like beta-endorphin, produce a negative feedback loop which effectively moderates tolerance to the original substance itself. interestingly, µ opioid agonism produces an indirect release of sigma, kappa, and delta agonists, which seem to 'reset' the neurons' feedback to µ opioid agonists. by this mechanism, not only does the brain prevent tolerance to its own painkillers, but the brain prevents addictive responses to stress and injury. when we are injured or extremely stressed, obviously the brain releases massive amounts of µ endorphins and morphine itself so that the body does not die from shock. but if this were the only mechanism involved, you would see humans and animals chronically and compulsively hurting themselves or walking into stressful situations in search of the opiate high that will follow. the mechanism i just described comes into play shortly after the µ opioid receptor (MOR) agonism prevents shock and agony. the brain releases dynorphins, which are highly selective for the kappa opioid receptor (KOR). these chemicals decrease the dopamine release caused by beta-endorphin, which acts as a negative feedback loop on the pleasure generated by MOR agonism. in addition to this, their agonism for the kappa opioid receptor induces dysphoria as well as analgesia. in this regard, dynorphins act as dysphoric opiates. they produce the same analgesia, but they do not produce the euphoric high, actually counterbalancing the euphoric high of beta-endorphin. other endorphins exist which provide similar mechanisms affecting the delta and sigma receptors, but these are of less importance. the dysphoria caused by dynorphins creates negative emotional feedback, so that the brain can associate the event with dysphoria. this mechanism, scientists theorize, is what gives us the motivation to not get hurt, and the fear of stressful situations. without this mechanism, we wouldn't mind getting our legs chopped off because we'd be super loaded. thus, the endorphin mechanism moderates its own addiction. in addition to providing this negative feedback loop, poorly understood mechanisms involving agonism at the KOR work to resensitize the MOR to beta-endorphin. this way, the biochemical process can occur again and again, every time the animal gets hurt.
when you bring exogenous opioids (hydrocodone, oxycodone, diacetylmorphine, etc) into the picture, the same mechanism comes into play. however, such massive MOR agonism causes massive releases of dynorphins to counterbalance the euphoria. this is believed to be one of the primary reasons for tolerance to the dopaminergic effects of opioids - remember that dynorphins reduce dopamine release. but these massive releases of dynorphins are only enough to counterbalance the effects of endogenous opioid peptides like beta-endorphin. the brain and spinal cord do not store enough dynorphin to counterbalance recreational abuse of opioids. low doses, sure, but the massive doses that we addicts use will throw the entire system off balance. the MORs are being agonized at much higher proportions relative to the KORs, which causes the neurons to effect a more long-term form of tolerance. the neurons begin to downregulate their MORs, in a desperate attempt to rebalance the feedback loop. now, with fewer MORs, the brain is less capable of perceiving the high produced by exogenous opioids, as well as the analgesia produced by endorphins. this is why long-term heroin addicts, even after recovering and abstaining, experience depression, anxiety, and hypersensitivity to pain. we are tolerating our bodies' own defense against pain and stress.
this alone should act as enough deterrent from using exogenous opioids. if you like getting high on opiates, don't do it. because you won't be able to get high for long, and when you stop, you will be unable to get high off your own endorphins. in other terms, when you stop using, you don't feel the same way you did before you started using. you are much more sensitive to pain and anxiety. take it from me, it fucking sucks. however high you think you're going to get, that's exactly how low you will feel after your stint with addiction reaches its end. anyway, i didn't mean this to be a lecture. back on topic. for a while, the opioid addicts who understand the biochemistry have had the unfortunate realization that it will take many years for their tolerance to return and their post-acute withdrawal syndrome to go away. this has led a great many people, including me, to get on long-term suboxone maintenance. only on suboxone do we seem to feel normal again. but these new studies regarding low dose antagonists provide the interesting idea that you can speed up the recovery process. basically, when it comes down to the biochemistry, tolerance, dependence, and withdrawal are multiple sides to the same coin. they are pretty much the same thing. the reason we experience withdrawal is because our brain tolerates our endorphins. we have assimilated the exogenous opioids into our neurological biochemical processes, meaning that our endorphins are not enough to maintain homeostasis. this tolerance to our own chemicals produces the withdrawal symptoms. fear of the withdrawal symptoms produces psychological dependence, while the lack of agonism necessary to produce the processes that our neurons have grown accustomed to produces the physical dependence. so you can see that these three terms are actually different words for the same process. this being true, scientists wanted to apply to exogenous opioid dependence the same negative feedback loop that our brain uses to mitigate tolerance to endogenous opioids. they figured, logically, that if the brain can prevent tolerance by balancing out MOR agonism with MOR antagonism and/or KOR agonism, that we can prevent early opioid users from developing tolerance if we balance out the increased MOR agonism with increased MOR antagonism. obviously, if you put proportional amounts of MOR agonists and MOR antagonists of equal affinity into the brain, it won't experience a high at all. even worse, since MOR antagonists usually have a higher affinity than agonists, the agonists won't be able to compete and the brain will actually experience precipitated withdrawal. but they wondered what would happen if you induced ultra-low antagonism long term, so that one by one each receptor in the brain would be antagonized enough to mitigate tolerance without producing a brain-wide antagonism which would cause withdrawal. i don't have the full story on this specific aspect of the concept. these studies are very recent, and the mechanisms they have implicated have not been fully researched, let alone introduced to clinical rigor. all of these studies were done in vitro. but i have attempted to test it using myself as the rat, or in this case, slice of brain tissue. being a sufferer or severe chronic pain from foraminal spinal closure, i don't just use suboxone to stay well. i even got off suboxone for long enough to get through the withdrawal and most of the post-acute withdrawal syndrome. but i still suffered severe pain in my back and left shoulder. so when i read these studies, of course i wasn't gonna sit around and wait for this shit to be put into practice. i have a prescription for naltrexone. i chipped off the tiniest grain imaginable, diluted it in water, and eyedropped a tiny drop (being a fraction of the grain i started with) under my tongue. after holding it there for 20 minutes, i swallowed. then i took my suboxone dose. when i started suboxone to get off heroin, i was on 16-24mg a day, depending on how i felt. after i stopped suboxone and got clean for a while, as i described earlier, i returned to bupe, using only 1mg a day, because i never want to experience those harsh withdrawals again. obviously this barely affected me. i've been on 1mg since. so i've been doing this naltrexone thing for a while. the study uses picomolar concentrations of naltrexone, which i sure as hell can't measure. but i figured what could the harm be in taking a tiny dose each day, regardless of how many millionths of a mole it turns out to equal. obviously, i never experienced precipitated withdrawal from such a low dose. literally nothing happened. for about 3 weeks. and then, progressively, my suboxone started to feel stronger. i started to actually feel moderate analgesia and paraesthesia when i closed my eyes and meditated. it wasn't long before i was sleeping like a baby every night. i shared this story with a friend of mine, who used to shoot dope with me. nowadays, he has promised himself never to go back to heroin, but he still abuses painkillers. he just doesn't shoot them, snort them, smoke them, plug them, etc. all he does is swallow. he wanted to try my technique, so i gave him a vial that i had prepared just like my own. very very tiny amount of naltrexone. worth virtually nothing. he did the same kind of trial that i did. now this is a guy who swallows 300-400mg of morphine and barely catches a buzz. i haven't done any regular opioid agonists since i started using naltrexone with my suboxone, so i can't verify this myself, but he says after a month of using the naltrexone he started to get pretty loaded off his usual dose of morphine.
i recommend this strategy to anyone struggling to get off opiates. it can be terrifying to anticipate withdrawal. if you've ever gone through it, you know what i mean. and the post acute symptoms can be horrible. even if you or your family drops a fat wad and you get weismann method treatment so you're knocked out for the acute withdrawal, you're still scared as hell of the anxiety, depression, lethargy, and insomnia that you're in for for the next few months. how fast you recover is basically dependent on how fast your brain can upregulate its MORs, upregulate its production of GABA, and downregulate its release of norepinephrine. all of these things can be sped up by taking naltrexone. high doses are believed to work faster, but they make you feel like shit. it is prescribed on label for this purpose, so naltrexone should be easy to obtain, and cheap if you have insurance.
for anyone who's not addicted yet, but wants to prevent tolerance and dependence, this is theoretically the way to do it. don't fuck with cimetidine or grape fruit juice, and especially don't fuck with benzos for potentiation. nothing potentiates opiates like MORE OPIATES. and inhibiting your liver enzymes is dangerous. CYP3A4 is necessary for metabolizing all kinds of chemicals in your body. inhibiting it is toxic to your liver, and can actually increase plasma concentration of other neurotransmitters that might make you feel like shit, i.e. dysphoric, sick, anxious. this would be the way to do it. just seek out an addiction specialist, tell em you're getting off dope and you'd like to try naltrexone. they might even give you some suboxone, which if you have a low tolerance can actually probably get you pretty loaded.
as a recovering and previously broke heroin addict, for a long time i was interested in potentiation of opiates. i was also interested in mitigating my withdrawal symptoms. for the first time in history, scientists have found a method of potentiation whose mechanism involves decreasing tolerance, rather than inhibiting the function of cytochrome enzymes or using other drugs unrelated to opiates to compound the high with their own effects. this method involves using opioid antagonists. for many years, scientists have known that opioid antagonists can precipitate withdrawal in opiate dependent individuals. in fact, large doses of naloxone can even precipitate withdrawal from endogenous peptides and endogenous morphine (yes, morphine has been discovered to be produced in the human brain) in users who have never even touched exogenous opioids. basically, we've always known that withdrawal decreases tolerance. anyone who's ever kicked opes knows that after a 30 day period of abstinence, much less drug is required to attain the same high that one used to get from large doses. however, no studies were ever attempted with ultra-low doses of antagonists. the scientists assumed that antagonists followed the same kind of dose-response curve that agonists do. that is, an ultra-low dose of an antagonist will produce an ultra-low, or nonexistent, incidence of antagonism. but recent studies have highlighted the mechanisms by which tolerance can be reduced without precipitating massive withdrawal with regular doses of an antagonist. they also highlight the mechanism by which the human brain moderates tolerance to its own opioid peptides.
essentially, releases of µ opioid receptor agonists, like beta-endorphin, produce a negative feedback loop which effectively moderates tolerance to the original substance itself. interestingly, µ opioid agonism produces an indirect release of sigma, kappa, and delta agonists, which seem to 'reset' the neurons' feedback to µ opioid agonists. by this mechanism, not only does the brain prevent tolerance to its own painkillers, but the brain prevents addictive responses to stress and injury. when we are injured or extremely stressed, obviously the brain releases massive amounts of µ endorphins and morphine itself so that the body does not die from shock. but if this were the only mechanism involved, you would see humans and animals chronically and compulsively hurting themselves or walking into stressful situations in search of the opiate high that will follow. the mechanism i just described comes into play shortly after the µ opioid receptor (MOR) agonism prevents shock and agony. the brain releases dynorphins, which are highly selective for the kappa opioid receptor (KOR). these chemicals decrease the dopamine release caused by beta-endorphin, which acts as a negative feedback loop on the pleasure generated by MOR agonism. in addition to this, their agonism for the kappa opioid receptor induces dysphoria as well as analgesia. in this regard, dynorphins act as dysphoric opiates. they produce the same analgesia, but they do not produce the euphoric high, actually counterbalancing the euphoric high of beta-endorphin. other endorphins exist which provide similar mechanisms affecting the delta and sigma receptors, but these are of less importance. the dysphoria caused by dynorphins creates negative emotional feedback, so that the brain can associate the event with dysphoria. this mechanism, scientists theorize, is what gives us the motivation to not get hurt, and the fear of stressful situations. without this mechanism, we wouldn't mind getting our legs chopped off because we'd be super loaded. thus, the endorphin mechanism moderates its own addiction. in addition to providing this negative feedback loop, poorly understood mechanisms involving agonism at the KOR work to resensitize the MOR to beta-endorphin. this way, the biochemical process can occur again and again, every time the animal gets hurt.
when you bring exogenous opioids (hydrocodone, oxycodone, diacetylmorphine, etc) into the picture, the same mechanism comes into play. however, such massive MOR agonism causes massive releases of dynorphins to counterbalance the euphoria. this is believed to be one of the primary reasons for tolerance to the dopaminergic effects of opioids - remember that dynorphins reduce dopamine release. but these massive releases of dynorphins are only enough to counterbalance the effects of endogenous opioid peptides like beta-endorphin. the brain and spinal cord do not store enough dynorphin to counterbalance recreational abuse of opioids. low doses, sure, but the massive doses that we addicts use will throw the entire system off balance. the MORs are being agonized at much higher proportions relative to the KORs, which causes the neurons to effect a more long-term form of tolerance. the neurons begin to downregulate their MORs, in a desperate attempt to rebalance the feedback loop. now, with fewer MORs, the brain is less capable of perceiving the high produced by exogenous opioids, as well as the analgesia produced by endorphins. this is why long-term heroin addicts, even after recovering and abstaining, experience depression, anxiety, and hypersensitivity to pain. we are tolerating our bodies' own defense against pain and stress.
this alone should act as enough deterrent from using exogenous opioids. if you like getting high on opiates, don't do it. because you won't be able to get high for long, and when you stop, you will be unable to get high off your own endorphins. in other terms, when you stop using, you don't feel the same way you did before you started using. you are much more sensitive to pain and anxiety. take it from me, it fucking sucks. however high you think you're going to get, that's exactly how low you will feel after your stint with addiction reaches its end. anyway, i didn't mean this to be a lecture. back on topic. for a while, the opioid addicts who understand the biochemistry have had the unfortunate realization that it will take many years for their tolerance to return and their post-acute withdrawal syndrome to go away. this has led a great many people, including me, to get on long-term suboxone maintenance. only on suboxone do we seem to feel normal again. but these new studies regarding low dose antagonists provide the interesting idea that you can speed up the recovery process. basically, when it comes down to the biochemistry, tolerance, dependence, and withdrawal are multiple sides to the same coin. they are pretty much the same thing. the reason we experience withdrawal is because our brain tolerates our endorphins. we have assimilated the exogenous opioids into our neurological biochemical processes, meaning that our endorphins are not enough to maintain homeostasis. this tolerance to our own chemicals produces the withdrawal symptoms. fear of the withdrawal symptoms produces psychological dependence, while the lack of agonism necessary to produce the processes that our neurons have grown accustomed to produces the physical dependence. so you can see that these three terms are actually different words for the same process. this being true, scientists wanted to apply to exogenous opioid dependence the same negative feedback loop that our brain uses to mitigate tolerance to endogenous opioids. they figured, logically, that if the brain can prevent tolerance by balancing out MOR agonism with MOR antagonism and/or KOR agonism, that we can prevent early opioid users from developing tolerance if we balance out the increased MOR agonism with increased MOR antagonism. obviously, if you put proportional amounts of MOR agonists and MOR antagonists of equal affinity into the brain, it won't experience a high at all. even worse, since MOR antagonists usually have a higher affinity than agonists, the agonists won't be able to compete and the brain will actually experience precipitated withdrawal. but they wondered what would happen if you induced ultra-low antagonism long term, so that one by one each receptor in the brain would be antagonized enough to mitigate tolerance without producing a brain-wide antagonism which would cause withdrawal. i don't have the full story on this specific aspect of the concept. these studies are very recent, and the mechanisms they have implicated have not been fully researched, let alone introduced to clinical rigor. all of these studies were done in vitro. but i have attempted to test it using myself as the rat, or in this case, slice of brain tissue. being a sufferer or severe chronic pain from foraminal spinal closure, i don't just use suboxone to stay well. i even got off suboxone for long enough to get through the withdrawal and most of the post-acute withdrawal syndrome. but i still suffered severe pain in my back and left shoulder. so when i read these studies, of course i wasn't gonna sit around and wait for this shit to be put into practice. i have a prescription for naltrexone. i chipped off the tiniest grain imaginable, diluted it in water, and eyedropped a tiny drop (being a fraction of the grain i started with) under my tongue. after holding it there for 20 minutes, i swallowed. then i took my suboxone dose. when i started suboxone to get off heroin, i was on 16-24mg a day, depending on how i felt. after i stopped suboxone and got clean for a while, as i described earlier, i returned to bupe, using only 1mg a day, because i never want to experience those harsh withdrawals again. obviously this barely affected me. i've been on 1mg since. so i've been doing this naltrexone thing for a while. the study uses picomolar concentrations of naltrexone, which i sure as hell can't measure. but i figured what could the harm be in taking a tiny dose each day, regardless of how many millionths of a mole it turns out to equal. obviously, i never experienced precipitated withdrawal from such a low dose. literally nothing happened. for about 3 weeks. and then, progressively, my suboxone started to feel stronger. i started to actually feel moderate analgesia and paraesthesia when i closed my eyes and meditated. it wasn't long before i was sleeping like a baby every night. i shared this story with a friend of mine, who used to shoot dope with me. nowadays, he has promised himself never to go back to heroin, but he still abuses painkillers. he just doesn't shoot them, snort them, smoke them, plug them, etc. all he does is swallow. he wanted to try my technique, so i gave him a vial that i had prepared just like my own. very very tiny amount of naltrexone. worth virtually nothing. he did the same kind of trial that i did. now this is a guy who swallows 300-400mg of morphine and barely catches a buzz. i haven't done any regular opioid agonists since i started using naltrexone with my suboxone, so i can't verify this myself, but he says after a month of using the naltrexone he started to get pretty loaded off his usual dose of morphine.
i recommend this strategy to anyone struggling to get off opiates. it can be terrifying to anticipate withdrawal. if you've ever gone through it, you know what i mean. and the post acute symptoms can be horrible. even if you or your family drops a fat wad and you get weismann method treatment so you're knocked out for the acute withdrawal, you're still scared as hell of the anxiety, depression, lethargy, and insomnia that you're in for for the next few months. how fast you recover is basically dependent on how fast your brain can upregulate its MORs, upregulate its production of GABA, and downregulate its release of norepinephrine. all of these things can be sped up by taking naltrexone. high doses are believed to work faster, but they make you feel like shit. it is prescribed on label for this purpose, so naltrexone should be easy to obtain, and cheap if you have insurance.
for anyone who's not addicted yet, but wants to prevent tolerance and dependence, this is theoretically the way to do it. don't fuck with cimetidine or grape fruit juice, and especially don't fuck with benzos for potentiation. nothing potentiates opiates like MORE OPIATES. and inhibiting your liver enzymes is dangerous. CYP3A4 is necessary for metabolizing all kinds of chemicals in your body. inhibiting it is toxic to your liver, and can actually increase plasma concentration of other neurotransmitters that might make you feel like shit, i.e. dysphoric, sick, anxious. this would be the way to do it. just seek out an addiction specialist, tell em you're getting off dope and you'd like to try naltrexone. they might even give you some suboxone, which if you have a low tolerance can actually probably get you pretty loaded.
