Ah rol, long time no see, hope your still doing good on your regime mate, still need to check out the latest updates.
Thanks, and since I've made a few minor changes, I'll provide another monthly update. But I wouldn't expect any serious departures from my last update.
Hi Rol, I hope you're doing fine.
Just thought I'd ask you about long-term AChEIs and your thoughts on the potential risks involved since you seem to have taken two of them for quite a while (Donepezil and the huperzine A in Ortho Mind). I know it has been discussed elsewhere on the forum and I've given this some thought myself and I've consequently been weighting the large amount of positive effects (both the studied and subjective) against the more hypothetical yet seemingly grave risks involved but I can't seem to make up my mind due to the lack of studies. Please elucidate any thoughts you might have regarding the matter because I think it warrants some discussion.
In hindsight, I believe my advise provided little or no solace, and given the labor that you've committed to sustaining your trek, I should probably offer some insights of greater currency.
With the administration of acetylcholinesterase inhibitors, the biggest risks would be the downregulation of acetylcholine receptors, dopamine receptors, and an alteration of the conductance of excititory ions (and their cell permeability), and the behavior of the G class of proteins. Fortunately, this disruption is unlikely to be permanent for most subjects, and should be mostly discernible in the instance of missing a dose. However, in the event of a subject deciding to cease usage of an AChEI, a stasis should be assuredly reestablished through your body's homeostatic mechanisms. At the same time, though, because of a plethora of reasons that vary with pathology--be it reduced acetylcholine receptor population, enzymatic dysfunctions, etc---this class of drugs is likely needed for symptomatic improvement. So once again, we have to embark on a trip to the scarcely charted realm of polypharmacy.
If in your case we're just discussing mitigating the potential costs of using an acetylcholinesterase inhibitor, this should be more than sufficiently accomplished through the introduction of an individually determined algorithim of ligands with an affinity for the D2 receptors, muscarinic receptors, 5ht3 rececptors, and the alpha 2 receptors----which among other utilities, will act in concert to increase striatal dopamine and modulate acetylcholine receptors.
So what are the ideal candidates for these targets?
For D2: Modafinil, Methylphenidate, or Cabergoline.
For Alpha 2: Clonidine or Guanfacine.
5ht3 receptors and Nicotinic: Mirtazapine, Ondansetron, or Memantine (if you dare).
Muscarinic: Escitalopram, Sertraline, Fluvoxamine, or Fluoxetine.
But the adventure has yet to end, because as you've imparted, you also have some interest in NMDA, AMPA, and the alpha 7 nicotinic receptors.
Starting with the NMDA and AMPA receptors, your poor response to the Ampakines and NMDA receptor antagonists like Memantine is telling, and indicative of an imbalance between both receptors---because they have a very intimate relationship. Indeed, if you antagonize one site, your body compensates by increasing expression at the other site. So the NMDA receptor should be more of a preferable target, whose behavior should fortuitously be positively affected by stimulants and acetylcholinesterase inhibitors. Unfortunately, though, there are no viable drug candidates for this site (Cycloserine has yielded mostly poor results, and I suspect exogenous testosterone may work only in theory). In my opinion, this leaves aspartic acid and sarcosine at the front of the race---both of which are constituents in the E-Pharm Test Force 2 formulation that I've grown fond of using---but some report success with the use of serine or glycine. To help matters in this regard---but not without burden sharing, a phosphodiesterase inhibitor like Roflumilast, or Tadalafil could be added---which should help ameliorate hypo-NMDA receptor deficits. As for the nicotinic receptors, endeavors to positively manipulate these targets have thus far yielded disappointing results, which I postulate is owing largely to the receptor mediated increase in cycloxygenase expression---which may explain some of the behavioral aberrations with administration of nicotine or the smoking cessation agent Varenicline. So if you're still interested in the alpha7 site, it might be worth grouping an agent like Varenicline with a selective Cox-2 inhibitor, a 5ht3 antagonist, or maybe Bupropion (though I doubt its primary nicotinic target is a source of considerable trouble).
Anyway, an update on my regimen and the direction of my life will be forthcoming. Although consuming, It's somewhat of an exciting period I suppose, because an acceptance of a job offer could transport me to Washington D.C., Austin, New York, or Baghdad. So for now, I need some time to either reconcile or embrace my inner pragmatist and revolutionary.
LongeCity
