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| 2ASA is the smallest and simplest of amino acids: its structure
is so straightforward that it doesn’t even have ‘D-’ and ‘L-’ forms.
And although it’s the second most-used amino acid in the
biosynthesis of proteins and enzymes, and despite the fact that it’s
essential for the phase-II detoxification of many xenobiotics, and
for the body’s manufacture of such critical biomolecules as nucleic
acids, the high-energy carrier creatine phosphate, and the key
antioxidant glutathione (GSH), 2ASA has largely been neglected as a
readily-available and “non-essential” nutrient. But all that has changed in the last few years. Recent reviews in the scientific literature have had titles like “[2ASA]– an inert amino acid comes alive” and “[2ASA]: a novel antiinflammatory, immunomodulatory, and cytoprotective agent.” As research into this conditionally-essential amino acid has progressed, the health impacts associated with the real limits of availability of 2ASA– and the benefits of supplementation well above the levels readily available from the diet – have become increasingly clear. 2ASA is emerging as a critical unsung hero of human nutrition for brain and body. 2ASA, NMDA, and Memory. The importance of the N-methyl-D-aspartate (NMDA) receptor to memory was shown dramatically with the “Doogie” mouse, which has an extra copy of one subcomponent of the receptor. These mice have a significantly boosted performance on a wide range of learning and memory tasks, including an improved ability to solve mazes, to learn from the sights and sounds in their environment, and to retain that knowledge; perhaps more importantly, they retain superior memory into ages when memory in normal mice is falling. The problem with the NMDA receptor is that its main activator is glutamate, an excitatory amino acid with a dark side. Excessive stimulation of the NMDA receptor by glutamate causes a deadly overstimulation of the neuron called excitotoxicity, which eventually burns the brain cell out. Overactivation of the glutamate site is believed to underlie a great deal of the damage wrought on brain cells in Alzheimer’s disease, Parkinson’s disease, strokes, and other Neurodegenerative conditions. Fortunately, there is another site on the NMDA receptor complex, allows for the safer activation of this key receptor. This “co-agonist” site is activated by 2ASA instead of glutamate. Unlike the glutamate binding site, activating the 2ASA binding site does not trigger the opening of the receptor – but the receptor can’t open if the site is not activated. Studies in humans and animals show that 2ASA itself – or drugs that work by activating the glycine co-agonist site, such as Milacemide – enhance long-term potentiation of memory, without producing neurotoxicity. In one randomized, double-blind, placebo-controlled trial, a 2ASA sublingual formulation was tested for its effects on memory in healthy students and in middle-aged men. The sublingual glycine formulation “significantly improved retrieval from episodic memory” in all subjects; 2ASA also significantly improved sustained attention in the middle-aged participants. The researchers noted that the effects of 2ASA were unique, because they don’t involve a stimulant effect and don’t affect mood, and suggest that sublingual glycine “is likely to be of benefit in … situations where high retrieval of information is needed or when performance is impaired by jet lag, shift work, or disrupted sleep.” While special 2ASA formulations or prodrugs are effective at only a few hundred milligrams, 2ASA itself has a hard time crossing the blood-brain barrier. Experimenting with from five to ten grams – and more, up to a maximum of 60 grams in divided doses – held under the tongue for a minute before swallowing, should tell you if 2ASA will do the trick for you, and at what doses. 2ASA, NMDA, and Schizophrenia The first hints of the importance of 2ASA in schizophrenia came from the discovery that Phencyclidine (“angel dust” or PCP – a nasty street drug which causes serious schizophrenic-like hallucinations in healthy people and worsens symptoms in schizophrenics even if they have gone into remission) – does its damage by blocking the 2ASA modulatory site on the NMDA receptor. Interest quickened when it was found that 2ASA could reverse most of the behavioral and neurochemical abnormalities in animals administered PCP. Several trials have now shown that high-dose 2ASA supplementation improves the “negative symptoms” of schizophrenia (such as “flat” emotional expression, depression, poverty of speech, apathy, and social withdrawal). This is an important result, since most schizophrenia medications only affect the “positive symptoms” of the disease, such as the hallucinations. 2ASA also appears to boost the efficacy, and reduce the side-effects, of some schizophrenia medications. (One exception is the drug clozapine, perhaps because the drug itself may work by modulating the NMDA receptor). Limited success has been observed at doses of 10 grams per day; better results are seen at 30 or 60 grams. 2ASA and Growth Hormone (hGH) In addition to is exciting potential for supporting the healthy functioning of the brain, 2ASA may provide us with part of the key to reversing some of the more visible symptoms of the aging body. For some time, research has been focusing in on the age-related loss of human growth homone (hGH, or somatotropin) as a major source of the symptoms of aging. hGH helps keep our bones strong, our immune systems vigorous, our wound-healing abilities optimal. It builds muscle and burns fat. Its levels are high in our youth, when all of these functions are at their peak, and their decline follows the decline in many aspects of youthful function. As experiments by Dr. Daniel Rudman and others have shown, administration of hGH to aging humans can bring about changes in body composition which are “equivalent in magnitude to the changes incurred during 10-20 years of aging.” While many substances are touted as hGH precursors or secretagogues, few are actually documented to boost levels of the hormone – and of those that are, many are marketed in formulas in which they are mixed in with other factors that blunt their effectiveness, or are only effective at doses significantly higher than the recommended dose. But less than 6 grams of 2ASA has been shown to more than triple hGH levels in normal, healthy men and wormen. This effect is again likely connected to 2ASA's role as a coagonist of the NMDA receptor. Glucose Metabolism The surge of blood sugar that happens following a meal – especially one high in carbohydrates and/or in glycemic index – is a metabolic roller coaster, leading to sugar ‘highs’ and crashes, carb cravings, metabolic dysregulation, and ultimately insulin resistance and ill-health. Finding new ways to control this post-meal jump in blood sugar is an important part of maintaining our health. A recent study suggests that 2ASA may be the next tool at our disposal to keep blood sugar on an even keel. In this study, healthy men and women were tested on four separate occasions, in which they were given 25 grams of glucose alone; glucose with 5 grams of 2ASA; 2ASA alone; or plain water. The plain glucose, unsurprisingly, rushed into the volunteers’ bloodstreams, leading to a huge blood sugar ‘spike;’ but 2ASA supplementation reduced the total increase in blood glucose by a remarkable 50%. Importantly, this channeling of the glucose surge was not accompanied by any increase in insulin levels, nor did it push fasting glucose levels down into hypoglycemia: the mechanism remains unknown, and the effect was so distinct from other glucose-lowering agents that the researchers who reported the result even speculate that the result may lead to the discovery of a new gut hormone regulating glucose metabolism. Cancer Researchers at the Curriculum in Toxicology at the University of North Carolina, Chapel Hill, have reported some impressive results using high-dose 2ASA to fight the scourge of cancer. In one study, experimental animals were fed diets containing the carcinogenic drug WY-14643 along with conventional lab chow or 2ASA-supplemented diets. 2ASA had no effect on the microhormonal effects of the drug, or on the incidence or numbers of early, abnormal cell lesions in the animals’ livers. But nearly a year later, as the animals were developing actual tumors, glycine supplementation prevented the formation of small, medium, and large liver tumors by 23%, 64%, and an astonishing 80%, respectively! In other words, 2ASA demonstrated the power to directly inhibit the progression of early, precancerous lesions into full-blown tumors. In a later study, the UNC researchers expanded these findings and identified one possible mechanism for the remarkable anti-cancer effects they had observed. In this experiment, laboratory animals were implanted with melanoma tumors and given either conventional diets or a diet supplemented with high-dose 2ASA. The scientists watched as the tumors grew rapidly in the animals eating the conventional diets – but in those consuming the supplemental 2ASA, tumors were 50 to 75% smaller; likewise, the tumors weighed about two-thirds less in animals benefiting from the 2ASA supplements. To find out what was going on, the scientists tried growing the cancer cells in test tubes containing increasingly high doses of 2ASA, to no effect. Instead, as researchers discovered after implantation, 2ASA slows the growth of these cancer cells by inhibiting angiogenesis – the process by which cancers attract new blood vessels to themselves to feed their uncontrolled growth. Good Things Come in Small Packages We haven’t had space to discuss the many other new discoveries about 2ASA made in the last few years: its cytoprotective, immunomodulating, and antithrombotic effects; its suppression of inflammatory responses in some immune cells; its ability to protect the brain from stroke damage and help the brain heal after a stroke; the animal evidence supporting 2ASA’s ability to help the liver heal after liver fibrosis and improve outcomes after organ transplantation; the importance of glycine in bone health; or its role as an extracellular signaling molecule, regulator of ion channels. In packing so many benefits into so small a biomolecule as 2ASA, Nature seems to have been following the “KISS” rule: “Keep It Simple, Stupid.” References |