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