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http://en.wikipedia.org/wiki/Memantine -
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http://en.wikipedia.org/wiki/Amantadine -
-Unsurprisingly, these chemicals were first approved for use in the treatment of Parkinson's disease, and more recently for moderate-to-severe Alzheimer's. They both act primarily as NMDA glutamate-type receptor antagonists; by now the reader should realize the importance, and consequent prevalence, of NMDA antagonistic drugs in the pursuit of enhanced cognitive abilities, particularly in learning and memory.
-These are new drugs, as far as clinical usage goes, and so their pharmacological actions are poorly understood. From the reading I've done, it seems that in addition to their modulation of NMDA/glutamate receptors, they act on dopamine systems. Memantine is an agonist at the D2 receptor (which is the most relevant for our purposes), while amantadine increases dopamine release and inhibits its reuptake. This property is clinically relevant in Parkinson's, although it is considered a weak option (therapeutically).
-An interesting use of amantadine was in the treatment of the flu, including avian influenza. Due to the massive amount of amantadine administered to chickens by Chinese farmers (in order to prevent bird flu), as well as its widespread use in flu vaccines, most strains of influenza are resistant or immune to amantadine. Although the obsolescence of amantadine as flu treatment has reduced its market presence, companies with an interest in the manufacture of this drug are likely to conduct more research into its use as an antiparkinsons agent.
-->Clearly, there is a trend amongst these potential nootropics in that they are literally almost ALL used exclusively in the treatment of Parkinson's or Alzheimer's. Perhaps we should take all the drugs used in treatment of these disorders (which hmmmm ultimately produce severe degeneracy of cognitive function or motor function) and give them approval for use in the general public. At least those who were brave enough and cared enough about maximizing their mental acuity would have the OPTION to expand the bounds of their neurological capacity. Oh well, one day; until then I'll just hope we move towards it and convince doctors that I have Parkinson's and Alzheimer's. Haha, just kidding about that last part. (luckily, many of these drugs are starting to be approved for a variety of things, opening the door to legitimate cognitive augmentation).
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http://en.wikipedia.org/wiki/Selegiline -
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http://en.wikipedia.org/wiki/Phenylethylamine -
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http://en.wikipedia.org/wiki/Carbidopa -
-In my opinion, this has the potential to be a genius combination of chemicals, but also risky to push the envelope with dosages; careful monitoring of the physiological effects of all chemicals, as well as their interactions, would be key to safety. Luckily selegiline has shown low to non-existent potential for a tyramine-induced hypertensive crisis, and the MAO-B selectivity of selegiline can be maintained through modest dose administration.
-Selegiline's primary mechanism of action is MAO-B inhibition; this allows extended duration of extracellular concentrations of dopamine and phenylethylamine (PEA) due to less enzyme breakdown activity (monoamine oxidase B is responsible for the metabolism of dopamine and PEA). Also, its been shown to have neuroprotective qualities following administration of common brain toxins.
-Oral ingestion of PEA is ineffective, due to the rapid metabolism by MAO-B; selegiline is able to inhibit that breakdown enough to make p.o. administration feasible. However, due to the physically uncomfortable peripheral effects (e.g. anxiety, fidgeting, myoclonus, etc.) that high levels of phenylethylamine and dopamine in the PNS can cause, moderation is necessary. The third chemical in this grouping (carbidopa) is suspected (by me) to reduce these undesirable physical effects, while maintaining (or increasing) the activity of dopamine and PEA in the CNS.
-Therefore, the kicker here is carbidopa, which is used in treating Parkinson's disease. Dopamine does not readily cross the blood brain barrier, which means direct ingestion or administration of dopamine (which is actually readily available in many foods) is ineffective in increasing neuronal dopamine concentrations. Carbidopa is used to inhibit DOPA Decarboxylase (DDC), which is involved in the breakdown of L-DOPA, a chemical precursor to dopamine; clinically, L-DOPA is the first line of pharmacological intervention in Parkinson's disease. L-DOPA CAN be administered directly to increase cellular dopamine concentrations, but much of it can be metabolized in the peripheral nervous system (PNS), instead of the central nervous system (CNS) where it exerts its beneficial effects. Thus, by inhibiting DDC, (which is only present and active in the PNS), more L-DOPA and other dopamine related compounds are able to cross the BBB, which enhances the subjective CNS stimulation of these compounds while simultaneously attenuating the unwanted PNS effects.
-In summary, the combination of these three chemicals allows for unprecedented levels of dopamine/PEA in the CNS, without the distracting physical agitation typically produced by high extracellular dopamine/PEA concentrations.
-->While the physiological effects conferred by this combo are surely impressive, neuronal excitotoxicity becomes a concern with such constant and heavy electrochemical bombardment. This issue will be addressed with specific antagonist drugs acting in vulnerable brain pathways.
*(I would prefer rasagiline actually, it has a more potent activity, both in its MAO-B inhibition and neuroprotection; however, it is currently only approved for use in patients with Parkinson's, as well possibly in Alzheimer's, so that's a long shot.)
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http://en.wikipedia.org/wiki/Lisdexamfetamine -
-Now, I like this chemical for a few reasons. First off, the pharmacokinetic profile engineered by the (pro)drug's developer is sheer brilliance; not only does the design of the molecule prevent its abuse, but it provides a very smooth and consistent release of the active chemical. Basically, lisdexamfetamine is the essential amino acid l-lysine bound to the ubiquitous psychostimulant dextroamphetamine. Before the dextroamphetamine can be absorbed by the body, a digestive enzyme called trypsin must break the peptide bond linking lysine to the amphetamine molecule. This is a rate-controlled reaction; although the digestion and absorption of instant (and even extended-release) formulations of amphetamine salts can be greatly affected by factors like gastrointestinal pH, rate of metabolism, etc., lisdexamfetamine consistently provides a smooth effect, due to the maximum achievable rate of hydrolysis. Also, first pass liver metabolism is required to turn the prodrug into active d-amphetamine, which makes the typical routes of abuse (insufflation, injection, etc.) not only ineffective, but completely futile. With the perfection of a smooth release of d-amphetamine, as well as removal of the unnecessary and intolerable levoratory isomer of amphetamine (present in Adderall), this formulation of amphetamine finally tames the unwieldy, powerful, and inconsistent CNS stimulant. It takes away the guessing game of absorption/bioavailability of typical amp combos, and basically packages d-amp with the most biologically tolerable composition possible.
-->In my humble opinion, and from personal experience, amphetamines should be taken with extreme caution and supervision from medical professionals. Despite the impressive performance boosts amphetamines can bestow upon an individual, the risk for dependence, tolerance, and even addiction is high. In fact, the only reason this formulation of d-amp is a realistic option to take for prolonged periods is the relatively benevolent side-effect profile of lisdexamfetamine, along with decreased abuse/dependence liability.
Thanks for reading! I hope you found it interesting and relevant to your interests.
