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Not every person bent on cognitive enhancement has the resources to procure pharmacological drugs for off-label use, which is probably the reason racetams are so popular in the nootropics community. Nevertheless, reversible acetylcholinesterase inhibitors are widely available. In fact, the reader may have used one and not realized it. The psychoactive drugs salvia and marijuana (tetrahydrocannibol or THC, specifically) are some of the more common acetylcholinesterase inhibitors, and salvia also agonizes the nAChRs directly.
An alkaloid from the Huperzia serrata plant called Huperzine A, is both a reversible cholinesterase inhibitor and, separately, an antagonist of the NDMA receptor that reacts to the neurotransmitter glutamate. Long used in Chinese folk medicine, Huperzine A has been studied for the treatment of AD, to mixed results. Notably, it is less toxic than donepezil and commonly available as a nutritional supplement. Note that glutamate is the main excitatory neurotransmitter of the nervous system and its receptor NMDA is a main culprit behind the excitotoxicity that causes neuronal death. Moreover, antagonism of the NMDA receptor has been shown to produce antidepressant effects. Consequently, Huperzine A’s secondary action in blocking NMDA may produce neuroprotective and antidepressant effects, particularly when included in polypharmacy.
GINKGO, BACOPA, BERBERINE, AND PALMATINE
There are four more interesting herbal extracts to cover. Gingko biloba and Bacopa monnieri both have dose-dependent effects on acetylcholinesterase inhibition. While bacopa is less inhibitory than gingko at higher doses, it also has anxiolytic (i.e. anti-anxiety) effects, which may be due to a serotonergic effect, while gingko produces an antioxidant effect due to its potent flavonoids. Palmatine and berberine exhibit inhibitory effects on acetylcholinesterase that are synergistic when used in combination. The combination is made more attractive by palmatine’s inhibitory effects on prostate cancer cell growth and berberine’s activation of the AMPK pathway and inhibition of the PCSK9 enzyme. The combination of palmatine and berberine could be considered (mildly) cognitive enhancing, longevity-promoting, chemoprotective, anti-diabetic, and cardioprotective.
ACETYLCHOLINE IS NOT SELECTIVE
But inhibiting the breakdown of acetylcholine is produces a nonselective effect on cholinergic function. As the careful reader will recall from the discussion of acetylcholine’s role in depression, inhibiting the acetylcholinesterase enzyme leads to more acetylcholine in the brain, which agonizes all the cholinergic receptors. Do we want to agonize all of them? Likely not. But to be more specific, we will have to review the receptor types individually, beginning with the less attractive of the lot – the five muscarinic cholinergic receptors.
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