| R(+)-Lipoic Acid is a key mitochondrial metabolites, needed by these cellular "power plants" to drive nerve cell metabolism. R(+)-Lipoic Acid is the natural, mitochondrial form of this critical orthomolecule - not to be confused with the artificial "racemic compound" sold as "lipoic acid" or "alpha-lipoic acid." R(+)-Lipoic Acid improves the efficiency of mitochondrial function, while preventing the age-related increase in free radical production which is exacerbated when ALCAR is taken alone. R(+)-Lipoic Acid has also been shown to reverse the buildup with age of iron in the brain of laboratory animals - a buildup associated with human neurological disorders. One open study supports the use of lipoic acid in Alzheimer's disease. The dose found in Ortho•Mind is there to "top up" the amount found in a core R(+)-Lipoic Acid supplement used for general health and anti-aging goals.
Vinpocetine and Ginkgo biloba both enhance cerebral microcirculation in the brain, keeping needed energy and oxygen flowing to the brain. Vinpocetine - a phytonutrient found in the periwinkle (Vinca minor) - is especially remarkable in this regard, as it does this without reducing blood flow elsewhere in the body, through reducing the resistance of fine blood vessels within the brain. It does this by reducing excessive activity by a form of the enzyme phosphodiesterase in the brain - a mechanism similar to Viagra® which affects another form of this enzyme in the penis.
Vinpocetine also supports the availability of oxygen and fuel by mechanisms not shared by Ginkgo. First, Vinpocetine enhances the ability of red blood cells to "flex" their shape so as to more easily deliver oxygen across the blood-brain barrier - the layer of tight cell-to-cell contacts that protects the brain from a potentially-toxic environment. Additionally, Vinpocetine allows blood sugar to cross the blood-brain barrier more efficiently, and makes it easier for brain cells to take up and release glucose. By subjecting experimental animals to mock strokes, scientists have been able to show that these properties provide protection against the brain damage that follows the cutting off of circulation that marks a stroke.
Many controlled trials have demonstrated the ability of both Ginkgo and Vinpocetine to support cognitive function. Ginkgo has also been shown to delay the onset of Alzheimer's disease in a large, double-blind, placebo-controlled study. The standard doses are from 15 to 45 milligrams of Vinpocetine and 100 milligrams and up for standardized Ginkgo.
Huperzine-A, an extract of the Chinese club moss (Huperzia serrata), is a unique, natural, nontoxic, and highly selective inhibitor of the enzyme acetylcholinesterase (AChE). AChE breaks down the neurotransmitter (brain messenger-molecule) acetylcholine, which is central to verbal and spatial memory. By inhibiting AChE, Huperzine-A prevents excessive destruction of this key memory-molecule. The only drugs specifically approved to treat Alzheimer's dementia are all AChE inhibitors. However, these drugs (including tacrine (Cognex®), rivastigmine (Exelon®), donepezil (Aricept®), and now galantamine (Reminyl®) have some serious side effects, including red liver damage, bloody or "coffee-ground"-like vomit, irregular heartbeat, fainting spells, seizures, depression, and hallucination. These side effects are due to the fact that these drugs either also bind to other enzymes that they aren't supposed to (such as butyrylcholinesterase (BuChE)), or because they bind in the wrong place (the liver instead of the brain), or because they bind to acetylcholine receptors in addition to AChE, or because of other effects unrelated to their AChE-inhibiting action.
By contrast, Huperzine-A has shown itself to be extremely selective for brain AChE. Joel Sussman, PhD, who helped reveal the molecular interaction between Huperzine-A and AChE, enthused in the Journal of the American Medical association that Huperzine-A "appears to bind more tightly and specifically to [AChE] than the other AChE inhibitors ... It is as if this natural substance were ingeniously designed to fit into the exact spot in [AChE] where it will do the most good." Other advantages of Huperzine-A that make it safer or more effective than the AChE-inhibitor drugs include the fact that it targets the brain much more selectively; that it does not bind to receptors in the central nervous system; and that it keeps working for up to eight hours, which is 10 to 12 times longer than the standard forms of these drugs.
Double-blind, placebo-controlled trials in victims of Alzheimer's disease show that a daily dose of 100 micrograms of Huperzine-A provides clear improvements in memory, cognitive, and behavioral parameters, working at least as well as Cognex® but without any specific side effects. Similar results have been reported in open studies involving persons with dementias caused by stroke or written off to the aging process. Just as importantly, a recent study reported that Huperzine-A improved scores on memory tests and performance in English and Chinese language lessons in young students at the same dose.
L-Pyroglutamic Acid, the so-called "forgotten amino acid," is the natural molecule behind the nootropic drugs, such as piracetam, oxiracetam, and pramiracetam: these drugs are chemically "tweaked" versions of L-Pyroglutamic Acid. No one quite understands how L-Pyroglutamic Acid or the nootropics work: they don't seem to significantly affect neurotransmitter levels, they don't bind to any known receptors, and their metabolism is extremely simple, nontoxic, and "clean."
But however they work, the nootropics' ability to improve learning, memory consolidation, and retrieval in normal, healthy people has been well-established in clinical trials. Piracetam, which is the most widely-researched of these "smart drugs," has also been found effective in dyslexia, although results in Down's syndrome and Alzheimer's disease have been inconclusive. One of the most interesting effects reported with piracetam, and believed to be universal to the nootropics, is its ability to facilitate communication between the left (verbal/logical) and right (spatial/ mathematical/creative) hemispheres of the brain. Subjectively, many users report that L-Pyroglutamic Acid and the nootropics "wake up your brain," although the effect is quite distinct from that of stimulants such as caffeine.
In one randomized, double-blind, placebo-controlled trial, 40 men and women with age-associated memory impairment were first run through a series of memory tests, and then took either a supplement providing 1276 milligrams of L-Pyroglutamic Acid or a look-alike pill for sixty days. At the end of the study, people taking L-Pyroglutamic Acid experienced a 37.8% improvement in their ability to remember words after a twenty-minute pause; a 17% jump in immediate recall of categorized words; a corresponding 30% boost in recall of those same words after a delay; and a 50% lower rate of "false positives" (wrongly "recognizing" faces that they had never seen before). People getting the placebo experienced no improvements.
Despite the sound of the name, L-Pyroglutamic Acid is not a potential "excitotoxin" like glutamate. Studies in laboratory animals have not only shown that feeding large doses of this nutrient to newborn mice are harmless, but that direct injection of L-Pyroglutamic Acid into the adult brain causes no negative effects. In fact, an animal experiment demonstrated that L-Pyroglutamic Acid actually protects the brain from glutamate excitotoxicity!
Citicoline (cytidine diphosphate choline) is not just a source of choline, the main building block of the neurotransmitter acetylcholine. Instead, Citicoline is a brain phospholipid booster.
Phospholipids such as phosphatidylcholine (PC) and phosphatidylserine (PS) are essential components of neural membranes, and their presence is needed for the normal responsiveness of the brain to neurotransmitter signals. Taking individual phospholipids, such as PS, forces more of the specific phospholipid that you're taking into the membranes of nerve and other cells. But it cannot restore the youthful balance of all brain phospholipids. By contrast, Citicoline enhances the brain's ability to synthesize its own phospholipids. As a result, studies in experimental animals show that Citicoline increases levels of all phospholipids in neural membranes - yet the normal, youthful proportions of the various phospholipids are not altered. Citicoline also increases the manufacture or release of key neurotransmitters, including acetylcholine, norepinephrine, dopamine, and serotonin.
Controlled human studies prove that Citicoline provides effective nutritional support in a wide range of cognitive disorders, including Alzheimer's disease, stroke, dementia associated with Parkinson's disease, and head trauma. Double-blind, placebo-controlled trials have also shown that Citicoline significantly improves memory function in persons with "normal" age-related cognitive decline. These trials have used daily Citicoline doses of 300 milligrams and up.
Bacopa monniera, an herb long revered in Ayurvedic tradition, has been used to "open the gateway of intelligence" in infants, and many of the studies documenting its cognitive-enhancing powers have been conducted in school children. Studies have also shown it to be helpful in relieving anxiety. The latest and best study on the brain-boosting powers of Bacopa has given the herb its strongest scientific endorsement yet. In this double-blind, placebo-controlled study, 46 healthy men and women took a battery of neuropsychological tests before the trial began. Then, Australian scientists provided half of them a daily supplement containing 300 milligrams of standardized Bacopa extract, while the remaining 23 people took placebos.
At the end of the twelve-week study, men and women supplementing with Bacopa showed significant improvements in cognitive function compared to the group taking the placebo pill, processing visual information 15% faster (as measured by the inspection time (IT) test), showing a 14% greater rate of learning - and a 33% lower rate of forgetting - verbal information, and a remarkable 108% better ability to consolidate new information without interference from previously-learned data (the problem of "proactive interference"). Few side effects were seen in the study, the most notable being increases in thirst and urination. Interestingly, in fact, the people taking Bacopa actually suffered fewer headaches than did those getting the dummy pills!
Recently, studies have begun to give us some exciting clues about the potential long-term, neuroprotective effects of this Ayurvedic secret. A recent animal study revealed that Bacopa boosts the brain's production of the key protective antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT).
Despite what you might hear, you can't boost levels of SOD or CAT by taking them as preformed supplements: even when taken sublingually, these enzymes are destroyed by other enzymes. One of the few things that can rev up the brain's production of these enzymes is the Parkinson's drug deprenyl (Eldepryl®); this jump in SOD and CAT has been associated - in a series of remarkable experiments in mice, rats, hamsters, and dogs - with remarkable jumps in lifespan. In the most dramatic of these experiments, deprenyl actually extended the built-in maximum lifespan of lab rats by as much as 24% - a feat unprecedented by any other drug or nutrient.
But the results of other studies show that the effect is inconsistent. The success or failure of deprenyl in extending life seems to be closely associated with whether the drug boosts CAT and SOD in these organisms under the conditions of a given study. So it's especially encouraging that the effects of Bacopa on these enzymes were shown to be even more broad-ranging than those of deprenyl, affecting a wider range of areas in the brain, and simultaneously boosting levels of the detoxifying glutathione peroxidase (GSH-Px) enzyme - an effect not seen with deprenyl.
The Grand Old Duke of York ...
If you want to get results with a cognitive support supplement - or any other supplement or drug - it's critical to ensure that you're getting the right dose. Far too few "kitchen sink" nutritional formulas throw in small, meaningless doses of various ingredients just so that they can list the nutrient in question on their labels.
Clinical trials are the "magnetic pole" that can guide us to the effective doses of a given nutrient. But combination cognitive support formulas present unique dosing challenges. Many "smart drugs," botanicals, and nutrients display an "inverted ‘U' response curve:" enough is enough, too little is too little - and too much is too much. Taking excessive amounts of cognitive-enhancing supplements, in other words, can actually make you dumber than taking a "just right" dose! And since these nutrients and botanicals also interact in hard-to-predict synergy, the optimal dose for a given supplement taken alone can be excessive when combined with synergistic partners.
Therefore, each individual must titrate his or her dose of cognition-enhancing nutrients to his or her own optimal level. Ortho•Mind is formulated with amounts of each individual nutrient which are at the low end of the spectrum of doses proven to be effective in controlled clinical trials. But for most people, the full six capsules will be too much, leaving them on the falling side of the inverted "U." So it's best to start low - one or two capsules a day - and build slow, adding one capsule every three days or so, using subjective experience and (if possible) objective tests to guide you to your personal peak in mental performance. For most people, this will be two to four capsules a day.
References
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iv. Grioli S, Lomeo C, Quattropani MC, Spignoli G, Villardita C. "Pyroglutamic acid improves the age associated memory impairment." Fundam Clin Pharmacol. 1990; 4(2):169-73.
v. Alvarez XA, Laredo M, Corzo D, Fernandez-Novoa L, Mouzo R, Perea JE, Daniele D, Cacabelos R. "Citicoline improves memory performance in elderly subjects." Methods Find Exp Clin Pharmacol. 1997 Apr; 19(3): 201-10.
vi. Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, Nathan PJ. "The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects." Psychopharmacology (Berl). 2001 Aug; 156(4): 481-4.
vii. Montgomery SA, Thal LJ, Amrein R. "Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease." Int Clin Psychopharmacol 2003 Mar; 18(2): 61-71.
viii. Hager K, Marahrens A, Kenklies M, Riederer P, Munch G. "Alpha-lipoic acid as a new treatment option for Azheimer type dementia." Arch Gerontol Geriatr 2001 Jun; 32(3): 275-282.
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