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Research Notes: Supplements and Cognitive FunctionRev Neurol (Paris). 2004 Sep. The brain is an organ elaborated and functioning from substances present in the diet. Dietary regulation of blood glucose level (via ingestion of food with a low glycemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the adult brain consumes 50 p. 100 of dietary carbohydrates, 80 p. 100 of them for energy purposes. The nature of the amino acid composition of dietary proteins contributes to good cerebral function; tryptophan plays a special role. Many indispensable amino acids present in dietary proteins help to elaborate neurotransmitters and neuromodulators. Omega-3 fatty acids provided the first coherent experimental demonstration of the effect of dietary nutrients on the structure and function of the brain. First it was shown that the differentiation and functioning of cultured brain cells requires omega-3 fatty acids. It was then demonstrated that alpha-linolenic acid (ALA) deficiency alters the course of brain development, perturb[ing] the composition and physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes (ALA). This leads to physicochemical modifications, induces biochemical and physiological perturbations, and results in neurosensory and behavioral upset. Consequently, the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (premature and term) conditions the visual and cerebral abilities, including intellectual abilities. Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects of cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's disease. Their deficiency can prevent the satisfactory renewal of membranes and thus accelerate cerebral aging. Iron is necessary to ensure oxygenation, to produce energy in the cerebral parenchyma, and for the synthesis of neurotransmitters. The iodine provided by the thyroid hormone ensures the energy metabolism of the cerebral cells. The absence of iodine during pregnancy induces severe cerebral dysfunction, leading to cretinism. Manganese, copper, and zinc participate in enzymatic mechanisms that protect against free radicals, toxic derivatives of oxygen. The use of glucose by nervous tissue implies the presence of vitamin B1. Vitamin B9 preserves memory during aging, and with vitamin B12 delays the onset of signs of dementia, provided it is administered in a precise clinical window, at the onset of the first symptoms. Vitamins B6 and B12, among others, are directly involved in the synthesis of neurotransmitters. Nerve endings contain the highest concentrations of vitamin C in the human body. Among various vitamin E components, only alpha-tocopherol is involved in nervous membranes. The objective of this update is to give an overview of the effects of dietary nutrients on the structure and certain functions of the brain. Altern Med Rev. 1999 Jun. Dementias and other severe cognitive dysfunction states pose a daunting challenge to existing medical management strategies. An integrative, early intervention approach seems warranted. Whereas, allopathic treatment options are highly limited, nutritional and botanical therapies are available which have proven degrees of efficacy and generally favorable benefit-to-risk profiles. This review covers five such therapies: phosphatidylserine (PS), acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through double-blind trials for improving memory, learning, concentration, word recall, and mood in middle-aged and elderly subjects with dementia or age-related cognitive decline. PS has an excellent benefit-to-risk profile. ALC is an energizer and metabolic cofactor which also benefits various cognitive functions in the middle-aged and elderly, but with a slightly less favorable benefit-to-risk profile. Vinpocetine, found in the lesser periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic enhancer with proven benefits for vascular-based cognitive dysfunction. Two meta-analyses of GbE demonstrate the best preparations offer limited benefits for vascular insufficiencies and even more limited benefits for Alzheimer's, while "commodity" GbE products offer little benefit, if any at all. GbE (and probably also vinpocetine) is incompatible with blood-thinning drugs. Bacopa is an Ayurvedic botanical with apparent anti-anxiety, anti-fatigue, and memory-strengthening effects. These five substances offer interesting contributions to a personalized approach for restoring cognitive function, perhaps eventually in conjunction with the judicious application of growth factors. Excerpts from the full text article: [...] Phosphatidylserine (PS) Phosphatidylserine (PS) is active at cell membranes, and is a major building block for nerve cells, which are rich in membranes.31 Phospholipids make up the continuous matrix of the outer membrane which separates every cell's living interior from the non-living exterior. All the cells of the human body contain PS and rely on its presence for such survival functions as ATP production, ionic homeostasis, and cell-level activation and deactivation. PS is particularly enriched in the membrane systems of nerve cells, including synaptic membrane zones which link each nerve cell to others. Extensive double-blind trials and other clinical testing have established that PS consistently benefits memory, learning, concentration, word choice, and other measurable cognition parameters, as well as mood and the capacity to cope with stress.31-36 Clinical research on PS began in Europe and extends back more than two decades. Double-blind trials conducted in Italy, Belgium, and Germany, as well as in the United States, demonstrate PS benefits older subjects with mild to moderate dementia, as well as middle-aged subjects with the accelerated cognitive decline which characterizes ARCD.37-42 In the 1991 U.S. trial on ARCD conducted by Crook et al, PS seemed to partially restore certain learning and recall capacities.7 On nameface matching, for example, PS improved performance from a functional age of 64 to a functional age of 52. PS is extremely versatile in its clinical application. In addition to its recognized cognitive benefits, in patients with advanced dementia PS will often improve sociability, attention to personal welfare, and cooperation with caregivers.33,36,37,42 PS consistently improves mood, relieving symptoms of anxiety and depression in elderly women.43 PS also improves hypothalamic-pituitary-adrenal integration, thereby improving adaptability to stress and restoring hormone rhythms which often decompensate with advancing age.44 Thus, in elderly men PS partially restored thyroid-stimulating hormone and prolactin secretion rhythms.45 The benefits of PS are not restricted to the middle-aged and elderly. In young, healthy males PS also can improve the process of coping with stress. Three double-blind trials established that in young, healthy male athletes subjected to heavy exercise regimens PS reduced cortisol production while controlling muscle soreness and other aspects of "overtraining." 32,34,35 PS also can benefit children. Two open-label, pilot studies found PS improved attention, behavior, and learning performance, and ameliorated negative mood in 15 out of 20 children aged 4-19 years.46,47 PS reinforced medical interventions which were already in place, such as Ritalin® therapy, and further raised the degree of functioning of these children. The original source of PS for nutritional supplementation was bovine brain, but as this source came into disrepute in Europe the production source was switched to soy. Although few clinical trials have been conducted utilizing soy-PS, it appears to work as well as PS from bovine brain.48,49 The molecular organization of PS is illustrated in Figure 2, alongside a diagrammatic representation of its preferred intra-membrane associations with key proteins, such as the ATPases, ion gates, and signal transduction assemblies. The "tails" of soy PS may differ from those of bovine brain PS, but in any case these are "customized" for use on an organ-by-organ basis after the greater PS molecule is absorbed.50 The indispensable "business end" of the PS molecule is the headgroup, for which native serine amino acid or other phospholipids cannot substitute.51 Findings from numerous experiments conducted with PS on aging animals, and on nerve cell preparations in culture, suggest PS may have trophic action in aging brain tissues, i.e., PS somehow encourages the regrowth of damaged nerve networks. In old rats, PS conserved nerve cell number, size, and functional capacities at the levels normal for young rats.53 PS also may work synergistically with growth factor substances to bring about the addition or restoration of nerve networks in the brain. Imaging techniques performed on demented individuals demonstrate PS can revitalize metabolism across the brain.54 The protein known as NGF (Nerve Growth Factor) has been demonstrated to regulate nerve development and help maintain nerve networks already in place, also boosting cellular antioxidant defenses.55 NGF operates by way of NGF receptors situated on the outer surfaces of nerve cells, particularly in the hippocampus and the cortex, which are the brain's main memory centers. As rats age, the receptors for NGF in the hippocampus tend to decline in number. For example, old rats with the lowest receptor densities performed most poorly on memory tests. In such aged rats, treatment with PS conserved the densities of receptors for NGF at higher levels characteristic of young rats. Simultaneously, PS improved the "intelligence" of these impaired rats toward levels resembling young, non-impaired rats.53 Effective intakes of PS range from 100 mg per day (for smaller children and for maintenance in healthy adults), through 300 mg/day for memory loss, and up to 600 mg/day for mood enhancement.31 PS has an extremely favorable benefit-to-risk profile: its benefits are often remarkable, adverse effects from its use are virtually never seen, and its compatibility with most common drugs is established. Acetyl-L-Carnitine Acetyl-L-Carnitine (ALC) is an orthomolecule which offers major metabolic benefits to the brain. ALC is a metabolic cofactor for the conversion of fatty acids into energy within the mitochondria of the nerve cells, thereby helping to keep them supplied with energy.56 ALC also provides acetylequivalents for the production of acetylcholine, one of the chemical transmitters. ALC is better absorbed than carnitine, its simpler analogue, and crosses the blood-brain barrier better than l-carnitine. A number of double-blind clinical trials suggest ALC may have clinical utility for the management of some forms of cognitive dysfunction.57-61 The latest and most sophisticated trial assessing ALC's benefit in Alzheimer's Disease (average subject age, 71 years)61 failed to find statistically-significant differences for the ALC group versus the placebo group. However, a subsequent "trilinear analysis" by Brooks et al,62 (see fig. 3) based on calculating the rates of change between successive time points over the one-year period of the trial, found ALC benefited the "younger-old" patients (ages 65 or less) over the "older-old" patients. The younger-old patients showed a slower rate of deterioration on the cognitive portion of the ADAS, the Alzheimer's Disease Assessment Scale.63 They may actually have experienced slight improvement, while the older-old continued to lose ground to the disease during the course of the trial. This finding helps explain some of the inconsistencies seen in previous controlled trials with ALC. There is no evidence to suggest ALC could delay the onset of dementia, but delaying dementia progression would still be a clinically meaningful benefit. Based on further calculations and projections, Brooks et al predicted the best age cut-off for ALC in dementia will prove to be 61 years.62 ALC has been employed in the management of other cognitive breakdown states. In one double-blind trial conducted with cognitively impaired ex-alcoholics aged 30-60 years, ALC improved memory, visuo-spatial capacity, and vocabulary recall when given at two grams per day over a test period of three months.64 ALC's beneficial effects on the brain also extend beyond cognition enhancement. In controlled trials, ALC improved depression as well as cooperation, sociability, and attention to personal appearance, though it did not consistently improve anxiety.65 Metabolic studies, many of them conducted in animals and a few non-invasively in humans with NMR (nuclear magnetic resonance) indicate ALC helps the brain maintain the constant supply of energy needed for effective homeostasis. Pettegrew et al found, using 31NMR, that in demented patients ALC boosted the levels of phospholipid precursors for membrane synthesis, while benefiting various measures of cognitive performance.66 This study represents a rare pairing of metabolic investigation with the clinical documentation of a beneficial agent. Its findings specifically suggest ALC facilitates phospholipid metabolism and could potentially synergize with PS. As a general brain energizer, ALC partially protects against ischemic brain damage, and can be helpful for stroke victims.67 ALC also offers survival potential to damaged neurons. In one in vitro study, ALC increased the production of nerve growth factor (NGF) by cultured nerve cells, and helped them respond better to NGF.68 Treatment of aged rats with ALC partially halted the loss of NGF receptors, while improving performance on maze tests. These findings also suggest ALC, like PS, has trophic effects with potential clinical utility. Relatively high intakes of ALC are required in order to best ensure chances for benefit. In the trials with cognitively impaired subjects, intakes ranged from 1,500 to 3,000 mg per day, with most trials using two grams or more. At these intake levels, ALC can intensify dream activity, and it may be contraindicated for subjects with epilepsy or bipolar conditions.56 Vinpocetine Vinpocetine is an alkaloid found in the lesser periwinkle plant, Vinca minor. The structure of vinpocetine is illustrated in Figure 4. Vinpocetine has the most clinical promise for the management of vascular insufficiencies involving the brain. In double-blind trials conducted with patients suffering from mild-to-moderate vascular dementia, vinpocetine benefited memory, learning, and global clinical measures of cognitive performance.69-71 Speech and language, but not mood or coordination, also was improved by vinpocetine. In the only double-blind trial conducted to date assessing vinpocetine's effect against Alzheimer's Disease, no significant benefits were reported.72 Vinpocetine may have clinical utility in the management of stroke sequelae, as suggested by an open-label trial conducted at 40 centers in Japan. The treatment design involved crossover every four weeks between vinpocetine, ifenprodil tartrate, and dihydroergotoxine mesylate.73 Administered at 15 mg per day, vinpocetine produced slight-to-marked improvement in two-thirds of the patients, which was superior to the other two agents tested. This finding was in general accord with a review by these researchers of the results of 13 other similar trials. The rare vascular dementia of the Binswanger type features multiple small infarcts of the cerebral white matter; the white matter which remains is highly vulnerable to further destruction because of widespread impairment of the microcirculation. In eight Binswanger patients vinpocetine improved the delivery of oxygen to these endangered zones, perhaps by adding to its primary vasodilating action an increase of red cell ATP levels.74 Vinpocetine is a highly potent vasodilator, acting by direct relaxation of the vascular smooth muscle. Vinpocetine enhances cerebral blood flow in patients with cerebrovascular disorders.75 Patients from this population who also manifest increased blood viscosity are at greater risk for thrombotic complications. In one such group of patients, vinpocetine had a viscosity-lowering effect on the blood and plasma.76 Vinpocetine is known to decrease platelet and red cell aggregation, and to increase red cell membrane flexibility in stroke patients, as well as in healthy subjects.77-80 Any or all of these mechanisms could be involved in vinpocetine's capacity to lower the viscosity of the blood in vivo. Vinpocetine has clinically substantiated anti-ischemic activity. Here vinpocetine does not have a "stealing" effect, i.e., to remove blood away from underperfused zones of ischemic damage, perhaps because it lowers blood viscosity sufficiently to allow blood flow to continue uninterrupted through these areas. In animal models of anoxia, vinpocetine reduced cerebral edema and prolonged survival.71 Many possible mechanisms underlie vinpocetine's clinical effects (see Nicholson71 for a review). It partially blocks hypoxic damage to brain tissue, and is a good scavenger of hydroxyl radicals.81 It has anticonvulsant action, possibly linked to its neuronal protective capacity and/or its modulation of several chemical transmitter systems. In these respects vinpocetine resembles adenosine, thought to be a major endogenous anticonvulsant and cerebral protectant; Vinpocetine happens to be an effective adenosine re-uptake inhibitor. It increases cerebral metabolism and raises ATP levels in nerve cells, perhaps also raising neuronal excitability more directly by modulating cellular enzymatic control systems. The clinically validated dose range for vinpocetine is 15-45 mg per day. Side-effects may include skin eruptions, flushing, and sometimes gastrointestinal side-effects, but these are rarely serious enough to warrant discontinuation of therapy. A relatively unique aspect of vinpocetine's enhancement of blood flow is that it increases cerebral blood flow more than at the periphery, even though its vasodilator action is similar around the body. Its capacity to selectively enhance brain metabolism may account for this discrepancy, but in any case this property renders vinpocetine potentially safer than many pharmacologic vasodilators. Yet another clinically useful property of vinpocetine is its metal-chelating capacity, which was successfully put to use reversing tumoral calcinosis in hemodialysis patients with renal failure.82 With its highly effective vasodilatory action and capacity to improve small-vessel perfusion, vinpocetine could rival Ginkgo biloba extract as a therapy for vascular insufficiency. In any case, vinpocetine offers impressive benefits for retinal microcirculation and the circulation of the inner ear, joining Ginkgo as a rare treatment for tinnitus.83 Ginkgo biloba Ginkgo biloba extract (herein abbreviated GbE) is the most clinically proven plant extract for the nutritional support of cerebral function. Many double-blind trials have been conducted with GbE, but generally these have been small and fraught with methodological errors; however, these errors have been sorted out in two meta-analyses. The meta-analysis is a statistically sophisticated re-assessment of an agent, generally based on grouping together all the double-blind trials in order to better assess benefits and risks. Out of the Ginkgo meta-analyses have emerged somewhat more objective estimates of its benefit-to-risk profile.84,85 Ginkgo's benefits for cognitive dysfunction and other symptoms of vascular insufficiency withstood the analytical rigor of a 1992 meta-analysis.84 Out of the 40 doubleblind trials compiled from the scientific literature, the six best were evaluated. These showed benefits — for as few as 17 percent of the elderly patients to as many as 71 percent of the younger patients — at dosages most typically 160 mg per day. Safety overall was rated quite good. Thus, for cognitive problems linked to vascular insufficiency, GbE stands with its limitations as an available therapeutic tool. Ginkgo's benefits for the non-vascular dementia of Alzheimer's Disease are relatively minor. When carefully scrutinized, the highly-publicized double-blind trial of LeBars and his collaborators which appeared in a prestigious publication actually demonstrates a minimal degree of benefit.86 LeBars et al reported that only 29 percent of their patients benefited from 120 mg per day of GbE, to an extent comparable to a six-month delay in disease progression. According to their analysis, the small proportion of patients who benefit from Ginkgo and the minor extent of benefit are both exceeded by high doses (160 mg per day) of tacrine, the first of the two pharmaceuticals approved for Alzheimer's Disease. But when prescribed at such high doses, tacrine is linked to a high frequency and severity of liver damage.28 In late 1998, Oken et al published a meta-analysis of Ginkgo for Alzheimer's.85 Including the LeBars et al trial, they found only four trials which met their quality criteria. These totaled 212 subjects in each of the Ginkgo and placebo groups. The calculated "effect size" for benefit was 0.40, or a three percent difference in the ADAS (Alzheimer Disease Assessment Scale)-cognitive subtest. This effect size was modest, even when compared against donepezil (Aricept®), the second approved drug for Alzheimer's, which they calculated had an effect size of 0.42-0.48. The clinical implications of this relatively small effect size for Alzheimer's patients' quality of life is unclear. The four GbE trials disagreed in the evaluations by clinicians, the patients' capacities for "activities of daily living," and the Relative's Rating Instrument, their functional rating scale. The four trials employed GbE doses of 120 or 240 mg per day; however, there was some suggestion from the data that the higher dose of 240 mg could be more effective.85 Ginkgo biloba extracts from different sources seem to have differing degrees of benefit.84,87 Current moves by certain suppliers to increase the "potency" of their extracts by changing the makeup of Ginkgo's flavonoids and terpenes are rarely grounded in clinical testing, and could prove dangerous to consumers. There are reasons to expect that alteration of the basic profile of the standardized Ginkgo biloba extract could transform its anti-inflammatory, protective character into pro-inflammatory biochemistry. In the face of the tremendous level of commercial promotion of Ginkgo extract, it is important for both consumers and health professionals interested in Ginkgo to understand "Ginkgo" has now become a kind of commodity in an opportunistic marketplace. Beyond the conclusions of the meta-analyses, which indicate the source of GbE can affect its clinical efficacy, electro-encephalographic (EEG) scanning techniques further indict the commodity preparations. The EEG studies confirm various GbE preparations have different EEG activation patterns, which might translate into varying degrees of clinical efficiency.87,88 The mechanisms of action of GbE are reasonably well established. The flavonoid constituents contribute mainly free radical scavenging and other antioxidant effects. The terpenes are antagonists of platelet activating factor (PAF), which has myriad pro-inflammatory effects, including adverse effects on neuronal function. With respect to the brain, the compound extract has been found to (1) partially protect against experimental cerebral lipid peroxidation and edema; (2) protect brain neurons against heightened oxidative stress; (3) decrease neuronal injury following ischemia; and (4) protect receptors for chemical transmitters.86 The clinical benefits observed with any Ginkgo extract are an outcome of the compounded actions of its many constituents, so not surprisingly the optimum activity of a GbE preparation depends on having a crucial internal balance between all these active constituents. Ginkgo biloba extracts are not easy to manufacture, but are a necessary vehicle for the administration of Ginkgo. The use of whole Ginkgo leaf by itself or as an additive to the standardized extract, whether undertaken by naive herbalists or by parties with other motivations, is potentially harmful, since the whole leaf can carry toxic compounds.89 Nor is the standardized extract guaranteed to be free of adverse effects. Documented side-effects of standardized GbE include very infrequent, but life-threatening, subdural bleeding.90-92 Hence the use of GbE in combination with blood-thinning drugs is emphatically contraindicated. The doses of GbE used in controlled trials generally ranged from 112 mg to 360 mg per day of the 24:6 standardized extract (standardized to contain at least 24 percent ginkgo heterosides and six percent terpenes). Current indications are that doses from 160 mg and up will prove most consistently beneficial. GbE's cognition-enhancing effects are real, if modest, but quality extracts are called for and their application to some patients with serious conditions should be kept under professional supervision. Bacopa monniera ("Brahmi") Bacopa (Bacopa monniera) or water hyssop, is the source of a centuries-old plant extract with specific cognition-enhancing benefits. In India it is a revered Ayurvedic herbal, popularly accepted for its effectiveness against mental illness and epilepsy.93 Its popular name "Brahmi" is derived from "Brahma," the mystical creator of the Hindu pantheon. Early references to Brahmi sometimes confusingly referred to Centella asiatica, the Indian penniwort more correctly known as "mandukaparni."93 Bacopa has been an important constituent of the Ayurvedic materia medica since at least the sixth century AD.94 According to Hindu concepts, the brain is the center for creative activity, so the agent which best improves this faculty of the brain was christened Brahmi. The active principles of Bacopa, derived from its leaves, are steroidal saponins, which include the bacosides (see Figure 5). These latter compounds are attributed with the capability to enhance nerve impulse transmission and thereby strengthen memory and general cognition. In 1990, Singh and Singh published the results from their open trial with Bacopa, conducted in India on 35 adult patients with anxiety neurosis.95 The dose was 12 g per day of the dried plant in syrup form, for four weeks. Concentration and immediate memory span were both significantly increased (p>0.05 and p>0.01, respectively). On-the-job mental fatigue, measured as total work output and errors committed per unit time, also was improved (p>0.001). Other major symptoms were significantly improved, including nervousness, palpitation, insomnia, headache, tremors, and irritability. The mean total anxiety level was significantly decreased (p>0.05). Mean maladjustment level also significantly improved (p>0.01), as did the disability level (p>0.05). In some cases, disability status was overcome. Side-effects were minor and not clinically important. Bacopa can also be beneficial to children. Traditionally it was used to anoint newborns with the hope of improving their intelligence, to "open the gate of Brahma." Nowadays it is given to schoolchildren for the same purpose. In 1987, Sharma and colleagues performed a single-blind trial in India, administering Bacopa to 40 schoolchildren aged 6-8. Maze learning improved, as did immediate memory and perception, and the children's reaction/performance times. The dose given was 1.05 grams per day for three months, of the dried plant extracted into a syrup form. No side-effects were seen.96 Animal experimentation in Indian laboratories has provided further indications of the memory-enhancing effects of Bacopa, and its protective effects in epilepsy.93, 94 Research continues into the biochemistry and pharmacology of the bacosides. Proc Natl Acad Sci USA. 1981 Jan. To explore the hypothesis that mental retardations are in part genetotrophic diseases (diseases in which the genetic pattern of the afflicted individual requires an augmented supply of one or more nutrients such that when these nutrients are adequately supplied the disease is ameliorated), we carried out a partially double-blind experiment with 16 retarded children (initial IQs, approximately 17-70) of school age who were given nutritional supplements or placebos during a period of 8 months. The supplement contained 8 minerals in moderate amounts and 11 vitamins, mostly in relatively large amounts. During the first 4-month period (double-blind) the 5 children who received supplements increased their average IQ by 5.0-9.6, depending on the investigator, whereas the 11 subjects given placebos showed negligible change. The difference between these two groups is statistically significant (P less than 0.05). During the second period, the subjects who had been given placebos in the first study received supplements; they showed an average IQ increase of at least 10.2, a highly significant gain (P less than 0.001). Three of the five subjects who were given supplements for both periods showed additional IQ gains during the second 4 months. Three of four children with Down syndrome gained between 10 and 25 units in IQ and also showed physical changes toward normal. Other evidence suggests that the supplement improved visual acuity in two children and increased growth rates. These results support the hypothesis that mental retardations are in part genetotrophic in origin. The full text article: About 30 years ago Williams and coworkers (1,2) formulated the concept of genetotrophic disease. A genetotrophic disease is one in which, because of his genetic nature, the afflicted person requires an augmented supply of one or more specific nutrients and in which fulfilling these needs prevents or at least ameliorates the disease. The genetotrophic hypothesis was in mind when G.S., a severely retarded child, was treated by the senior author. When first seen, the patient was 7 years old and in diapers, could not speak, and had an estimated IQ of 25-30. At her instigation, his blood and tissues were analyzed in the laboratories of Mary B. Allen, a biochemist in Richmond, VA. With the cooperation of a physician, Allen devised a nutritional supplement and G.S.'s parents agreed to administer it. There were no noticeable results for several weeks, but after some constituents of the supplement were increased G.S. suddenly began to improve. In a few days he was talking a little; in a few weeks he was learning to read and write, and he began to act like a normal child. When G.S. was 9 years old he read and wrote on the elementary school level, was moderately advanced in arithmetic, and, according to his teacher, was mischievous and active. He rode a bicycle and a skate board, played ball, played a flute, and had an IQ of about 90. It appeared that, even after 7 years of deprivation, G. S. responded to some nutrients in the supplement in a remarkable fashion. His case seemed to support the genetotrophic hypothesis as applied to mental retardation. On the basis of G.S.'s remarkable response and the somewhat less striking responses of several others, we decided to carry out a controlled study of children classified as retarded (IQ less than 75). Experimental Plan. Allen died in 1977. From her records and the laboratory records in our own file it became evident that her subjects showing mental response were those given a supplement similar to that given G.S. We decided to give our subjects this supplement, consisting of 11 vitamins and 8 minerals as shown in Table 1. We also decided to include in the program of supplements, as Allen frequently did, extra thyroid hormone for those children found to be in need of it. All subjects except one were found to need thyroid according to the Barnes method (3) (morning axillary temperature below 36.60C), and thyroid was administered from the beginning for both experimental and control subjects, with the exception of two whose parents refused this part of the program (see Table 2). All parents were asked to restrict the patients' intake of less nutritious, sugary foods and soft drinks and to supply fruits and milk freely.
The daily dose was 6 tablets. The tablets also contained microcrystalline cellulose, povidone, stearic acid, sodium silicoaluminate, hydroxypropylmethylcellulose, propylene glycol, silica gel, polyethylene glycol, titanium dioxide, oleic acid, and tribasic sodium phosphate as excipients. The placebo tablets contained lactose, microcrystalline cellulose, stearic acid, povidone, propylene glycol, hydroxypropylmethylcellulose, titanium dioxide, and oleic acid. The study consisted of two 4-month experimental periods. During the first period, one group of subjects (group I) received supplements and the other group (group II) received placebos. During the second period both groups received supplements. (We recruited the subjects with the understanding that all would eventually receive supplements.) Mental tests and other measurements were carried out before the supplement or placebo regimen was started and were repeated at the end of each 4-month period. The other measurements included height, weight, and urine tests for pH, specific gravity, protein, and blood cells. Electroencephalograms were also made. Parents' reports of compliance and observations were obtained when they returned to obtain monthly supplies oftablets. Subjects. Twenty-two retarded children living in or near Norfolk, VA, were enrolled by their parents. We accepted all volunteers as they were available. About one-third had Down syndrome (see Table 2) and the rest were unclassified (none was microencephalic). About one-third were Black and the rest were Caucasian. Their initial intelligence test scores and other information were sent to William Shive (The University of Texas at Austin) who divided the subjects into two groups matched primarily on the basis of IQ. Originally, there were 10 subjects in group I and 12 subjects in group II. These group assignments were not made known to any of the experimenters until all of the test data were collected and recorded in Shive's office. The group assignments were made known to Bronson Pharmaceuticals (La Canada, CA), the company that furnished the supplements and placebos. Sealed bottles of tablets were given to the parents each month; each bottle labeled only with the child's name and the dosage: six tablets to be swallowed each day, preferably two at each meal. During the first 4 months, six subjects dropped out, mostly because of transfers of military families to new locations. Five of these were in group I. The 16 subjects who completed the first 4-month experimental period are described in Table 2, which also shows their initial IQ scores. The groups of 5 and 11 members were reasonably well matched with respect to IQ (mean + SEM IQ 46.3 + 3.6 and 48.5 + 5.2, respectively). Mental Tests. Parents were asked to obtain two mental tests of their child during each of the three testing periods; one test was administered by the principal investigator (R.F.H.) and the other by the parents' choice among six local psychologists. All seven psychologists were either licensed or certified; some were school psychologists and others were in private practice. When two concurrent IQ scores differed by 10 points or more a third test by a third examiner was sought. Most testing (84%) was done with the Stanford-Binet Intelligence Scale, Form L-M, because it is standardized for the low mental age of most of our subjects. R.F.H. used the Stanford-Binet test throughout, except that for two mute children (D.D. and D.H.) the Cattell Infant Scale was used. The Wechsler Intelligence Scale was used by the other testers to obtain the following results: D.M., 49; S.R., 70, 70; J.B., 61; T.C., 65, 80; D.D., 36; E.H., 40; B.M., 40; S.O., 50; M.W., 43; G.W., 47. R.F.H. knew that all subjects at the third (8-month) testing had received supplements (hence this portion of the experiment was not double-blind); the other testers did not know this. Testing these severely retarded children was difficult because some ofthem had multiple handicaps. Some were subject to seizures and were taking anticonvulsive drugs, some were unresponsive or hostile, two were mute, and some had impaired vision or hearing. In two children, vision or hearing impairments were sometimes not detected or allowed for in the testing (see Table 2).
Results Intelligence Quotients. Table 2 lists all the IQ measurements obtained for the 16 subjects who completed the first 4-month period. Table 3 shows an analysis of the data. Initial IQs ranged from about 70 to 17. IQ changes after 4 and 8 months are shown in Table 3 in two ways: (i) based upon the means of measurements by two or more of the seven psychologists, and (ii) based upon the measurements by the principal investigator (R.F.H.) only. The results after the first 4-month period appear promising. The mean value for the five subjects given the supplement increased by a mean of 5.0 (for R.F.H. values, 9.6), whereas that for the 11 placebo subjects did not increase significantly (0.0; R.F.H. values, 1.1). This difference between supplemented and placebo subjects is statistically significant by the one-tailed t test: P < 0.05 (R.F.H. values, P < 0.005). If we exclude the subject who took supplements only sporadically and exclude the other dubious measurements noted in Table 2, the mean increase in four subjects is 10.8 (R.F.H. value, 10.3), compared to minor changes in the placebo subjects (0.1; R. F. H. value, 1.5). This exclusion increases the statistical significance to P < 0.001 (R.F.H. value, P < < 0.001). By the end of the second 4-month period the 10 remaining subjects of group II showed a mean IQ increase of 10.2 (R.F.H. value, 11.2). These increases are statistically significant compared to the minor changes for the same subjects on placebos: P < 0.001 (R.F.H. value, P << 0.001). If we exclude the dubious IQ measurements marked by footnotes in Table 2, the mean IQ improvement increases slightly to 11.2 (R.F.H. value, 11.3). According to the IQs measured by R.F.H., 13 of 14 children given supplements showed IQ score improvement of 6 or more, up to 25. The one exception (B.M.) was known to have often refused the tablets. Score differences of 6 or more are probably real, because only 1 of 11 of R.F.H.'s measurements in the placebo subjects indicated changes of more than 4. Six of the 14 children given supplements displayed gains of 15 or more as measured by R.F.H. At least three of the five children who received supplements during both 4-month periods showed further improvements in IQ during the second period, for an overall average gain of nearly 16. After completion of the planned 8-month experiment the children in group II were given supplements for an additional 4 months, for a total of 8 months of supplementation. Their IQs then were measured by one of us (R.F.H.) and compared to the initial IQs measured by her. With the exception of subject B.M., who was known to take supplements only sporadically and whose improvement in IQ score was only 2, the increases after 8 months of supplementation ranged from 12 to 24 for the nine subjects measured. The mean (+-SEM) increase was 16.0 ?2.2, which is similar to the gain (15.8 +- 3.4) found for group I after 8 months of supplementation (Table 3). Judging from modest but statistically significant non-zero linear correlation coefficients, the data indicate that the greatest improvements tended to occur in the younger children. However, G.W. was a notable exception (age 13; IQ increase, 19 points), and we hesitate to emphasize this analysis on the basis of our limited study.
Heights and Weights. In both groups, during their first 4 months of supplementation the children gained in height on the average more than twice as much as did the group II subjects on placebo: 2.13 +- 0.64 cm in 4 months for 14 measured subjects vs. 0.89 ?0.43 cm in 4 months for 11 subjects (means +-SEM). Weight changes were too irregular to be meaningful. Urinalyses. Routine urinalyses made by the Department of Pathology of Norfolk General Hospital at 4-month intervals were monitored by two of us (J.P. and L.R.R.). All values of pH, specific gravity, protein, and blood cell counts were normal. Electroencephalograms. Two encephalographers at the same hospital, James E. Ethridge, Jr., and one of us (L.R.R.), found no changes that could be correlated with the regimen of supplements. Visual Acuity. During the second or third mental testing periods, one of us (R.F.H.) noted that three of the four subjects who wore glasses (J.B., S.R., and C.D.) removed their glasses when they wished to see the task at hand clearly. After the code was broken she found that in each case this observation was made after the child had received supplements for 4 months. Subsequently, two of the children (S.R. and C. D.), long accustomed to wearing glasses, were advised by their ophthalmologists to discontinue wearing them. One child (S.R.), a 9-year-old girl with Down syndrome, developed cataracts which were discovered by her ophthalmologist at about the time the experiment began. S.R. received supplements throughout the experiment. At 6-week intervals the ophthalmologist examined S.R.'s eyes for growth of the cataracts. After 8 months, near the study's end, he reported the condition as "stabilized, not worsening, not progressing as most cataracts do." This finding is consistent with earlier findings in humans (4) and in animals (5) that cataracts may be prevented or delayed by nutritional improvements. Improvements in Down Syndrome. The children with Down syndrome were the only ones whose physical appearance changed notably during the study. These changes were noted by the principal investigator and by the parents and were visible in photographs taken of the subjects at 4-month intervals. Three of these children (C.D., S.R., and L.A.) tended to lose the accumulated fluid in their faces and extremities. The largest IQ gain observed (25 units) occurred in L.A. after 8 months of supplementation. The lone drop-out during the second period (E.H.) occurred because the parents were unprepared for the changes in the formerly docile subject's personality. Other Effects. Several children improved greatly in school achievement. For example, J.B. (age 5-6), who said only single words such as "Mama" or "bye-bye" initially, could recite without prompting the Pledge of Allegiance after 8 months of supplementation and could read the first-grade primer. Two (T.C. and R.S.) have been transferred from programs for the mentally retarded to regular schools and grades, on their teachers' recommendations. There were no unfavorable side effects noted or brought to our attention in any of the children. There were some favorable reports on improved texture of finger nails, healthier hair or skin, and (in six cases) cessation of hyperactivity. Discussion The concept of genetotrophic disease prompted the clinical trials that led to this exploratory study. According to this concept, maladies of many sorts may be caused by genetically determined insufficiencies that may be prevented or at least ameliorated by an augmented supply of one or more specific nutrients. There are a number of well-recognized genetic diseases that clearly are genetotrophic in origin, in particular several diseases that respond to increased intakes of vitamin B6 (6) or of vitamin D or its metabolites (7). In some cases the augmented supply of nutrients appears to enhance the impaired activity of defective enzymes that use vitamin B6 as a cofactor or to increase the availability of biochemically active derivatives of vitamin D. In view of the ubiquitous occurrence of biochemical individuality (2), including the vast amount of genetic variability that is detectable in humans and in other species by protein electrophoresis (8), it seems likely that the currently recognized examples of genetotrophic disease represent only the most simple and obvious members of a large class. Although none of our 15 subjects given supplements responded as spectacularly as did G.S., and further studies are required, our exploratory double-blind study supports the hypothesis that mental retardations in part have genetotrophic origins and that suitable nutritional intervention can improve the IQ and functioning of severely retarded children. All of our subjects who cooperated in taking the supplements showed improvement, sometimes dramatic and surprising to the teachers and other professionals who dealt with them. If our findings are confirmed by more extensive experiments, they bring new hope for improving the quality of life for the mentally retarded 3.2% of our population. We hope that our results will attract other competent investigators to this field and that nutritional studies to explore the prevention and treatment of mental retardation will become commonplace. There are many questions such as the effects of age, initial IQ, type of retardation, and characteristics of the supplementation that can be answered only by more extensive studies. It is likely, on theoretical grounds and on the basis of our evidence of a correlation with age, that the earliest possible use of supplementation for potentially retarded children will bring the greatest improvements. Prenatal supplementation should be considered in this connection. It seems certain that better supplements can be found than the particular combination we tested. Our supplement includes no provision for anyone who needs augmented intakes of the individual essential amino acids, choline (9), fatty acids, biotin, vitamin K, or trace minerals such as chromium, selenium, or molybdenum. And it fails to provide normal metabolites or food factors that ordinarily are not dietary essentials, such as vitamin metabolites, glutamine (10, 11) and other "nonessential" amino acids, inositol, pangamic acid, and coenzyme Q. All of these items must be considered in any thorough attempt to discover and prevent genetotrophic diseases. Ultimately it should be possible to tailor supplements to meet individual needs, at which time perhaps several of the nutrients we included could be reduced or eliminated in individual cases (different nutrients for different individuals), and even greater amounts of specific nutrients might be called for on an individual basis. This will require long and careful research aimed at answering specific detailed questions. The administration of a number of drugs at the same time, sometimes referred to as the "shotgun" approach, is a dubious procedure. The administration of several nutrients at the same time should not be confused with this approach because of the scientific fact that a number of nutrients often do work together as a team to promote normal metabolism (5). At least until adequate methods become available for assessing the needs of individual mentally deficient children, we suggest that the most rapid and greatest potential benefits for them will come from research using generous, limited-risk supplements at least as broad as the one we tested. The lack of IQ changes in the placebo subjects indicates that, in this experiment, thyroid administration alone had no appreciable effect on IQ. Related Research. One of us (R.F.H.) has published several related studies in which children's IQs have been raised slightly by the administration of thiamin (12, 13) and in which the children of pregnant and nursing mothers, given limited supplements had statistically higher IQs measured at age 3 (14). Hall has reviewed a large number of suggestive reports on the effect of various nutrients on subjects with mental retardation or other mental problems (15). Kubala and Katz (16) found the average IQ score to be 4.5 higher in 72 students with plasma ascorbic acid levels >1.1 mg/dl than in 72 students matched by socio-economic criteria but with plasma levels <1.1 mg/dl. Most of this difference in IQ was abolished after both groups were given supplemental orange juice for 6 months. From these statistically significant results they concluded that some of the variance in intelligence test performance is determined by the "temporary nutritional state of the individual, at least with regard to . . . ascorbic acid." Kershner and Hawke (17) recently studied the effects of an improved diet and four vitamins on the IQ, school achievements, and other measurements in 20 learning-disabled children. For 6 months, large amounts of ascorbic acid, niacinamide, calcium pantothenate, and pyridoxine were given to 10 of the children on a double-blind basis. The improved diet seemed to produce benefits, but the supplement added to the diet produced little additional effect. However, there were suggestive improvements in IQ and in reading tests that occurred only in the group given the supplement. Several physicians have reported that nutritional supplements help ameliorate Down syndrome, but the reports of benefits, including IQ improvements, are difficult to evaluate. Many drugs were used concurrently, and the reports generally lack data or statistical analysis (18, 19). |
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