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Preventing nicotine tolerance


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#1 aLurker

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Posted 26 September 2010 - 02:59 PM


Well, this post will touch on different subjects and I didn't know in which topic(s) to post - hence the creation of a new one. This thread is pretty closely related to things I'll bring up here though.

What this topic is mainly about: preventing tolerance to nicotine.
Since nicotine has basically cured my deep rooted procrastination issues my main priority is to maintain the motivational and executive functioning enhancing effects of the nicotine. I'm not even sure yet if tolerance develops to these effects but I'm going to do my best to make sure I maintain them either way. I'm also toying with the idea of trying other meds since my amazing response to nicotine is probably an indication of ADD.

Concerning nicotine; warding off desensitization of nicotinic acetylcholine receptors is a primary concern (hence combining the nicotine with a PAM). Related concerns might be PKA, PKC and downstream down-regulation of other receptors such as dopamine. The cardiovascular effects are already discussed elsewhere and I'll probably start with dealcoholized red wine or something in the near future.

A few possible options that _might_ prevent tolerance:
*A PAM might help. Galantamine is a PAM. I refer to the thread I linked to in the beginning for more info on this.

*Memantine can according to medievil reverse/prevent tolerance to nicotine and many other substances. I haven't investigated this very thoroughly myself yet though. How it would achieve this is interesting since it both works on NMDA receptors and is a nAChR antagonist. Perhaps something related to these mechanisms would also be worth exploring then.

*Extracellular adenosine is involved in nAChR desensitization so hypothetically something like tea/coffee might help too although I'm unsure to how that would work long-term considering the rapid tolerance to caffeine. Other substances with adenosine mechanisms might also be relevant such as modafinil.

*Taking periods off nicotine might help. Although I'd prefer not to personally since I have trouble getting things done without it (as I did before). I've paused for a day or two during a weekend and there isn't any withdrawal or cravings at all so far though.

I've got mild concerns regarding both galantamine and memantine and any caffeine gives me eye twitches yet the thought of developing a persistent tolerance to nicotine is far scarier to me. It might not even become an issue for me but what can be done to prevent tolerance to nicotine?

I've tried galantamine in doses varying from 1-4 mg the last few days. So far the effects are very mild if they are even noticeable. Subjectively I'd say it offers a mild potentiating effect on nicotine so far though although the prospect that a PAM could help against desensitization of nAChRs is a huge upside to me personally.

Brief description of my experience with nicotine.
When I first put on a piece of a nicotine patch I went from procrastinating, messy, unable to make decisions and unmotivated to getting things done, organized, efficient and highly motivated. I dread the thought of going back to my old habits and I'm working hard on changing them while the nicotine lasts (hence my absence from these boards compared to my regular posting in the past). It most certainly also isn't in my head since I've got an amazing amount of things done since I started the patch: everything around me is much cleaner and organized (both externally and cognitively), I secured several attractive competing offers for my masters diploma work, accepted the most interesting and challenging one of them and started plowing through tutorials in a couple of new programming languages among MANY other things. In just over two weeks of nicotine bliss I've done far more than during the rest of 2010. So you can see why I've been busy. I didn't really have time to log my nicotine use since I was so productive. Beyond merely the motivational aspects it has also given me clarity of mind and reduced my over-analytical inner dialogue significantly although I fear it might be coming back some due to tolerance although that might just be my mind playing tricks on me and trying to regain the part of my life it had previously.

Addendum: My current regimen
(very much still a work in progress; hence my post here instead of in the proper forum although I suspect chrono might be tempted to move this post since I'm including this but hands off for now)

Upon waking up:
1 g of ALCAR
800-900 mg of Piracetam
exercise
3.5 mg transdermal nicotine, (1/6 of a 21 mg GSK Niquitin Clear which I guess is the same as Nicoderm CQ. I follow pretty much the same routine as chrono described in an earlier post in another nicotine related thread; I secure the piece of patch in place with 3M Micropore surgical tape and store the remains of the patch in the initial packaging put in a ziplock bag that is then put in a book to press out the air before I seal it.)

With breakfast:
1 mg selegiline/deprenyl
2000 IU D3 in softgel form
LEF vitamin K EOD,
A few caps of fish oil.
a multivitamin on some days

With lunch:
More fish oil.
I've tried 1-4 mg of galantamine just to gauge the subjective effects. When I decide on a dose I'll take this with breakfast to cover more of my time with a nicotine patch on. I'm also unsure how long the PAM-effect of galantamine lasts and this might make me take it with a snack later during the day too.

At 14:00 or so:
800-900 mg of Piracetam
1 g ALCAR (often less if I've taken galantamine)

22:30
0.25 mg of melatonin, still deciding my dosage and time here but this seems to work pretty ok against my DSPS right now which is huge for me.
I also remove my nicotine patch somewhere between here and midnight.
I've used 3 mg of LDN before going to sleep in the past although my use is now much more sporadic right now since I didn't get any clear results from this. Some evidence of nAChR antagonism from naltrexone might make this route worth exploring some more though although the potential benefits from that are very unclear to me at the time.

I'll probably adjust a lot of the dosages over the next weeks because of the recent addition of galantamine although I think all of the current components in this regimen, with the possible exception of LDN, are real keepers. Probably more Piracetam and less ALCAR due to the AChE inhibition of galantamine.


My sage advice, less monotherapy, and more polypharmacy. More importantly, look at the body of evidence as a whole, and not selected results.

Although my regimen is already somewhat polypharmaceutical, what would you urge me to modify/add considering my borderline miraculous response to nicotine? Deprenyl didn't have that much of an impact on my motivation yet nicotine has been amazing leading me to believe it isn't just dopamine related.

Concluding remark
Well, that's a lot of text and I would write even more if I had the time. If anyone has anything to say about nicotine tolerance (has it been an issue for you and how? what might help?), galantamine (especially with nicotine) or my regimen in general (additions, interactions, synergy, dosage etc.), feel free to post something.
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#2 medievil

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Posted 26 September 2010 - 03:01 PM

Answer is simple: memantine.

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#3 medievil

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Posted 26 September 2010 - 03:10 PM

Deprenyl didn't have that much of an impact on my motivation yet nicotine has been amazing leading me to believe it isn't just dopamine related.

Its not as simple as that, you can raise dopamine with complete garbage or with sexy stuff, some people with ADHD dont respond to ritalin, that however doesnt mean their issue's arent dopaminergic in nature, just that people respond to differend meds (and for example in that case dexedrine may work.)

#4 aLurker

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Posted 26 September 2010 - 03:17 PM

Answer is simple: memantine.

Yeah you keep telling me that :)
Would memantine interact with anything else I'm taking?

#5 medievil

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Posted 26 September 2010 - 03:20 PM

My only concern could have been piracetam but people have been saying they work synergetically, id say memantine should be fine in your regime.

A PAM can keep the nicotinic receptors open but they cant prevent downstream dopamine downregulation, or tolerance to the rewarding effects of nicotine.

Memantine will probably inhibit nicotine the first few days.

#6 aLurker

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Posted 26 September 2010 - 03:23 PM

Deprenyl didn't have that much of an impact on my motivation yet nicotine has been amazing leading me to believe it isn't just dopamine related.

Its not as simple as that, you can raise dopamine with complete garbage or with sexy stuff, some people with ADHD dont respond to ritalin, that however doesnt mean their issue's arent dopaminergic in nature, just that people respond to differend meds (and for example in that case dexedrine may work.)


Well I was just alluding to that I might respond better to stimulants that affect both norepinephrine and dopamine (such as nicotine, ritalin, amp and so on) instead of deprenyl. So the norepinephrine part of this might be more important for me than I thought before I tried nicotine.

#7 medievil

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Posted 26 September 2010 - 03:25 PM

MAOB inhibition doesnt raise dopamine in the mesolimbic area's, something witch nicotine does.

#8 bacopa

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Posted 26 September 2010 - 04:28 PM

A Lurker, I chew the gum, but there is some concern over the potential carcinogenicity, of even nicotine in alone, in pure form without the other thousands of chemicals in cigarettes.

However, although I remember reading about potential concerns, even with the patch, the patch would seem to be the safest form of NRT available.

Yes, nicotine is the only thing that has helped me with my lethargy, and motivation, as no other supplement, or dopamine precursor, has done much of anything.

You may want to do some investigation online, to ensure that the patch is a totally safe bet.
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#9 maxwatt

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Posted 26 September 2010 - 04:54 PM

ALurker:
Recalling a 10 year-old paper: it was found nicotine caused lymphocytes to cluster over cancer (tumor) cells, protecting them from killer T cells. Don't know if this was confirmed, or what serum levels.

Just wondering if you tried ritalin, concerta, amphetamines, or Provigil before using nicotine? And what was your reaction? I found Provigil helped with similar procrastination problems for me.

Bupropion: may be useful to allow cycling nicotine, as it reduces withdrawal cravings. It may work in place of nicotine for your purposes, a possibility, but I don't really know. Bupropion is a dopamine and norepinephrine re-uptake inhibitor. Bupropion can increase dopamine neurotransmission in the frontal cortex, as I think does nicotine. Bupropion might substitute for nicotine in your regimen. Might not want to take it with deprenyl.

Edited by maxwatt, 26 September 2010 - 05:08 PM.
more info


#10 aLurker

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Posted 26 September 2010 - 04:56 PM

A Lurker, I chew the gum, but there is some concern over the potential carcinogenicity, of even nicotine in alone, in pure form without the other thousands of chemicals in cigarettes.

However, although I remember reading about potential concerns, even with the patch, the patch would seem to be the safest form of NRT available.

Yes, nicotine is the only thing that has helped me with my lethargy, and motivation, as no other supplement, or dopamine precursor, has done much of anything.

You may want to do some investigation online, to ensure that the patch is a totally safe bet.


I did an obsessive amount of research on nicotine before I put the patch on and concluded that this isn't much of a problem. Potential carcinogenicity and NNK have been discussed before and I concluded that transdermal nicotine is way superior to using lozenges or gum. I'm sure I can find better sources but here is one:

Indeed, people using nicotine patches don't have elevated concentrations of NNK in their urine, Hecht finds.

That factoid leads me to believe that transdermal nicotine is pretty safe in that regard.

#11 aLurker

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Posted 26 September 2010 - 05:19 PM

Recalling a 10 year-old paper: it was found nicotine caused lymphocytes to cluster over cancer (tumor) cells, protecting them from killer T cells. Don't know if this was confirmed, or what serum levels.


Just wondering if you tried ritalin, concerta, amphetamines, or Provigil before using nicotine? And what was your reaction? I found Provigil helped with similar procrastination problems for me.


I'm considering all of them but I haven't given any of them a proper try yet. I tried a too high dose of concerta once in the past and that was overall a pretty unpleasant experience (teeth grinding, elevated heart rate, I lost the ability to see the big picture because I got lost in details and so on) although I might give it a shot at a more reasonable dose. I'm in the process of getting my ADD diagnosed which basically is a must for any of those controlled substances to be a viable long-term solution for me so maybe after that. Side effects and tolerance are still issues with all of them too, perhaps even more so. You are perfectly right to suggest them though since they might be even more effective for me and in that case I'll have to evaluate whether the substance is worth any potential risks. Nicotine is definitely worth it so far from an effectiveness standpoint.

#12 chrono

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Posted 26 September 2010 - 05:58 PM

I'm curious to hear what you find with regard to tolerance. Between the putative carcinogenesis concerns and the confirmed vasoactivity, I can't convince myself to take it more than 2-3 times a week at most, so I've never developed any tolerance. I think bgwithadd may have worked his way up to a full 21mg patch over the course of 9 months, IIRC from his thread.

I'm also curious how memantine's nAChR antagonism would play out when combined with nicotine's agonism; it doesn't seem ideal, but it may not be an issue. Amantadine and agmatine are other options to consider, but I believe they both share the antagonistic mechanism. Taking days off will help no matter what you decide on, though.

And I'm wondering if you'll have any luck getting a diagnosis, without fudging it a little. While motivational problems can certainly derive from dopaminergic dysfunction, I can't picture a doctor being willing to diagnose and/or prescribe psychostimulants if you don't really have any problem with attention. You may want to start reading up on atomoxetine, bupropion and guanfacine, as they may be easier options. And maxwatt's suggestion about modafinil is probably a good one, as it will have fewer drawbacks and be easier to obtain (assuming you can import it).

EDIT: I didn't find Hup A to act as an effective counterpart to piracetam, or to modulate the effect of ALCAR to any degree, and its AChEI is much stronger/longer than galanatamine's. Let us know if you find differently.

Edited by chrono, 26 September 2010 - 09:39 PM.


#13 bacopa

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Posted 26 September 2010 - 07:03 PM

A Lurker, I chew the gum, but there is some concern over the potential carcinogenicity, of even nicotine in alone, in pure form without the other thousands of chemicals in cigarettes.

However, although I remember reading about potential concerns, even with the patch, the patch would seem to be the safest form of NRT available.

Yes, nicotine is the only thing that has helped me with my lethargy, and motivation, as no other supplement, or dopamine precursor, has done much of anything.

You may want to do some investigation online, to ensure that the patch is a totally safe bet.


I did an obsessive amount of research on nicotine before I put the patch on and concluded that this isn't much of a problem. Potential carcinogenicity and NNK have been discussed before and I concluded that transdermal nicotine is way superior to using lozenges or gum. I'm sure I can find better sources but here is one:

Indeed, people using nicotine patches don't have elevated concentrations of NNK in their urine, Hecht finds.

That factoid leads me to believe that transdermal nicotine is pretty safe in that regard.

nice find, interesting, unfortunately the patch never worked for me at all, but even the smallest dosage of gum, works like a charm.

#14 medievil

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Posted 26 September 2010 - 07:13 PM

I'm also curious how memantine's nAChR antagonism would play out when combined with nicotine's agonism; it doesn't seem ideal, but it may not be an issue.

Subjectively memantine works fine with nicotine and 2 people confirmed to me that memantine helps tolerance, and so far it does that for me too, but my experience is short term.

My experience with nicotine without memantine wasnt favorable in the long run.

#15 aLurker

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Posted 26 September 2010 - 08:25 PM

I'm curious to hear what you find with regard to tolerance. Between the putative carcinogenesis concerns and the confirmed vasoactivity, I can't convince myself to take it more than 2-3 times a week at most, so I've never developed any tolerance. I think bggwithadd may have worked his way up to a full 21mg patch over the course of 9 months, IIRC from his thread.

I'm also curious how memantine's nAChR antagonism would play out when combined with nicotine's agonism; it doesn't seem ideal, but it may not be an issue. Amantadine and agmatine are other options to consider, but I believe they both share the antagonistic mechanism. Taking days off will help no matter what you decide on, though.

And I'm wondering if you'll have any luck getting a diagnosis, without fudging it a little. While motivational problems can certainly derive from dopaminergic dysfunction, I can't picture a doctor being willing to diagnose and/or prescribe psychostimulants if you don't really have any problem with attention. You may want to start reading up on atomoxetine, bupropion and guanfacine, as they may be easier options. And maxwatt's suggestion about modafinil is probably a good one, as it will have fewer drawbacks and be easier to obtain (assuming you can import it).

EDIT: I didn't find Hup A to act as an effective counterpart to piracetam, or to modulate the effect of ALCAR to any degree, and its AChEI is much stronger/longer than galanatamine's. Let us know if you find differently.


I'm not that worried about getting a diagnosis, if I skip my daily regimen I certainly don't have to fake the attentional difficulties part unless all of their tests are somehow insanely interesting and I sincerely doubt that. Modafinil is classified as a narcotic here so that might get me in serious trouble if I don't have a prescription. Concerning medication in the meantime atomoxetine or bupropion might be a little more interesting in my case. I can get both without any trouble. Atomoxetine: the pharmacology certainly looks interesting. I've looked into Bupropion too and that might be worth a shot as well since I've heard reports of increased motivation on that too. I haven't given guanfacine much consideration yet.

I'm skimming through the reviews of Strattera (atomoxetine) on revolutionhealth right now and it seems very hit or miss. It is very expensive and seems to be either terrible or super effective. I can't find much indicating tolerance might be an issue here so that's definitely a good thing. There are A LOT of reports about all sorts of serious side effects and the medication is quite new so who knows about long-term.

The bupropion might mess up my nicotine-induced mojo so I'll stay clear of that for now since I'm on a roll :D maybe later though.

Edited by aLurker, 26 September 2010 - 08:54 PM.


#16 Pike

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Posted 26 September 2010 - 10:57 PM

you could also drink some more grapefruit juice or pomegranate juice. they're inhibitors of the cyp1A2 enzyme, which metabolizes nicotine.

#17 chrono

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Posted 27 September 2010 - 02:31 AM

you could also drink some more grapefruit juice or pomegranate juice. they're inhibitors of the cyp1A2 enzyme, which metabolizes nicotine.

This might be useful, but wouldn't inhibition of this enzyme just prolong the duration of effect—if anything, increasing tolerance?

#18 Rational Madman

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Posted 27 September 2010 - 02:40 AM

Well, this post will touch on different subjects and I didn't know in which topic(s) to post - hence the creation of a new one. This thread is pretty closely related to things I'll bring up here though.

What this topic is mainly about: preventing tolerance to nicotine.
Since nicotine has basically cured my deep rooted procrastination issues my main priority is to maintain the motivational and executive functioning enhancing effects of the nicotine. I'm not even sure yet if tolerance develops to these effects but I'm going to do my best to make sure I maintain them either way. I'm also toying with the idea of trying other meds since my amazing response to nicotine is probably an indication of ADD.

Concerning nicotine; warding off desensitization of nicotinic acetylcholine receptors is a primary concern (hence combining the nicotine with a PAM). Related concerns might be PKA, PKC and downstream down-regulation of other receptors such as dopamine. The cardiovascular effects are already discussed elsewhere and I'll probably start with dealcoholized red wine or something in the near future.

A few possible options that _might_ prevent tolerance:
*A PAM might help. Galantamine is a PAM. I refer to the thread I linked to in the beginning for more info on this.

*Memantine can according to medievil reverse/prevent tolerance to nicotine and many other substances. I haven't investigated this very thoroughly myself yet though. How it would achieve this is interesting since it both works on NMDA receptors and is a nAChR antagonist. Perhaps something related to these mechanisms would also be worth exploring then.

*Extracellular adenosine is involved in nAChR desensitization so hypothetically something like tea/coffee might help too although I'm unsure to how that would work long-term considering the rapid tolerance to caffeine. Other substances with adenosine mechanisms might also be relevant such as modafinil.

*Taking periods off nicotine might help. Although I'd prefer not to personally since I have trouble getting things done without it (as I did before). I've paused for a day or two during a weekend and there isn't any withdrawal or cravings at all so far though.

I've got mild concerns regarding both galantamine and memantine and any caffeine gives me eye twitches yet the thought of developing a persistent tolerance to nicotine is far scarier to me. It might not even become an issue for me but what can be done to prevent tolerance to nicotine?

I've tried galantamine in doses varying from 1-4 mg the last few days. So far the effects are very mild if they are even noticeable. Subjectively I'd say it offers a mild potentiating effect on nicotine so far though although the prospect that a PAM could help against desensitization of nAChRs is a huge upside to me personally.

Brief description of my experience with nicotine.
When I first put on a piece of a nicotine patch I went from procrastinating, messy, unable to make decisions and unmotivated to getting things done, organized, efficient and highly motivated. I dread the thought of going back to my old habits and I'm working hard on changing them while the nicotine lasts (hence my absence from these boards compared to my regular posting in the past). It most certainly also isn't in my head since I've got an amazing amount of things done since I started the patch: everything around me is much cleaner and organized (both externally and cognitively), I secured several attractive competing offers for my masters diploma work, accepted the most interesting and challenging one of them and started plowing through tutorials in a couple of new programming languages among MANY other things. In just over two weeks of nicotine bliss I've done far more than during the rest of 2010. So you can see why I've been busy. I didn't really have time to log my nicotine use since I was so productive. Beyond merely the motivational aspects it has also given me clarity of mind and reduced my over-analytical inner dialogue significantly although I fear it might be coming back some due to tolerance although that might just be my mind playing tricks on me and trying to regain the part of my life it had previously.

Addendum: My current regimen
(very much still a work in progress; hence my post here instead of in the proper forum although I suspect chrono might be tempted to move this post since I'm including this but hands off for now)

Upon waking up:
1 g of ALCAR
800-900 mg of Piracetam
exercise
3.5 mg transdermal nicotine, (1/6 of a 21 mg GSK Niquitin Clear which I guess is the same as Nicoderm CQ. I follow pretty much the same routine as chrono described in an earlier post in another nicotine related thread; I secure the piece of patch in place with 3M Micropore surgical tape and store the remains of the patch in the initial packaging put in a ziplock bag that is then put in a book to press out the air before I seal it.)

With breakfast:
1 mg selegiline/deprenyl
2000 IU D3 in softgel form
LEF vitamin K EOD,
A few caps of fish oil.
a multivitamin on some days

With lunch:
More fish oil.
I've tried 1-4 mg of galantamine just to gauge the subjective effects. When I decide on a dose I'll take this with breakfast to cover more of my time with a nicotine patch on. I'm also unsure how long the PAM-effect of galantamine lasts and this might make me take it with a snack later during the day too.

At 14:00 or so:
800-900 mg of Piracetam
1 g ALCAR (often less if I've taken galantamine)

22:30
0.25 mg of melatonin, still deciding my dosage and time here but this seems to work pretty ok against my DSPS right now which is huge for me.
I also remove my nicotine patch somewhere between here and midnight.
I've used 3 mg of LDN before going to sleep in the past although my use is now much more sporadic right now since I didn't get any clear results from this. Some evidence of nAChR antagonism from naltrexone might make this route worth exploring some more though although the potential benefits from that are very unclear to me at the time.

I'll probably adjust a lot of the dosages over the next weeks because of the recent addition of galantamine although I think all of the current components in this regimen, with the possible exception of LDN, are real keepers. Probably more Piracetam and less ALCAR due to the AChE inhibition of galantamine.


My sage advice, less monotherapy, and more polypharmacy. More importantly, look at the body of evidence as a whole, and not selected results.

Although my regimen is already somewhat polypharmaceutical, what would you urge me to modify/add considering my borderline miraculous response to nicotine? Deprenyl didn't have that much of an impact on my motivation yet nicotine has been amazing leading me to believe it isn't just dopamine related.

Concluding remark
Well, that's a lot of text and I would write even more if I had the time. If anyone has anything to say about nicotine tolerance (has it been an issue for you and how? what might help?), galantamine (especially with nicotine) or my regimen in general (additions, interactions, synergy, dosage etc.), feel free to post something.


Well, you've developed a modest, but nonetheless sound regimen, and since your overarching goal is increased motivation, you should consider the following targets: a7 nAChR upregulation, reelin promotion, D2 receptor modulation, D1 receptor stimulation, increasing catechloamine volume, 5ht blockade, and increasing (not decreasing) NMDA rececptor activity.

My reccomendations are as follows:
Reelin Promotion: low dose amisulpride, low dose valproic acid, prescription retinoic acid, or vitamin A.
D1: Cabergoline, or maybe Apomorphine.
Catechloamines: amphetamines, Modafinil, Atomoxetine, Methylphenidate, Wellbutrin, Amineptine, Rasagiline, Selegiline, or Entacapone.
5ht Blockade: Amisulpride, Fluoxetine, Valdoxan, or Mirtazapine.
D2 modulation: Modafinil, Cabergoline, and Amisulpride.
Nicotinic: Nicotine patch, acetylcholinesterase inhibitors, and alcohol.
NMDA: Ampakines, psychostimulants, freeze dried coffee, pyroglutamic acid, or glycine.

For the time being, I would increase your Deprenyl dosage to 10 mg/day, and titrate the Galantamine that you procured until optimal results are achieved. In fact, you should increase the dosages for just about everything, which are exceedingly timid, and are doubtlessly delivering disappointing results.

As for supplements, protein synthesis should be your greatest comfort, so at the very least, try ribose or methylenetetrahyrofolate. Beyond that, I urge you to contemplate using one or all of the following: luteolin, resveratrol, or Master Gene P16.

Rather than getting on the Memantine train, which my own dalliance rendered me permanently disdainful, the use of xanthines, alcohol, or Valproic Acid should help with guarding against the onset of nicotine tolerance. Additionally, for both amphetamine and nicotine tolerance, I'm becoming increasingly convinced that dopa decarboxylase and tyrosine hyrdroxylase enzyme alterations are of more importance, and thus, the co-administration of MAO inhibitors, tyrosine, NADH, or anti-Parkinson's drugs might be more efficacious than the more deleterious Memantine. I say this knowing full well that my position is likely to attract spirited rebuttals from the many advocates pervading this forum, but consider the skeptics (myself, former champion FunkOdyssey, and Frangible at Mind and Muscle), and the literature findings (which don't unanimously endorse usage, and are highly dubious about its treatment potential outside of its indication). Throw as many selective findings at me as you want, but antagonizing the NMDA receptor is a daft choice for those concerned about cognitive changes, which is a desire that you've made very plain. And given my burgeoning skepticism of antagonizing this target, I think Atomoxetine is worth scrutinizing a bit more. But like I said in a separate thread, careful dosing, and co-adminstration with other agents should neutralize the unwanted effects. On a personal note, my memory is exceptional, but my eventual goal is something close to eidetic memory, which I believe is attainable, and would be impeded by agents with an antagonistic affinity for NMDA sites.

Edited by Rol82, 27 September 2010 - 05:05 AM.

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#19 iago

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Posted 27 September 2010 - 05:11 AM

How long did it take for the nicotine to have noticeable effects?

#20 chrono

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Posted 27 September 2010 - 05:16 AM

Throw as many selective findings as you want at me as you want, but targeting the NMDA receptor is a daft choice for those concerned about cognitive changes, which is a desire that you've made very plain.

To quote a piece of sage advice from one of our esteemed members here: try not to become fixated on pathways, and don't allow confounding variables to stop you if a modality possesses merit. :-D Sorry, just having some fun; the joke practically makes itself. ;) A lot of those recommendations are great, in different circumstances, though several have seemed to be much more detrimental to cognition than memantine, in practice.

Of more relevance to the issue of tolerance and desensitization, this free paper poses some interesting possibilities; among them, that nAChR agonism and antagonismm can both have the same effect under certain conditions.

It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.
Picciotto MR, Addy NA, Mineur YS, Brunzell DH.

Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

PMID: 18242816 [PubMed - indexed for MEDLINE]


@iago: At least some of nicotine's effects are acute (i.e. immediate), though I'm certain they would be modulated somewhat with chronic usage.

Edited by chrono, 27 September 2010 - 05:24 AM.


#21 Rational Madman

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Posted 27 September 2010 - 06:07 AM

Throw as many selective findings as you want at me as you want, but targeting the NMDA receptor is a daft choice for those concerned about cognitive changes, which is a desire that you've made very plain.

To quote a piece of sage advice from one of our esteemed members here: try not to become fixated on pathways, and don't allow confounding variables to stop you if a modality possesses merit. :-D Sorry, just having some fun; the joke practically makes itself. ;) A lot of those recommendations are great, in different circumstances, though several have seemed to be much more detrimental to cognition than memantine, in practice.

Of more relevance to the issue of tolerance and desensitization, this free paper poses some interesting possibilities; among them, that nAChR agonism and antagonismm can both have the same effect under certain conditions.

It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.
Picciotto MR, Addy NA, Mineur YS, Brunzell DH.

Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

PMID: 18242816 [PubMed - indexed for MEDLINE]


@iago: At least some of nicotine's effects are acute (i.e. immediate), though I'm certain they would be modulated somewhat with chronic usage.


Indeed, very funny.

Yeah, some of the agents included have a mixed reputation in terms of cognitive enhancement, but I think dosage and combination is key. For Valproic Acid, for instance, I'm only contemplating a very low dosage. Because there have been some exciting findings about its effects on long term induction, but when given at established therapeutic doses assigned for manic depressive disorders, it's a pretty pernicious drug.

Edited by chrono, 28 September 2010 - 01:29 AM.
combined responses


#22 aLurker

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Posted 27 September 2010 - 08:02 AM

How long did it take for the nicotine to have noticeable effects?


I started out on 5.25 mg and within an hour I was frantically cleaning my room for the entire day. The next day I engaged in more mental pursuits since I was done cleaning and ready to go to work on other stuff I had procrastinated.

Edited by aLurker, 27 September 2010 - 08:02 AM.


#23 medievil

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Posted 27 September 2010 - 11:41 AM

I'm becoming increasingly convinced that dopa decarboxylase and tyrosine hyrdroxylase enzyme alterations are of more importance, and thus, the co-administration of MAO inhibitors, tyrosine, NADH, or anti-Parkinson's drugs might be more efficacious than the more deleterious Memantine.

Altough only based on one anecdotal report, a good friend of me with severe depression has used MAO inhibitors, LDOPA and other stuff with amphetamine and he got completely tolerant, so i'm doubtfull those things would work, imo receptor downregulation is the biggest issue.

He now noticed a COMPLETE reversal of nicotine, tramadol, klonopin and amphetamine tolerance since he added in acamprosate, wich also modulates glutamate, but isnt a direct NMDA antagonist and may be a good alternative for memantine, altough he does take 10 mg memantine with it, he couldnt tolerate higher doses of memantine.

#24 medievil

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Posted 27 September 2010 - 12:33 PM

Btw, rol i share your doubts about NMDA antagonism and cognition, like ive said in my recent posts in my nmda antagonists thread i beleive that memantine will be cognitively impairing and that the rumores about it enhancing cognition are probably nonsense and arent relevant to healthy subjects.

Still its generally agreed that cognitive impairment by memantine is very minimal, and the only reasons i take it is for tolerance and for my OCD.

#25 medievil

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Posted 27 September 2010 - 12:43 PM

I'm quoting ex dubio from mind and muscle:

To quote from the study:

Quote
[Morphine tolerance] was completely reversed by curcumin, an inhibitor of CREB-binding protein histone acetyltransferase activity. As the daily injection of curcumin completely reversed the morphine tolerance, this epigenetic control seems to be related to a BDNF-mediated counterbalance effect to reduce morphine analgesia.


This occurred at doses from 10-100 mg/kg p.o. in mice, which is fairly realistic and comparable to human doses that we've discussed. As the mechanism was via CREB, this should in theory apply to tolerance for any drugs of addiction. However altering CREB activity in the brainstem is going to alter analgesic tolerance without changing reward/NAc tolerance; this study did not assess whether CREB activity was changed in the NAc. If it was, then yes, curcumin should reverse amphetamine tolreance too, at least to some extent.

But no, there are no studies that have directly looked at this.

If he's correct then inhibiting CREB activity in the NAc should be a alternative to NMDA antagonism, perhaps anyone here knows of any substances that inhibit CREB activity in the NAc and wheter its something that has a positive or negative impact on cognition.

#26 aLurker

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Posted 27 September 2010 - 05:05 PM

OP


Well, you've developed a modest, but nonetheless sound regimen, and since your overarching goal is increased motivation, you should consider the following targets: a7 nAChR upregulation, reelin promotion, D2 receptor modulation, D1 receptor stimulation, increasing catechloamine volume, 5ht blockade, and increasing (not decreasing) NMDA rececptor activity.

My reccomendations are as follows:
Reelin Promotion: low dose amisulpride, low dose valproic acid, prescription retinoic acid, or vitamin A.
D1: Cabergoline, or maybe Apomorphine.
Catechloamines: amphetamines, Modafinil, Atomoxetine, Methylphenidate, Wellbutrin, Amineptine, Rasagiline, Selegiline, or Entacapone.
5ht Blockade: Amisulpride, Fluoxetine, Valdoxan, or Mirtazapine.
D2 modulation: Modafinil, Cabergoline, and Amisulpride.
Nicotinic: Nicotine patch, acetylcholinesterase inhibitors, and alcohol.
NMDA: Ampakines, psychostimulants, freeze dried coffee, pyroglutamic acid, or glycine.

For the time being, I would increase your Deprenyl dosage to 10 mg/day, and titrate the Galantamine that you procured until optimal results are achieved. In fact, you should increase the dosages for just about everything, which are exceedingly timid, and are doubtlessly delivering disappointing results.

As for supplements, protein synthesis should be your greatest comfort, so at the very least, try ribose or methylenetetrahyrofolate. Beyond that, I urge you to contemplate using one or all of the following: luteolin, resveratrol, or Master Gene P16.

Rather than getting on the Memantine train, which my own dalliance rendered me permanently disdainful, the use of xanthines, alcohol, or Valproic Acid should help with guarding against the onset of nicotine tolerance. Additionally, for both amphetamine and nicotine tolerance, I'm becoming increasingly convinced that dopa decarboxylase and tyrosine hyrdroxylase enzyme alterations are of more importance, and thus, the co-administration of MAO inhibitors, tyrosine, NADH, or anti-Parkinson's drugs might be more efficacious than the more deleterious Memantine. I say this knowing full well that my position is likely to attract spirited rebuttals from the many advocates pervading this forum, but consider the skeptics (myself, former champion FunkOdyssey, and Frangible at Mind and Muscle), and the literature findings (which don't unanimously endorse usage, and are highly dubious about its treatment potential outside of its indication). Throw as many selective findings at me as you want, but antagonizing the NMDA receptor is a daft choice for those concerned about cognitive changes, which is a desire that you've made very plain. And given my burgeoning skepticism of antagonizing this target, I think Atomoxetine is worth scrutinizing a bit more. But like I said in a separate thread, careful dosing, and co-adminstration with other agents should neutralize the unwanted effects. On a personal note, my memory is exceptional, but my eventual goal is something close to eidetic memory, which I believe is attainable, and would be impeded by agents with an antagonistic affinity for NMDA sites.


From what I've gathered so far here is what I'll investigate further:

Atomoxetine looks like it could be the most promising thing for me. I'll research it further but I'll probably wait to try it until I've got a diagnosis since I heard you have to taper it off. Or could I try this and cease taking it a few days before the tests? Increasing NE and DA in my PFC sounds like a pretty sweet deal for my executive function, prioritization, focus and motivational issues, assuming I don't get any of the dreaded side effects. Guanfacine might also be an option, or bupropion later down the road if I decide to give nicotine up entirely. I'd rather try atomoxetine than memantine right now because of the possible memory side effects of memantine and the alpha 7 antagonism.

Like I said before, although probably a good idea - a prescription stim isn't really a viable long-term solution until I get a diagnosis.

A hyperRDA dose of vitamin A might be beneficial to me not only because of the good reasons Rol82 has mentioned previously but also because I have very oily skin and even topical isotretinion isn't enough to keep it fully under control so the potential upside seems multifaceted.

Alcohol is a no-no for me as my IQ drops in half by just looking at the stuff. I get seriously stoopid if I consume even minuscule amounts.


I'll also consider increasing the dose of the stuff I'm taking. I shouldn't have any trouble increasing Piracetam and ALCAR (to 1g/1g for instance) and taking it thrice daily. Regarding the deprenyl I'd rather keep it quite low for now but I could easily double the dose to 2 mg.

I'll at least look at Cabergoline too even if I've never even heard of it before.

Luteolin, reservatrol and MasterGene P16 all look good and what I go with there is basically a price/performance issue rather than anything else.

Xanthines are also worth investigating further to decide which one is most prudent in my own case. I still seem to get eye twitches every time I try any amount of caffeine, even white tea after trying to extract the caffeine with hot water - perhaps occasional lack of sleep or other factors aggravate it though. I'll try cocoa instead since theobromine is an adenosine receptor antagonist and prevents angiogenesis; both aspects are very relevant since adenosine is involved in tolerance to nicotine and nicotine induces angiogenesis. It is also a vasodilator. No idea how much and when I should take the cocoa though.

Curcumin is all-around awesome and I use it very regularly in my cooking. Maybe I'll make it a part of my regimen for medicinal purposes too and start measuring up a minimum daily dose. Again, any info on suggested dosage here?

Edited by aLurker, 27 September 2010 - 05:29 PM.


#27 medievil

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Posted 27 September 2010 - 05:12 PM

I'm taking 500mg MCT curcumin from revgenetics, wich is equavalent to 1600mg i beleive.

If i havent posted the link before, here's a good overview of all research on curcumin:
http://www.mindandmu...showtopic=41876

#28 aLurker

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Posted 27 September 2010 - 05:22 PM

Well, a teaspoon or two of turmeric with a pinch of black pepper is my preliminary plan since it's cheap, has poor bioavailability and I've already got lots in my kitchen.

#29 health_nutty

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Posted 28 September 2010 - 12:12 AM

Nicotine patches are not cheap! How much does this regimine run you a month?

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#30 medievil

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Posted 28 September 2010 - 12:33 AM

Cognition-enhancing and anxiolytic effects of memantine.
Minkeviciene R, Banerjee P, Tanila H.

Department of Neurobiology, A.I.Virtanen Institute for Molecular sciences, University of Kuopio, Kuopio, Finland.
Abstract
Memantine, a moderate-affinity NMDA receptor antagonist, is clinically used for the treatment of Alzheimer's disease (AD). Both clinical and preclinical studies have shown that memantine, at doses producing a steady-state plasma level of 0.5-1 microM, is well tolerated and improves cognition. Here we tested the effects of chronic oral administration of memantine (10, 30 and 100mg/kg per day) producing steady state plasma drug levels ranging between approximately 0.5 and 6 microM on motor, social, emotional and cognitive behavior in normal C57BL/6J mice. Memantine dose-dependently reduced escape latency (hidden platform) and decreased wall swimming tendency in the Morris water maze test, increased time spent in open arms in the elevated plus-maze test, and reduced the number of isolation-induced aggressive attacks, but did not affect exploratory activity in the open field. These data indicate that high, stable doses of memantine improved cognition and exhibited a potential anxiolytic response in normal mice.


I wonder about study's on humans, i think 30mg caused some cognitive decline according to a study chrono posted.




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