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Preventing nicotine tolerance


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#31 iago

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Posted 28 September 2010 - 02:28 AM

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


A pack of 7 x 21mg patches costs just over $20. Each patch lasts 6 days (he said he cuts the patches into 6 strips). That's $20 for 49 days, or 41 cents a day, or $12.30 a month, probably closer to $13 a month since I know they are usually a bit over $20.

Edited by iago, 28 September 2010 - 02:29 AM.


#32 health_nutty

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Posted 28 September 2010 - 02:34 AM

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


A pack of 7 x 21mg patches costs just over $20. Each patch lasts 6 days (he said he cuts the patches into 6 strips). That's $20 for 49 days, or 41 cents a day, or $12.30 a month, probably closer to $13 a month since I know they are usually a bit over $20.


Not too bad. I'm sooo tempted if I can just get over the negative stereotype of nicotine (and the worries over addiction and tolerance)...

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#33 aLurker

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Posted 28 September 2010 - 08:33 AM

Unless you're taking a MAO A inhibitor (tobacco has this effect), nicotine addiction shouldn't be much of an issue and we can save the negative stereotypes for more close-minded people. The more pressing concerns from my perspective are vascular effects and tolerance.

Everything I'm taking right now is very affordable and my regimen was designed with budgetary concerns in mind. The price/performance and safety profile (except possibly the nicotine) of it is pretty good if I may say so myself.

Trying nicotine has been somewhat of a personal revelation to me how much I stand to benefit from medication. The difference when I first put on a nicotine patch was night and day. Even if I develop a complete tolerance to nicotine it has shown me what is possible to achieve. I'll probably step up my regimen pretty considerably and I'll be willing to take few more risks in pursuit of something more optimal since I've seen how much I stand to benefit from the right medications/supplements. I've realized how my excessive overly analytical worrying and procrastination have been huge hurdles for me to live my life. The potential side effects of for instance Atomoxetine would probably have scared me off in the past but now I'll probably give it a shot down the line.

Even though I'm very health-conscious and this might go against the popular opinion on this particular website; I'd rather live my life to the fullest now than cling to the notion of living forever and thus wasting the present moment.

Change isn't always easy but seeing that such massive improvements are possible motivates me to push further forward.
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#34 NR2(x)

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Posted 28 September 2010 - 09:19 AM

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.


You are entirely correct here. Reduced CREB, some NMDA antagonists and most drugs of abuse(especially cocaine) increase LONG TERM DEPRESSION in the NAc, which can enhanced cognition in the generally population. Greater LONG TERM DEPRESSION in the NAc allows the "third eye" or "central executive" to have greater plasticity in higher level thought. This allows greater intergration of mind, hemispheres, frontal lobes.

Nicotine MOA may involve decreased CREB

My goal is to enhance CREB function while also increasing Long Term Depression. GOD STATE. Increased CREB should enhance the quantity of proceed data, while enhanced LTD should allow more effective filtering. While neutralising the negatives. In stack terms were talking something like cocaine and rolipram, just for example.

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 subjec


If i remmeber you are taking a dose of 40mgs per day?
Therefore you have based this statement on that dosage. It should be expected that memantine would show cognitive enhancing effects at a low dose and cognitively impairing effects as dose increases. This is a traditional INverse parabolic function. I am quite sure than 40mg exceeds optimal dosage, unless a serious neurodegenerative disease exists. THe improved cognitive effects would be of a executive nature, memory would suffer.

Even though I'm very health-conscious and this might go against the popular opinion on this particular website; I'd rather live my life to the fullest now than cling to the notion of living forever and thus wasting the present moment.


I bet all of us could live more in one month than we will in a life time, I definitly could choose to die for reward, even of a moral basis

Edited by chrono, 30 September 2010 - 11:39 AM.


#35 medievil

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Posted 28 September 2010 - 10:22 AM

I dont notice any cognitive impairment a day at 40mg myself, but i havent done any cognitive tests to see wheter there is any real decline in my cognition. Its generally accepted that cognitive decline with memantine is very minimal, but i have my doubts about it enhancing cognition.

#36 aLurker

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Posted 28 September 2010 - 11:18 AM

I dont notice any cognitive impairment a day at 40mg myself, but i havent done any cognitive tests to see wheter there is any real decline in my cognition. Its generally accepted that cognitive decline with memantine is very minimal, but i have my doubts about it enhancing cognition.


As far as I know there is no data which NMDA antagonist might be the most effective one to minimize tolerance, assuming it even works. When choosing a NMDA antagonist partly for this purpose the therapeutic value and effect of the NMDA antagonist alone should obviously play a large role. Memantine seems to be a good choice for you since you stand to benefit greatly both from the effects it has on OCD and ADHD. Personally I'm leaning more towards trying Atomoxetine first since it has more potential to improve my executive function by its actions in the prefrontal cortex and it doesn't interfere with my nicotine.

A hollistic view of ones regimen and each part in it is required to reach optimal effects for each specific individual. My problems differ from yours and we must choose different pieces to solve what's puzzling us accordingly and I encourage everyone to look over what they're ultimately trying to achieve and proceed in a prudent manner.

#37 medievil

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Posted 28 September 2010 - 11:30 AM

In rodents NMDA is involved in nicotine tolerance.

The NMDA antagonist dizocilpine (M K801) attenuates tolerance to nicotine in rats
Mohammed Shoaib
Present address: Preclinical Pharmacology Branch, Addiction Research Center, PO Box 5180, Baltimore, MD 21224, USA
Ian P. Stolerman
Section of Behavioural Pharmacology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
Abstract

The N-methyl-D-aspartate antagonist dizocilpine (MK801) has been shown to attenuate neuroadaptations of the locomotor activity responses seen after chronic nicotine administration in rats. The aim of the present study was primarily to examine the effects of dizocilpine on tolerance to the aversive stimulus effect of nicotine, as measured in a conditioned taste aversion (CTA) paradigm. A second aim was to determine whether the previously reported effect of dizocilpine on tolerance to the locomotor depressant effect of nicotine could be confirmed. CTA was assessed from changes in the consumption of saccharin and salt solutions and locomotor activity was measured during 30 min sessions in photocell cages. In control rats, the administration of nicotine (0.4 mg/kg s.c.) produced strong CTA and a biphasic effect on locomotor activity (depression followed by facilitation). Daily treatment for 7 days with nicotine (0.4 mg/kg s.c.) produced tolerance to the CTA and motor effects. This tolerance was not detectable in rats that had received dizocilpine (0.3 mg/kg s.c.) 30 min before each daily injection of nicotine during the period of chronic treatment. The chronic administration of dizocilpine alone did not prevent locomotor effects and CTA when nicotine was administered subsequently. These results suggest that the NMDA receptor may be involved in adaptation to both unconditioned and conditioned behavioural responses to nicotine.

The role of NMDA receptor antagonists in nicotine tolerance, sensitization, and physical dependence: a preclinical review.
Jain R, Mukherjee K, Balhara YP.

National Drug Dependence Treatment Centre and Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, Pin 110029, India. rakajain2001@yahoo.com
Abstract
Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation.

Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists.
Shoaib M, Benwell ME, Akbar MT, Stolerman IP, Balfour DJ.

Department of Psychiatry, Institute of Psychiatry, De Crespigny Park, London.
Abstract
1. The repeated co-administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (0.1 and 0.3 mg kg-1, i.p.) with nicotine (0.4 mg kg-1, s.c.) attenuated the development of tolerance to the locomotor depressant effect of the nicotine in rats. 2. The repeated co-administration of the competitive NMDA antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid, 2 and 8 mg kg-1, i.p.) also attenuated tolerance to the locomotor depressant effect of nicotine. 3. Dizocilpine (0.3 mg kg-1, i.p.) pretreatment attenuated sensitization to the locomotor stimulant effect of nicotine (0.4 mg kg-1, s.c.) and prevented sensitization of nicotine-induced dopamine release in the nucleus accumbens. However, pretreatment with dizocilpine alone caused a modest enhancement of the behavioural response to a subsequent acute dose of nicotine. 4. D-CPPene (2.0 mg kg-1, i.p.) pretreatment prevented sensitization to the nicotine-induced dopamine release in the nucleus accumbens. There was no enhanced locomotor response that could be attributed to nicotine pretreatment when D-CPPene was co-administered with nicotine. However, pretreatment with D-CPPene alone enhanced the locomotor response to an acute dose of nicotine. 5. The results suggest the involvement of NMDA receptors in adaptations of the behavioural and neurochemical effects of nicotine that occur as a result of repeated administration of the drug.


My problems differ from yours and we must choose different pieces to solve what's puzzling us accordingly

I 100% agree, but nicotine tolerance is something pretty universal, i'm only sharing my experience that without memantine all the beneficial effects disappeared, and became replaced with nicotine cravings and irratibility and that memantine not only reversed my nicotine addiction but up till now also kept the same tolerance problems at bay.

This thread was dedicated to nicotine tolerance itself, so far i havent seen any other data on mechanisms behind the development of tolerance to nicotine besides the NMDA complex, if there are other options id be glad to hear them.

Edited by medievil, 28 September 2010 - 11:32 AM.

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#38 aLurker

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Posted 28 September 2010 - 11:52 AM

Looking at the data in your very interesting NMDA antagonists for tolerance thread I'm pretty convinced they can help somewhat with this but I still have no idea how they rank in effectiveness against each other. Anecdotally memantine does seem to have a lot of support for the purpose of preventing tolerance although that might be because of you and others increasing awareness about memantine specifically thus leading to more people trying it for this purpose.

I'm sure you got my point though. It might be wise to look at the big picture when choosing which NMDA antagonist might benefit ones specific overall situation more. For instance taking a NMDA antagonist just to avoid tolerance to something doesn't strike me as very wise when there might be a more suitable NMDA antagonist with additional benefits.

Edit: Thanks for posting those studies, very interesting and relevant.

Edited by aLurker, 28 September 2010 - 11:57 AM.


#39 medievil

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Posted 28 September 2010 - 11:57 AM

Altough he added it to memantine after adding acamprosate my friend noticed that nicotine worked again (togheter with he's other stuff) its not a direct nmda antagonist, here's more info on acamprosate:

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acamprosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 microM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 +/- 1.1 microM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50 of 645 microM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 microM range. However, under conditions of maximal receptor activation (100 microM glutamate, 30 microM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations >100 microM). When these binding studies were performed in the presence of 1 microM spermidine, the enhancing effects of acamprosate on [3H]dizocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

Abstract
Background:  Glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) have been suggested to be involved in the positive reinforcing and dopamine elevating effects of ethanol. Recent studies have also shown that ethanol high-preferring rats substantially decrease their ethanol intake when treated with a glycine transporter 1 inhibitor (ORG 25935). Acamprosate, a drug used for relapse prevention in treatment of alcohol dependence, has also been demonstrated to elevate extracellular dopamine levels in the nAc. However, the underlying mechanism of action of acamprosate is not fully understood. Here we investigated whether acamprosate interferes with a neuronal circuitry that previously has been demonstrated to be involved in the dopamine elevating effects of ethanol and taurine.

Methods:  In vivo microdialysis in freely moving rats was used to assess accumbal dopamine levels before and during local (nAc) or systemic administration of acamprosate.

Results:  Perfusion of 0.5 mM acamprosate in the nAc significantly increased dopamine levels. Pretreatment either with 10 μM strychnine in the nAc or 100 μM mecamylamine in the VTA, completely antagonized the acamprosate-induced elevation of accumbal dopamine levels. Also, systemic acamprosate administration elevated accumbal dopamine output, an effect that was abolished by local (nAc) pretreatment with 10 μM strychnine.

Conclusions:  These results suggest that both systemic and local application of acamprosate elevate extracellular dopamine levels in the nAc by activating accumbal GlyRs, and, secondarily, tegmental nAChRs.

Titre du document / Document title
Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption : relationship to acamprosate actions
Auteur(s) / Author(s)
BLEDNOV Yuri A. ; HARRIS R. Adron ;
Résumé / Abstract
Recent studies have demonstrated that metabotropic glutamate receptor 5 (mGluR5) antagonists decrease alcohol self-administration and suggest that the anti-craving medication, acamprosate, may also act to decrease mGluR5 function. To address the role of mGluR5 in behavioural actions of ethanol and acamprosate, we compared mutant mice with deletion of the mGluR5 gene and mice treated with a mGluR5 antagonist (MPEP) or acamprosate. Lack of mGluR5 or administration of MPEP reduced the severity of alcohol-induced withdrawal (AW), increased the sedative effect of alcohol (duration of loss of righting reflex; LORR), and increased basal motor activity. The motor stimulation produced by ethanol was blocked by deletion of mGluR5, but not by injection of MPEP. Both acamprosate and MPEP increased ethanol-induced LORR and reduced AW. Importantly, the protective effects of both MPEP and acamprosate on AW were found when the drugs were injected before, but not after, injection of ethanol. This indicates that the drugs prevented development of dependence rather than merely producing an anticonvulsant action. No effects of acamprosate or MPEP on ethanol-induced LORR and AW were found in mGluR5 knockout mice, demonstrating that mGluR5 is required for these actions. mGluR5 null mutant mice showed decreased alcohol consumption in some, but not all, tests. These data show the importance of mGluR5 for several actions of alcohol and support the hypothesis that some effects of acamprosate require mGluR5 signalling.


Just throwing things out here that have worked for some, and the mechanism behind the drug.

I'm sure there are far more options then memantine, but lets review them all here in the thread :)
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#40 medievil

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Posted 28 September 2010 - 12:00 PM

I'm sure you got my point though. It might be wise to look at the big picture when choosing which NMDA antagonist might benefit ones specific overall situation more. For instance taking a NMDA antagonist just to avoid tolerance to something doesn't strike me as very wise when there might be a more suitable NMDA antagonist with additional benefits.


That was actually the only reason i started taking memantine :-D It seemed to be the best NMDA antagonist out there because its a very weak nmda antagonist basicly and lacks most of the side effect seen with other nmda antagonists.

For me it only dramatically reduces my ocd, for the rest it feels like placebo if i dont take it with something else (except maybe increased feeling of wellbeing).

#41 aLurker

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Posted 28 September 2010 - 12:07 PM

I'm sure you got my point though. It might be wise to look at the big picture when choosing which NMDA antagonist might benefit ones specific overall situation more. For instance taking a NMDA antagonist just to avoid tolerance to something doesn't strike me as very wise when there might be a more suitable NMDA antagonist with additional benefits.


That was actually the only reason i started taking memantine :-D It seemed to be the best NMDA antagonist out there because its a very weak nmda antagonist basicly and lacks most of the side effect seen with other nmda antagonists.

For me it only dramatically reduces my ocd, for the rest it feels like placebo if i dont take it with something else (except maybe increased feeling of wellbeing).


Intriguing. If memantine is a very weak NMDA antagonist and still seems to work fine for the purpose does the degree of NMDA antagonism (and perhaps also the mechanism) have an effect on how much the antagonist affects tolerance?

Edited by aLurker, 28 September 2010 - 12:09 PM.


#42 medievil

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Posted 28 September 2010 - 12:10 PM

I'm sure you got my point though. It might be wise to look at the big picture when choosing which NMDA antagonist might benefit ones specific overall situation more. For instance taking a NMDA antagonist just to avoid tolerance to something doesn't strike me as very wise when there might be a more suitable NMDA antagonist with additional benefits.


That was actually the only reason i started taking memantine :-D It seemed to be the best NMDA antagonist out there because its a very weak nmda antagonist basicly and lacks most of the side effect seen with other nmda antagonists.

For me it only dramatically reduces my ocd, for the rest it feels like placebo if i dont take it with something else (except maybe increased feeling of wellbeing).


Intriguing. If memantine is a very weak NMDA antagonist and still seems to work fine for the purpose does the degree of NMDA antagonism have an effect on how much the antagonist affects tolerance?

huh? i dont understand your question.

Its kinda works like a "partional antagonist" allowing normal glutaminergic transmission but blocking excess transmission.

Because memantine has a low-to-moderate affinity for NMDA receptors, it does not seem to block normal glutamate transmission; rather, it reduces abnormal neurotransmitter-mediated activation of the receptors,4

http://www.jaoa.org/cgi/content/full/106/6/358

#43 aLurker

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Posted 28 September 2010 - 12:20 PM

Sorry if I was a bit unclear.
I was alluding to that depending on the mechanism on the NMDA receptors and the degree of antagonism different NMDA antagonists might be more or less effective when it comes to preventing tolerance to substances.

A specific example: memantine might be more or less effective compared to atomoxetine when it comes to preventing tolerance to nicotine and this might in turn be because they work in a different way on the NMDA receptors.

I hope this illustrates what I was attempting to communicate.

#44 medievil

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Posted 28 September 2010 - 12:27 PM

The only way to find that out is by reading anecdotal reports, memantine is a weak nmda antagonist yet strong enough to prevent tolerance for many people. I havent seen any report on strattera and its possible the dose needed for tolerance is higher then the therapeutic dose.

I only beleive a certain nmda antagonist works for tolerance when ive seen consistent and convincing anecdotal reports.

#45 aLurker

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Posted 28 September 2010 - 12:53 PM

Ok. Both memantine and atomoxetine are open-channel blocking non-competitive NMDA receptor antagonists so they have a lot in common although I'll have to look at it in more detail later. Memantine has a low-to-moderate affinity for NMDA receptors and right now I have no idea what affinity atomoxetine has but at least atomoxetine shows some promise too although I admit at least one anecdotal report would be comforting. The study showing NMDA antagonism is from 2010 and I had personally no idea Strattera even had the potential to combat tolerance until Rol82 posted his regimen. Any anecdotes whether atomoxetine works or not for this purpose are most welcome. I suspect that many of the anecdotes about memantine are due to how well known this potential effect is by now. Perhaps some snooping around on addforums is in place since I'm sure a few there use Strattera and a stim concurrently. I don't have time for that right now though but if anyone finds any success stories or utter failures please let me know.

#46 medievil

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Posted 28 September 2010 - 01:00 PM

Personally i wouldnt count on strattera doing any favors for tolerance, its also a NMDA antagonist yes but we have no idea about apropiate dosing or anything else.

D4 receptors dont downregulate when chronically activated by a ligand, wich is the reason amphetamine keeps working for ADHD without tolerance for years, D4 plays the biggest role in activating the prefrontal cortex and ADHD.
Ppl with ADHD that take the combo of strattera and a stimulant for years without tolerance doesnt mean a thing in other words.

#47 aLurker

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Posted 28 September 2010 - 01:06 PM

Interesting. From what I've seen before on the addforums tolerance to stims seems to be quite common over there too. You might have a point though, a more relevant question might then be if anyone has experienced a reversal of tolerance due to Strattera since you claim that this is possible with memantine.

#48 medievil

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Posted 28 September 2010 - 01:11 PM

Good luck finding an answer for that, from my digging trough anecdotal reports i havent seen anything convincing that strattera helped anyone with tolerance.

I only claimed memantine reversed my nicotine addiction, all the rest it can only slow or block the onset of tolerance and reverse it faster when going on a break.

#49 aLurker

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Posted 28 September 2010 - 01:16 PM

Okay, thanks for indulging my inquisitiveness. I'm a little dishearten though since you seem to have looked through a lot of anecdotes for your NMDA tolerance thread. :/

#50 chrono

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Posted 28 September 2010 - 04:07 PM

I think medievil's recommendation of memantine is a very good one, in the context of this thread. It has a number of studies demonstrating a specific ability to reverse tolerance, and positive anecdotal evidence on pretty much every relevant forum to back it up. Whether it works for nicotine is more debatable, but the papers medievil posted make it a pretty good bet, I think.

The cognitive effects are certainly a variable. This thread on ADDforums seems to be mostly positive, as was this trial on ADD kids. Also closer to home, Pike mentioned yesterday that it's his favorite nootropic.

The extent and relevance of its interference with a7* is pretty debatable too, I think. Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons seems fairly damning, but this response letter makes some excellent points:

Although it has been shown that α7 nAChR agonists enhance cognition and are neuroprotective, it is not clear whether these effects are the result of receptor activation per se or activation-induced receptor desensitization, because α7 nAChRs are known to rapidly desensitize following activation (Quick and Lester, 2002). Furthermore, some effects of α7 nAChR agonists can be mimicked by selective α7 nAChR antagonists (Fujii and Sumikawa, 2000; Ferchmin et al., 2003). Thus, although the authors demonstrate that memantine inhibits α7 nAChR-mediated currents in rat hippocampal neurons, the statement drawn from these data are not supported either by the current state of the field or recent clinical experience.
...
Another important consideration is the reported species differences with respect to the pharmacology of α7 nAChRs, also acknowledged by the authors. For example, Aracava et al. (2005) report a noncompetitive inhibition of rat hippocampal α7 receptor-mediated currents by memantine with an IC50 of 0.34 μM. By contrast, Maskell et al. (2003) have shown that memantine inhibits human α7 nAChRs expressed in Xenopus oocytes with an IC50 approximately 5 μM. The therapeutic concentration of memantine achieved at clinical doses in AD patients is ∼1 μM (Kornhuber and Quack, 1995).


The first paragraph suggests that thinking 'memantine will interfere with nicotine's (beneficial) agonism of a7' is an oversimplification, at least. And the IC50 values are interesting, as well; Kornhuber and Quack, 1995 list plasma levels from 5-30mg doses at 0.025-0.529 μM, with CSF levels strongly correlated to ½ the plasma concentration. This suggests that the brain levels achieved by 20mg may be well below the IC50. However, regarding the possibility that the IC50 is really 5μM, it's important to note that cloned a7 subunits are highly dependent upon the host cells for many of their characteristics [1] [2], so human cells hosted in Xenopus may not possess the same characteristics as in their natural habitat. This complicates, though not necessarily invalidates, the point that the actual IC50 may be higher in humans than in rats.

Another interesting result was an upregulation of a7 and a4, and downregulation of NMDA in rats at high dosages [3].

Memantine also blocks a4b2, but with an IC50 of 6μM [4], making it less likely to be clinically relevant.

As you say, all the effects of any medication should be considered, and not just its putative ability to prevent tolerance. Memantine would be a gamble, but an interesting one. Personally, I would be more hesitant to take strattera. I'm tempted to think that the lack of reports on tolerance reduction is indicative, even in the absence of suggestion. Tolerance to some of the more beneficial effects of adderall (especially motivation) is relatively quick and noticeable, and I couldn't find a single mention of straterra having an impact on it (though admittedly it's complicated by the reinforcement of NRI). My own brief trial didn't go very well; at 25mg it had an effect on my motivation and social anxiety that was much more pronounced than nicotine (whose effect is quite subtle, though noticeable), but around day 3-4 it began to affect my mood in an unacceptable way, making me very uncharacteristically cranky and anhedonic. I'm sure the effect would be different if I stuck with it, but I only have 3 pills left, and my initial excitement at my positive reaction has faded, to say the least. It's perhaps indicative that at ADDforums, they had to create a sticky to collect positive experiences, because they were swallowed up by the tide of negative ones. As rol82 suggested, this may be one that makes more sense if you're on a psychostimulant. I think I would be more inclined to try guanfacine in the future, as there are markedly fewer reports of negative side effects, and impact on mood/personality.

Though having said all that, I don't think you should be using anything (including piracetam/ALCAR) if your diagnosis depends on attentional tests. Give yourself a couple of days' washout before.

Edited by chrono, 30 September 2010 - 11:40 AM.
grammatical clarification

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#51 longevitynow

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Posted 28 September 2010 - 06:09 PM

I have found nicotine gum to be very useful for my procrastination, focus, and energy dips. But I use it very sparingly. I get the 4mg pieces and typically chew 1/8th to 1/4 of a piece. Leave it in my mouth for hours, chew a little more aggressively (or add a little more gum) when the effects are waning(unless it is really late, just chew aggressively for a minute or two). Some times I do it daily, but typically not. I think the idea of constantly using the patches will certainly create tolerance and/or dependence. I use adrenal glandulars, green tea, DHEA, B vitamins (and occassional low dose deprenyl) to balance out my energy, and then use the nicotine gum as a last ditch rescue effort. It works like a charm, but again, I use it 1x a day or less. I think it works great for me because I keep it out of my system for the most part.

#52 aLurker

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Posted 28 September 2010 - 07:25 PM

Chrono, awesome post, very educational.

I'll try to contact my doctor and ask how long I have to wait until they test me. If it takes too long I might give memantine a shot in the meantime and stop it well before the tests. Hell, my procrastination issues are borderline OCD anyway and I'm already starting to suspect some tolerance since I've been wasting my time here at imminst too much the last couple of days. :p
Still a lot better than baseline though.

Also, I know you know this already (but others reading might not): atomoxetine (Strattera) is more of a long-term thing and you have to give it time for it to see if it really works for you. Sometimes the side effects are transitory and subside after some use according to some. The side effects of that stuff are truly atrocious on the other hand and it is a miracle they got it approved in the first place considering how common they are, no wonder it has got a bad rep.

Even though most people seem to loath it because of side effects it seems to produce very sustainable long-term results for the few it works for according to a four year study. I don't know of any ADHD medication that can top that in terms of long-term efficacy, perhaps stims in combination with memantine could although that would require a huge study and years of patience to find out. Too bad I left my billion dollar big pharma company and Zen master patience in my other pair of pants.

Edited by aLurker, 28 September 2010 - 07:26 PM.


#53 Rational Madman

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Posted 29 September 2010 - 09:13 AM

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?


At the risk of sounding like the right arm of RevGenetics, they're having a big sale on a number of signature products, so if cost is influencing your reluctance, now would be the time to act.

As for the alcohol, dose and type matters a great deal. Because subjectively speaking, I feel quite terrible and thick when drinking gin, vodka, and beer for some obscure reason. But there are others that I find to be quite integral to everyday living. Here is a rough guide of my observations....

For social functions: Irish whiskey (I suspect the magical green barley plays a role) and pinot noir. For pinot noir, I'm pretty loyal to Maison Louis Jadot, which is ridiculously commercial, and makes me the the subject of peer criticism, but to each his own. But, I like wine from the Bordeaux region especially, and Chateau Haut Beyzac in particular, which is an affinity that's probably owing more to my French ancestry than rationality. The ancestry variable also may play a role in my preference for only Irish and Scottish whiskey, but both countries also have the distinction of producing the most exceptional whiskey in the world, so I suppose its more understandable than my odd aversion to domestic wine. With Irish whiskey, though, I have less of a cognizance/regard of some boundaries, so I become more opinionated, and more daring with my romantic overtures since I'm less susceptible to rejection, and considerably more charming (as confirmed by others)----so less deterred. The green barley beverages are pretty exceptional, and I'm still trying to find a completely satisfactory scientific rationale for their relative effects. If asked to suggest a brand, I would say Jameson's, which is noted for its use of green barley in its blended whiskey.

For sleep: Single malt whiskey is by far the most sedatory, especially when used in conjunction with melatonin. The Islay and Speyside scotches are probably the most indulged, but I like to sample the regions.

Celebratory: Cognac, but its after effects aren't always agreeable, so I rarely indulge.

For cognition: Either Irish whiskey or Champagne, which may deliver cognitive benefits superior to that of red wine----which I may elaborate on sometime.

Overall, I just feel better in every domain when drinking moderately. But, tolerance levels vary, of course, but beware of the fact that not all alcohol is created equal. And remember, crappy beverages will always deliver crappy outcomes, so it's worth paying a bit more.

Edited by chrono, 30 September 2010 - 11:30 AM.


#54 aLurker

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Posted 29 September 2010 - 10:06 AM

At the risk of sounding like the right arm of RevGenetics, they're having a big sale on a number of signature products, so if cost is influencing your reluctance, now would be the time to act.

As for the alcohol, dose and type matters a great deal. Because subjectively speaking, I feel quite terrible and thick when drinking gin, vodka, and beer for some obscure reason. But there are others that I find to be quite integral to everyday living. Here is a rough guide of my observations....

For social functions: Irish \whiskey (I suspect the magical green barley plays a role) and pinot noir. For pinot noir, I'm pretty loyal to Maison Louis Jadot, which is ridiculously commercial, and makes me the the subject of peer criticism, but to each his own. But, I like wine from the Bordeaux region especially, and Chateau Haut Beyzac in particular, which is an affinity that's probably owing more to my French ancestry than rationality. The ancestry variable also may play a role in my preference for only Irish and Scottish whiskey, but both countries also have the distinction of producing the most exceptional whiskey in the world, so I suppose its more understandable than my odd aversion to domestic wine. With Irish whiskey, though, I have less of a cognizance/regard of some boundaries, so I become more opinionated, and more daring with my romantic overtures since I'm less susceptible to rejection, and considerably more charming (as confirmed by others)----so less deterred. The green barley beverages are pretty exceptional, and I'm still trying to find a completely satisfactory scientific rationale for their relative effects. If asked to suggest a brand, I would say Jameson's, which is noted for its use of green barley in its blended whiskey.

For sleep: Single malt whiskey is by far the most sedatory, especially when used in conjunction with melatonin. The Islay and Speyside scotches are probably the most indulged, but I like to sample the regions.

Celebratory: Cognac, but its after effects aren't always agreeable, so I rarely indulge.

For cognition: Either Irish whiskey or Champagne, which may deliver cognitive benefits superior to that of red wine----which I may elaborate on sometime.

Overall, I just feel better in every domain when drinking moderately. But, tolerance levels vary, of course, but beware of the fact that not all alcohol is created equal. And remember, crappy beverages will always deliver crappy outcomes, so it's worth paying a bit more.


I share your penchant for the Islay scotches and would never say no to a taste of Lagavulin, Laphroig or Caol Ila. I loathed whiskey with a passion prior to my first sip of the wonderfully peaty Lagavulin 16 y.o. A glass of red wine has pretty extensively documented health benefits and I drink that too occasionally. Regarding other alcoholic beverages I very much enjoy traditionally made and prepared absinthe too, none of those Czech excuses though.

That said I still consider alcohol in general a guilty pleasure rather than anything that enhances my cognition in any way and I keep my intake very very low. Of course we shouldn't discount the more individual effects alcohol has on our biochemistry, what works for you might not work for me. I read your post in your regimen thread regarding alcohol and while it was very interesting and historically educational it didn't include enough scientific data to convince me of the merits of alcohol itself. If it works for you and your intake is moderate I say go for it, perhaps you should keep track of exactly how much you drink though since the more intelligent someone is the better they are at rationalising their bad habits. I know this from experience and you seem very intelligent and exceedingly good at rationalising your use of alcohol. I'm sure you see past what might be wrongfully interpreted as preachy and see that I'm merely advocating honesty to oneself in conjunction with moderation. I would never give up alcohol entirely myself I would certainly encourage others to taste some of the finer things in life, some of which contain a generous amount of alcohol.

Some of my troubles with alcohol and the stark difference in how we respond to it might also be psychological - I believe alcohol has a detrimental effect on my cognition whereas you believe it enhances yours. Thinking makes it so.

Thanks for the recommendations and I'll make sure to try some of them at social functions where drinking is somewhat expected.

Edited by chrono, 30 September 2010 - 10:45 AM.


#55 medievil

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Posted 29 September 2010 - 10:40 AM

The dose makes all the difference, i remember a study showing a low ammount of alcohol is cognitive enhancing.

#56 aLurker

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Posted 29 September 2010 - 11:42 AM

The dose makes all the difference, i remember a study showing a low ammount of alcohol is cognitive enhancing.


I'd love to see it so I know how full my glass of Laphroaig should be ;)

#57 medievil

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Posted 29 September 2010 - 12:13 PM

http://www2.potsdam....0322154127.html
I'l come up with a better source later.

#58 aLurker

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Posted 29 September 2010 - 02:03 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.


Yes I was specifically thinking of piracetam and memantine together since both has an effect on NMDA, with memantine it is even the hypothesized primary mechanism. My profound ignorance regarding how NMDA receptors work leaves me somewhat perplexed as to how they would work together. Even if there is some anecdotal synergy short-term: how does it look theoretically and how might piracetam interfere with the anti-tolerance effects?

I wouldn't have any real trouble giving piracetam up even though I still notice a slight acute effect regarding mental clarity. If I give atomoxetine a go I'd probably have to consider leaving my deprenyl behind and I would consider that a much bigger loss.

#59 medievil

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Posted 29 September 2010 - 02:27 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.


Yes I was specifically thinking of piracetam and memantine together since both has an effect on NMDA, with memantine it is even the hypothesized primary mechanism. My profound ignorance regarding how NMDA receptors work leaves me somewhat perplexed as to how they would work together. Even if there is some anecdotal synergy short-term: how does it look theoretically and how might piracetam interfere with the anti-tolerance effects?

I wouldn't have any real trouble giving piracetam up even though I still notice a slight acute effect regarding mental clarity. If I give atomoxetine a go I'd probably have to consider leaving my deprenyl behind and I would consider that a much bigger loss.

I think piracetam only modulates NMDA in brainarea's related to cognition and thus not interfere with memantine, they seem very synergetic. Youll have to experiment.

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#60 aLurker

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Posted 29 September 2010 - 03:07 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.


Yes I was specifically thinking of piracetam and memantine together since both has an effect on NMDA, with memantine it is even the hypothesized primary mechanism. My profound ignorance regarding how NMDA receptors work leaves me somewhat perplexed as to how they would work together. Even if there is some anecdotal synergy short-term: how does it look theoretically and how might piracetam interfere with the anti-tolerance effects?

I wouldn't have any real trouble giving piracetam up even though I still notice a slight acute effect regarding mental clarity. If I give atomoxetine a go I'd probably have to consider leaving my deprenyl behind and I would consider that a much bigger loss.

I think piracetam only modulates NMDA in brainarea's related to cognition and thus not interfere with memantine, they seem very synergetic. Youll have to experiment.


Seems largely unknown what, if anything, piracetam actually DOES with the NMDA receptors but the results seem to be increased NMDA receptor density and perhaps also sensitivity. I couldn't find anything indicating piracetam being a NMDA agonist/antagonist though so I guess that's a good thing from an interaction standpoint since I can't find anything indicating any DIRECT action on the NMDA receptors. Piracetam is an allosteric modulator at AMPA receptors though so perhaps that mechanism indirectly affects NMDA receptors (or if one cares to speculate it might also modulate NMDA receptors). Either way the lack of direct effect on NMDA is somewhat encouraging for me when considering concurrent usage with memantine. I'd love for someone more knowledgeable to school me here though since this is the result of 10 min of research.

Edited by aLurker, 29 September 2010 - 03:13 PM.





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