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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 16 of 16. This is the beginning of the thread.
Posted by jlbl2l on May 9, 2004, at 11:00:20
Neurontin, for me has had the "poop out" or tolerance effect only after just a few weeks use. Then, i tried it again 4 months later, and it worked again..! But Yet again, it has pooped out and stopped working recently after only 2 weeks time. I am dumbfounded onto why this occurs. So i decided to expierment. Knowing both a lot about neurontin's mech of action and benzo's mech's of action, i decided to test some possible theories.
Today, I took klonopin. Once i felt the klonopin kick in, i took the neurontin (neurontin had totally pooped out at this point - i tried 3600mg to no avail days before this) anyways - when i added the neurontin after taking the klonopin, i noticed that neurontin's effects were established again (which I can readily identify from klonopin). The dosage was 1500mg. This is leading me to various theories on why neurontin "poops out".
I want to know why neurontin poop's out or a user gains tolerance. If it has to do with calcium channels etc, id love to get into that. Ive thought of various ways to stop this poop out effect.
The fact that 4 months ago it pooped out (i thought i had just gained tolerance and it would never work again) but then i decided to try it again - and to my surprise 4 months later it worked just like originally. It seems that it doesn't have tolerance, but perhaps I am overloading my system to much, therefore depleting glutamine and the production of gaba? So I thought maybe adding glutamine in may stop the poop out effect totally. Then again, what about the calcium channels (the way neurontin works). Perhaps there is some sort of inborn feedback mech. to prevent this kind of thing itself, how could i reverse that? Add calcium to my diet, or the reverse, magnseum?
chemist, anyone suggestions?
jlbl2
Posted by jlbl2l on May 9, 2004, at 11:02:48
In reply to neurontin poop out after awhile, fixable, chemist?, posted by jlbl2l on May 9, 2004, at 11:00:20
has anyone had success in any form of reversing the poop out or tolerance to neurontin if you experienced it.
thanks
jlbl2l
Posted by Kon on May 9, 2004, at 15:14:13
In reply to neurontin poop out after awhile, fixable, chemist?, posted by jlbl2l on May 9, 2004, at 11:00:20
This wasn't adressed to me but I thought I'd post because I've very interested in this topic. I believe this is the norm with many drugs...taking a "drug holiday" often restores drug effect (ie. reverses tolerance or poop-out). Not sure if tolerance over the long-term develops faster with repeated cycling of drug. Based on my limited experience with tolerance to sedation side-effect of benzos, I think it may occur faster with repeated cycling of a drug.
I have read of recommendations for cycling neurontin and klonopin to prevent tolerance/poop-out. They recommend using klonopin until tolerance develops to it, then switch to a different class of drugs like neurontin and stay on it until tolerance/poop-out occurs then switch back to klonopin...keep repeating cycle. From what I've read... the longer the half life, the longer the drug will remain in the body and the longer the drug holiday should be to clear the drug out of one's body. Not sure how accurate this info is or how long cycles should be set based on half-lives???
Curious...what are some of these readily identifiable drug effect differences between neurontin and klonopin that you have?
Posted by chemist on May 9, 2004, at 20:55:43
In reply to neurontin poop out after awhile, fixable, chemist?, posted by jlbl2l on May 9, 2004, at 11:00:20
> Neurontin, for me has had the "poop out" or tolerance effect only after just a few weeks use. Then, i tried it again 4 months later, and it worked again..! But Yet again, it has pooped out and stopped working recently after only 2 weeks time. I am dumbfounded onto why this occurs. So i decided to expierment. Knowing both a lot about neurontin's mech of action and benzo's mech's of action, i decided to test some possible theories.
>
> Today, I took klonopin. Once i felt the klonopin kick in, i took the neurontin (neurontin had totally pooped out at this point - i tried 3600mg to no avail days before this) anyways - when i added the neurontin after taking the klonopin, i noticed that neurontin's effects were established again (which I can readily identify from klonopin). The dosage was 1500mg. This is leading me to various theories on why neurontin "poops out".
>
> I want to know why neurontin poop's out or a user gains tolerance. If it has to do with calcium channels etc, id love to get into that. Ive thought of various ways to stop this poop out effect.
>
> The fact that 4 months ago it pooped out (i thought i had just gained tolerance and it would never work again) but then i decided to try it again - and to my surprise 4 months later it worked just like originally. It seems that it doesn't have tolerance, but perhaps I am overloading my system to much, therefore depleting glutamine and the production of gaba? So I thought maybe adding glutamine in may stop the poop out effect totally. Then again, what about the calcium channels (the way neurontin works). Perhaps there is some sort of inborn feedback mech. to prevent this kind of thing itself, how could i reverse that? Add calcium to my diet, or the reverse, magnseum?
>
> chemist, anyone suggestions?
>
> jlbl2well, Kon's reply seems to indicate, in concert with your experience, that some desensitization of the receptors involved occurs over a certain period of time. this facet is not unique to neurontin/benzos but to many drugs, and the mechanisms (as you both point out) for GABAnergic transmission being increased are different for neurontin and, say, a benzodiazepine such as klonopin. from what i have read and from my own extensive use of benzodiazapines and xanax, it appears as if these drugs don't really ``poop-out'' but rather an escalation in dose - albeit a small one - keeps the effects coming. from what you are saying about neurontin, it just stops working, and i assume (please correct me if i am wrong) that you tried upping the dose of neurontin but to no avail. the mechanism(s) by which neurontin exerts increased GABAbergic transmission are, in my opinion, more circuitous than the benzodiazepenes, and thus the answer is likely to involve more than one neurotransmitter or receptor. in short, i just don't know, and will have a look at the literature, although i am sure you will find that some of the common posters for subjects related to neurontin are a better source, especially in addressing your concern on how to alleviate....all the best, chemist
Posted by Viridis on May 10, 2004, at 0:26:50
In reply to neurontin poop out after awhile, fixable, chemist?, posted by jlbl2l on May 9, 2004, at 11:00:20
The effects of Neurontin wore off after about three days for me. I took it for a long time with no discernable effect whatsoever at any dose (good or bad) My pdoc, who was somewhat enthusiastic at first, now calls it an expensive placebo. But it does seem to keep working for some people. Based on my experience only, I tend to agree with my pdoc.
Posted by zero on May 10, 2004, at 11:23:07
In reply to neurontin poop out after awhile, fixable, chemist?, posted by jlbl2l on May 9, 2004, at 11:00:20
Neurontin 300mg./day gave me significant help w. anxiety. Began to "poop" at about 6 mo., and after 8 mos. I felt it was doing nothing.
Upped dose to 400mg./day and effectiveness resumed. Now, after about 3mos. at this increased level, it is "pooping" again.
Posted by chemist on May 10, 2004, at 12:20:34
In reply to Re: neurontin poop out after awhile, fixable, chemist? » jlbl2l, posted by chemist on May 9, 2004, at 20:55:43
sorry, jlb121, i neglected to answer you question about calcium/magnesium supplements for augmenting the efficacy of neurontin...i don't think that supplements of either cation would make a difference, although there is one report i was able to find (perhaps there are more) in the literature in which researchers were seeking to identify the calcium-channel involvement of neurontin. they found that magnesium chloride - which, upon hydration, gives you a hexahydrated Mg^{2+} cation and Cl^{-} (cannot recall first solvation shell, but likely >> 6 and not relavent here) - injected into the spinal cords of rats that were pre-dosed with neurontin non-competitively inhibited the action of neurontin when the rats were exposed to painful stimuli (Anesthesiology, 98:1472-1479, 2003). there is a (what appears to me) contradictory finding (for neurontin blocking pain sensation at the spinal level), see J. Korean Med. Sci. 18:255-261, 2003. there are a few reports of people taking a ``mineral supplement'' who feel better than before, but there is no specific mention of what receptors are hit and i think we all, in general, feel better when our diets are well-balanced and we are getting enough vitamins and minerals. if you take a supplement - and maybe some other posters out there have had success, i just don't know - you might want to avoid magnesium and go for a chelate of calcium (not a salt of an inorganic, e.g., carbonate), such as the gluconate. elimination in solution (what i mean: how much you will lose in urine) should be lower for the chelate, as it will partition into your fatty tissue and stick around longer. i would also recommend that you do not take anything acidic (e.g., orange juice), as the solubility of metals increases with decreasing pH, and you might want to take an antacid to further buffer your stomach acid. calcium and magnesium do induce different effects in other systems, such as in skeletal muscle, where the calcium-ATP hydrolysis rate is faster than the magnesium-ATP hydrolysis rate. magnesium is almost always in the hexavalant hydrated state, whereas calcium has been observed with 7-9 waters of hydration. these cations will substitute for each other provided there is enough room to do so, and there usually is, and the effects can be quite pronounced. in summary: there seems to be a chance that calcium supplements might help, but you'd have to get it into your system such that it reaches the channels in addition to all the other places where it is needed, and i'd say that short of going right into the CSF, it doesn't look promising, although i hope some other poster (or you) will enlighten me.....anyways, sorry for the long-winded answer, and all the best, chemist
Posted by jlbl2l on May 10, 2004, at 17:37:24
In reply to Re: neurontin and the Ca or Mg thing.... » chemist, posted by chemist on May 10, 2004, at 12:20:34
chemist, thank you for your help.
i thought about adding a chelate of calcium could do something in theory since we are dealing with calicum channels - neurontins mech of action.
my questions :
I had 1 grand-mal seizure so it is possible i am prone to seizures. since magnesium increases the seizure threshold, does calcium lower it? this could be dangerous if i were to take high amounts.
second, should i take the calcium and neurontin at the same time, or take the calcium before (im assuming before....) and also, i imagine the larager the dosage, the more likely success i would have in it getting to my brain. what dosage would you suggest.
third, your suggestion of antacids is a nice thought, but for neurontin, it is contradicted as well as magnesium as it lowers its absorption quite a bit (it states this on the prescricing information) I would need to let 2 hours elapse at least. Also, I was planning to do this all on an empty stomach.
fourth, in theory, what is the best carrier for calcium to the brain rather than other parts of the body (we already discussed dosages above). I prefer not glutamate or glutamine chelates as my seiure threshold could be lowered. magnesium glycinate is known for one of the best absorbption rates from the gut to prevent "the runs" perhaps there is a chelate of calcium glycinate, though i dont know chemistry.
Finally, this theory esentially involves adding calcium to the calcium channels in the brain to make neurontin more effect, or at least help me lost some of its tolerance? Is this really a good option?
I've told my story in the first post, which is why this baffles me so much. Oh, and chemist, don't always rely on pubmed studies to confirm everything, a lot of what is out there can be found on the net through personal tetimonais and message boards, and any help I can get is apperciated, if studies can't find it..
all the best :-)
jlbl2l
Posted by chemist on May 10, 2004, at 18:15:28
In reply to Re: neurontin and the Ca or Mg thing...., posted by jlbl2l on May 10, 2004, at 17:37:24
hey jlb121, sorry about the contraindication in re: neurontin and antacids: thanks for the heds-up! didn't know about the seizures, and i think that in light of (from what little knowledge i have concerning epilepsy/seizures), hypercalcemia seems to be a recurring theme, so it would seem prudent to back off on the issue, as it is clear that the voltage-gated channels that are sensitive to calcium are either not working properly or are working too well. you need GABA without the risk of lowering your seizure threshold, so i think that it would be best not to introduce calcium. as for a glycinate, i don't see why not, or a chelate with any other amino acid, perhaps aspartic acid, although it, too, it an excitory neurotransmitter, to maybe not....in any event, i am at a loss how to target one section of your brain with orally-dosed calcium, as even the chelates get strewn throughout the body. sorry about the lame-duck answer, but in my opinion, the proposed plan to keep neurontin working via intake of calcium would be detrimental vs. looking for something like neurontin that does not leave you in the dust after a few months of therapy....let me know your thoughts, and all the best, chemist
> chemist, thank you for your help.
>
> i thought about adding a chelate of calcium could do something in theory since we are dealing with calicum channels - neurontins mech of action.
>
> my questions :
>
> I had 1 grand-mal seizure so it is possible i am prone to seizures. since magnesium increases the seizure threshold, does calcium lower it? this could be dangerous if i were to take high amounts.
>
> second, should i take the calcium and neurontin at the same time, or take the calcium before (im assuming before....) and also, i imagine the larager the dosage, the more likely success i would have in it getting to my brain. what dosage would you suggest.
>
> third, your suggestion of antacids is a nice thought, but for neurontin, it is contradicted as well as magnesium as it lowers its absorption quite a bit (it states this on the prescricing information) I would need to let 2 hours elapse at least. Also, I was planning to do this all on an empty stomach.
>
> fourth, in theory, what is the best carrier for calcium to the brain rather than other parts of the body (we already discussed dosages above). I prefer not glutamate or glutamine chelates as my seiure threshold could be lowered. magnesium glycinate is known for one of the best absorbption rates from the gut to prevent "the runs" perhaps there is a chelate of calcium glycinate, though i dont know chemistry.
>
> Finally, this theory esentially involves adding calcium to the calcium channels in the brain to make neurontin more effect, or at least help me lost some of its tolerance? Is this really a good option?
>
> I've told my story in the first post, which is why this baffles me so much. Oh, and chemist, don't always rely on pubmed studies to confirm everything, a lot of what is out there can be found on the net through personal tetimonais and message boards, and any help I can get is apperciated, if studies can't find it..
>
> all the best :-)
> jlbl2l
Posted by jlbl2l on May 10, 2004, at 20:03:48
In reply to Re: neurontin and the Ca or Mg thing.... » jlbl2l, posted by chemist on May 10, 2004, at 18:15:28
thanks for the help again...
but theorize here w/me for a sec...
in my original post, i stated that i had been on neurontin previously, and within weeks i had to raise the dose to get the same effect, and then i got no effect at all at *any* dose. What would this indicate? This happened in a matter of 2 weeks. Calcium channels? Do you think there is an inborn feedback mechnizsm in the channels/brain that is stopping the neurontin's effect? This seems very odd only after a few weeks use.
Also, theorize, how could we subvert this? As i stated in my original post, a few months later, i restarted neurontin, and to my surprise, it worked full force again! YET again within 2 weeks time the same pattern as above followed.
Could there be a build up or calcium ? desensitation of receptors (rapid) and then (rapid) resensitation? It just doesn't add up...
Your a chemist my friend, brain storm some theories for me. I'll give you more info since your a benzo expert. After the neurontin had stopped working, i took klonopin. Once i felt the klonopin kick in, i took the neurontin, just to see what would happen. Keep in mind they both work through totally different mechinisms. But guess what? I got the neurontin feeling back, while it wasnt full force, it wasn't "nothing". This brings into effect the gaba rasining abilty of neruontin and klonopin. Now how could, if neurontin is completly gained tolerance in me (or i feel so) could i have felt anything from it, when combining it with klonopin? It just doesn't make sense.
I'm still willing to try calcium chelate route, but what dose? Very high correct? and then I would have to wait 2 hours or so before taking neurontin ? or are calcium chelate's not considered antacids as well?
jlbl2l
Posted by jlbl2l on May 10, 2004, at 20:56:01
In reply to Re: neurontin and the Ca or Mg thing...., posted by jlbl2l on May 10, 2004, at 20:03:48
chemist,
the antacids things, i was just thinking, neurontin is effectively blocked (its absorbtion) when antacids or magnesium are present in the stomach within 2 hours approx.
This presents some intersting theories.
antacids are calcium, are they not? and magnesium increases the seizure threshold while calcium effectvely lowers it. neurontin works via calcium channels. do you see what i am getting at?
how could both calcium and magnesium inhibit the absorbtion of neurontin? they must compete to cross the same space in the BBB?
If this is true, then , I dunno. I just have a lot of novel theories on many diverse diseases. What do you think about this (sorry to keep irritating you on this, but I keep coming up with some interesting ideas/points. I;m not a chemist like yourself so im sure this is easy to answer for you, but a lot of people tell me I'm going to cure diseases one day..!
jlbl2l
Posted by chemist on May 10, 2004, at 22:16:32
In reply to Re: neurontin and the Ca or Mg thing...., posted by jlbl2l on May 10, 2004, at 20:03:48
hey there, gimme until tommorow or later tonight to get my ducks in a row. initial guess: rapid desensitization of calcium-channels, add-on benzodiazapine, reduce calcium inhibition by glutamate release, stimulate GABA via the preexisting route...but let me confirm/deny/adjust...as for the chelates: these will not be antacids with the base being - especially for the non-formally charged amino acids at physiological pH - the deprotonated form of, e.g., glycine....more later, let me look into this and see what i can find.....all the best, chemist
> thanks for the help again...
>
> but theorize here w/me for a sec...
>
> in my original post, i stated that i had been on neurontin previously, and within weeks i had to raise the dose to get the same effect, and then i got no effect at all at *any* dose. What would this indicate? This happened in a matter of 2 weeks. Calcium channels? Do you think there is an inborn feedback mechnizsm in the channels/brain that is stopping the neurontin's effect? This seems very odd only after a few weeks use.
>
> Also, theorize, how could we subvert this? As i stated in my original post, a few months later, i restarted neurontin, and to my surprise, it worked full force again! YET again within 2 weeks time the same pattern as above followed.
>
> Could there be a build up or calcium ? desensitation of receptors (rapid) and then (rapid) resensitation? It just doesn't add up...
>
> Your a chemist my friend, brain storm some theories for me. I'll give you more info since your a benzo expert. After the neurontin had stopped working, i took klonopin. Once i felt the klonopin kick in, i took the neurontin, just to see what would happen. Keep in mind they both work through totally different mechinisms. But guess what? I got the neurontin feeling back, while it wasnt full force, it wasn't "nothing". This brings into effect the gaba rasining abilty of neruontin and klonopin. Now how could, if neurontin is completly gained tolerance in me (or i feel so) could i have felt anything from it, when combining it with klonopin? It just doesn't make sense.
>
> I'm still willing to try calcium chelate route, but what dose? Very high correct? and then I would have to wait 2 hours or so before taking neurontin ? or are calcium chelate's not considered antacids as well?
>
> jlbl2l
Posted by chemist on May 10, 2004, at 22:23:47
In reply to addendem to previous post..., posted by jlbl2l on May 10, 2004, at 20:56:01
comments below.....delineated with ***, all the best, chemist
> chemist,
>
> the antacids things, i was just thinking, neurontin is effectively blocked (its absorbtion) when antacids or magnesium are present in the stomach within 2 hours approx.
>
> This presents some intersting theories.
>
**** calcium, magnesium, etc. are lewis acids, not bases. the base is what comes along in the supplement (e.g., carbonate, glutamate)****> antacids are calcium, are they not? and magnesium increases the seizure threshold while calcium effectvely lowers it. neurontin works via calcium channels. do you see what i am getting at?
>
**** magnesium and calcium in hydrated cationic form are of similar size (and exact charge, though different charge density) so they can competitively bind at each other's site...that's why either Ca^{2+} or Mg^{2+} will inhibit, but one will be a slightly better fit...*****> how could both calcium and magnesium inhibit the absorbtion of neurontin? they must compete to cross the same space in the BBB?
>
****not in the BBB: as hydrated moieties, they are subject to diffusion through the BBB, and my guess is that Mg^{2+} crosses faster due to fewer waters of hydration than Ca^{2+}....****
> If this is true, then , I dunno. I just have a lot of novel theories on many diverse diseases. What do you think about this (sorry to keep irritating you on this, but I keep coming up with some interesting ideas/points. I;m not a chemist like yourself so im sure this is easy to answer for you, but a lot of people tell me I'm going to cure diseases one day..!
>
> jlbl2l****hey, it's not irritating, it's of use for all of us......gimme some time to get the jist of this and perhaps i can provide a lucid answer....keep 'em coming!....all the best, chemist
Posted by chemist on May 13, 2004, at 23:37:12
In reply to addendem to previous post..., posted by jlbl2l on May 10, 2004, at 20:56:01
working on it, not forgotten...all the best, chemist
Posted by jlbl2l on May 16, 2004, at 20:02:09
In reply to working.... » jlbl2l, posted by chemist on May 13, 2004, at 23:37:12
thank you chemist, i didn't forget about it, but i am also finding interesting info.
combining klonopin (once it kicks in) and then adding the neurontin, prevents the lack of neurontin's effect, and neurontin then again works well. this is constant... replicate finding for me, but i dont want to rely on benzos at the moment.
jlbl2l
also, we should coordinate efforts on this because pregabalin is coming out soon and i think you'll be getting a lot of questions on this eventually. these, are both novel drugs with very interesting modes of action (in my opinion) pregablin was found to be superior to both xanax and effexor for GAD. i must locate that study, but that was very surprising.
Posted by chemist on May 16, 2004, at 22:33:27
In reply to Re: working.... (to chemist) / neurontin etc etc.., posted by jlbl2l on May 16, 2004, at 20:02:09
> thank you chemist, i didn't forget about it, but i am also finding interesting info.
>
> combining klonopin (once it kicks in) and then adding the neurontin, prevents the lack of neurontin's effect, and neurontin then again works well. this is constant... replicate finding for me, but i dont want to rely on benzos at the moment.
>
> jlbl2l
>
> also, we should coordinate efforts on this because pregabalin is coming out soon and i think you'll be getting a lot of questions on this eventually. these, are both novel drugs with very interesting modes of action (in my opinion) pregablin was found to be superior to both xanax and effexor for GAD. i must locate that study, but that was very surprising.shoot me an email to:
todd at lanczos dot cm dot utexas dot edulet's continue this discussion of this board, shall we? all the best, tjm
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