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December 1, 2002
Phospholipid mixtures such as lecithin were amongst the first health foods, and lately more sophisticated preparations have emerged as versatile nutraceuticals and ingredients for functional foods. Parris M. Kidd, PhD, reviews their clinical efficacy and safety record.
Phospholipids, found in all life forms, are the prime building blocks of life.1 Some phospholipids may be classified as conditionally essential nutrients because enzymes and co-factors are required for their in vivo synthesis. Dietary phospholipid intake on the part of most people in the West has declined, mainly due to increased food refining and processing. Foods most enriched in phospholipids are eggs, muscle and organ meats, milk, and peanut butter.
Phospholipids are orthomolecules—literally, "molecules orthodox to the body," as defined by the late Nobel Laureate biochemist Linus Pauling.2 Phospholipids have a unique molecular organisation that likely rendered them integral to life from the very beginning.
The phospholipid molecule is amphiphilic, which means that it is charged at one end (hydrophilic, water-friendly) and uncharged at the opposite end (lipophilic, fat-friendly). This endows phospholipids with unique emulsifying and wetting properties. As emulsifiers, for example in the bile digestive fluid, phospholipids ensure fine dispersion of fatty food molecules in the water phase, thus improving digestion and absorption. As surface-active wetting agents, for example in the lungs, intestines and kidneys, phospholipids ensure miscibility at air-liquid and liquid-solid interfaces.
Phospholipid molecules also can spontaneously self-assemble into structured aggregates, as for example in forming the circulating lipoprotein particles that transport fat-soluble nutrients and cholesterol throughout the body. But the most pivotal function of phospholipids for life is in cell membrane systems. These three-dimensional, sheet-like molecular assemblies consist mainly of catalytic proteins built into a continuous matrix or foundation of phospholipids with a small amount of cholesterol.
The phospholipid story began with lecithin, derived from lekithos, the Greek word for egg yolk, by Maurice Gobley when he isolated it from eggs around 1847.4 But egg lecithin was too expensive for industrial use, and widespread commercial application had to await production from the soybean.
Commercial soybean lecithin was first prepared in Germany in the 1920s. Today, lecithin is widely used in the food industry as an emulsifier, wetting agent for food instantising, flow agent for chocolate manufacture, baking stabiliser and pan-release slip agent, flour improver and animal feed additive.
Industrially, lecithins are initially prepared as an oily crude derived from the oil de-gumming process following the soybean crush. Using selective solvent extraction, the less water-miscible, oily components (mostly triglycerides) are first removed. The resulting oil-free, 'de-oiled' lecithin, enriched in phospholipids, can then be further processed to enrich selected phospholipids in the mixture. These are the raw material bases for the commercially available nutraceutical phospholipid formulations.
Chemically, the term phospholipid derives from the fact that these molecules contain phosphorus. They are charged lipids, insoluble in acetone but soluble in polar solvents, such as ethyl alcohol. Hundreds of different phospholipids exist, but currently the nutraceutical phospholipids all come from one class: the glycerophospholipids.
Phosphatidylcholine (PC) used to be called lecithin, being the most abundant single lecithin constituent. To date, findings from all of nine double-blind trials indicate PC clinically supports liver recovery from toxic chemical attack or acute or chronic viral damage.1 In the most recent, a multicentre double-blind trial, 176 patients with chronic viral hepatitis (B or C) were begun on interferon alpha for 24 weeks, then randomised to 1.8g/day PC or placebo for 24 weeks. Significantly more patients with hepatitis C responded to PC. Those with hepatitis B did not respond as favourably to PC. Biochemical response to therapy was defined as a reduction of serum alanine aminotransferase value by more than 50 per cent of pre-treatment values.5 PC also exhibited potentially lifesaving benefit against pharmaceutical and deathcap mushroom poisoning, alcoholic liver damage and the hepatitis B virus.6
The liver is the workhorse organ of the body, and its parenchymal cells depend heavily on the membrane phospholipids to optimally process newly absorbed nutrients, assemble circulating lipoproteins (LDL and HDL cholesterol, among others) and detoxify thousands of potentially toxic incoming chemicals. But membranes are highly vulnerable to toxic or infectious-inflammatory activity, and turnover is high as a result of detoxicative activity. PC is the most abundant phospholipid of cell membranes, therefore the most important building block to furnish replacement membrane mass.
Through its choline headgroup, PC supplies other ingredients for liver regeneration within the methyl groups, which support many key metabolic pathways that are necessary for the gene duplication that precedes cell division. These complementary qualities endow PC with unparalleled importance in liver cell activation, proliferation, maturation and regeneration following damage.
PC has good emulsifying properties, which the liver draws upon to produce the bile fluid. It also has excellent surfactant properties, on which the lung and intestinal lining cells rely for their gas and fluid exchange functions. PC also protects the human GI mucosa against toxic attack.7 PC and other egg phospholipids have been added to infant formula to markedly reduce life-threatening necrotising enterocolitis in hospitalised preterm babies.8 And PC is the predominant building block for the circulating lipoproteins.1,6 PC is safe and well tolerated up to approximately 20 grams daily intake.9 and is affordable for manufacture into functionalised foods. However, PC is not well suited for beverages.
The efficacy of phosphatidylserine (PS) for cognition and other higher brain functions has been established through 20 double-blind trials. The majority of these trials involved subjects aged 50 and older. During the 1990s, two such definitive trials with bovine brain-derived material were conducted in the USA by memory pioneer Thomas H Crook III and colleagues.10,11 In their first trial, 149 patients with age-associated memory impairment took 300mg/day PS or placebo for 12 weeks. Using well-validated tests related to learning and memory tasks of daily life, they found that a patient subgroup that was more severely affected to begin with, improved significantly after taking PS, relative to those taking placebo.7 Crook concluded that PS could "turn back the clock on aging."7
PS may also be helpful to children with cognitive and mood problems.12 CA Ryser, MD, recruited 27 ADHD children three to 19 years old, with their parents' informed consent. She individualised their ADHD regimens with nutrients and pharmaceuticals, as per her usual practice, then added soy PS to their treatment plans. Each received 200mg or 300mg PS daily, depending on body size, for four months.
Ryser concluded that PS yielded clinically significant benefit to 25 of the 27 children. PS improved attention, concentration, learning, behaviour and academic performance, seemingly extending their level of benefit once they had "plateaued" on fish oil and other nutritional supplements. Those prescribed methylphenidate (Ritalin) or other pharmaceuticals also seemed to derive additional benefit from PS which also benefited the depression and anxiety commonly seen in these children. No adverse effects or drug interactions were noted, consistent with PS' 20-year record of safe clinical use. The evident clinical benefit to children from PS in this study—albeit an uncontrolled, unblinded, preliminary study—is consistent with its benefits to memory conservation, brain revitalisation and stress management in adult subjects.
In initial research with PS, researchers used preparations extracted from bovine brains. With the advent of bovine spongiform encephalopathy (mad cow disease), this source became commercially non-viable and a soy source was developed. Subsequently, several double-blind trials have validated soy-derived PS as a viable plant source.13-15
The PS derived from soybeans differs from that of bovine brain in its fatty acid molecular tail profile, but this is not vital for efficacy since most of the tails are clipped off prior to absorption by lipase enzymes; following PS absorption, tails are selectively added or removed by acyltransferase enzymes to meet local tissue requirements.16
In 2001 a double-blind trial was published, with the authors concluding that soy PS was ineffective against age-associated memory impairment (AAMI).17 Critical examination revealed that many of their tests did not adequately measure extent of memory impairment, and many were not sensitive to the effects of age on memory function in AAMI subjects.18 This study failed to make any useful contribution to the current understanding on the efficacy of PS.
Don't Stress Over PS
During the last two years, Benton and collaborators at the University of Wales studied the capacity of PS to ameliorate stress in young, healthy men.19 Forty-eight young male university students were randomly allocated to a PS test group (300mg/day) or placebo (triglycerides). After 30 days of supplementation, the subjects took standard acute stress test: either hard mental arithmetic calculations without a calculator, or strenuous exercise on a bicycle. Students who tended toward being 'neurotic' experienced significantly less stress and significantly improved mood if taking PS, compared to placebo.
This finding is consistent with two previous double-blind trials by P Monteleone and colleagues in Italy, in which injected or oral brain cortex-derived PS significantly lowered stress hormone levels in untrained young men subjected to stressful exercise exertion.20,21 PS likely achieved these antistress and mood improvement effects by improving stimulus coordination in and between the hypothalamus, pituitary and adrenal glands (the HPA axis).21
Altogether, the controlled trials with PS establish its benefits for higher brain functions, such as memory, learning and word recall, mood elevation and coping with stress.1
The physico-chemical characteristics of PS are well suited to conventional dietary supplement dosage forms, functionalised spreads, powder mixes, cereals and bars. Like PC, it is unstable in water solution, and thus poorly suited for beverage applications.
Glycerophosphocholine (GPC) is a pro-phospholipid nutrient, lacking the molecular 'tails' of membrane phospholipids. Precisely because it lacks these hydrophobic tails, GPC is readily soluble in water and will not produce off-flavours from fatty acid rancidification.
GPC is readily absorbed by mouth, and is an important metabolic precursor for membrane phospholipids.22 Enzymes can tack fatty acid tails onto GPC to make PC, and/or modify its headgroup to generate other phospholipids. Like the membrane phospholipids PS and PC, GPC has orthomolecular status. It has proven protective function in the kidneys and brain,23 and was extremely well tolerated in 19 human supplementation studies involving more than 4,000 human subjects.24
GPC is a metabolically pivotal substance. Efficiently absorbed into the blood, it rapidly reaches the brain,22 where it serves as a primary reservoir for the important transmitter acetylcholine (ACh). GPC is also a preferred choline reservoir, even attaining high concentrations in mother's milk to support the developing organs of the newborn child.25 And as an osmotic buffer, GPC fills a unique protective niche.
Being zwitterionic—positively charged on one side and negatively charged on the other—the GPC molecule helps protect against intra-cellular fluctuations in ions and charged molecular species that generate osmotic stress. Skeletal muscle has such extreme ionic fluctuations, and interestingly, Duchenne muscular dystrophy patients have markedly lowered GPC in their most-affected muscle fibers.26
GPC benefits mental sharpness in young, healthy subjects, as well as in the middle aged and elderly. In two controlled trials conducted in Italy,27,28 GPC (1,200 mg/day) benefited immediate recall and attention in a group of young adult males (ages 19 to 38), compared with placebo. In middle-aged and elderly subjects, it benefited reaction time, improving energy generation and electrical coordination within the brain.29,30 In several controlled trials on older subjects with vascular dementia, GPC (1,200 mg/day) improved aspects of cognition along with emotional state, confusion and apathy.24 In other clinical studies involving almost 2,500 subjects, GPC (1,000mg/day intramuscularly for one month and then orally 1,200mg/day for five months) accelerated the recovery of subjects afflicted by stroke or other ischemic damage.24,31
Several controlled trials with GPC involved comparisons against other brain nutrients or pharmaceuticals. GPC (at 1,200mg by mouth or 1,000mg intramuscularly) tested superior to citicoline (CDP-choline), acetylcarnitine, idebenone, aniracetam and oxiracetam, on measures of attention, concentration, immediate recall, verbal fluency and overall mental performance.24 GPC's superior efficacy on diverse measures of brain performance is directly related to its multiple mechanisms of action, the ease with which it enters the brain, and its central role in brain phospholipid metabolism. GPC is readily converted to PC without substantial energy investment, and being water-soluble, is a more ready source of choline than is PC.
GPC may also help revitalize pituitary function. As humans reach middle age, they produce less than optimal quantities of key hormones from the pituitary gland, the body's "master gland." Pilot studies indicate that when predosed with GPC (1g/day, intramuscularly), both youthful and ageing healthy volunteers responded to GHrH (growth hormone releasing hormone) by releasing greater quantities of growth hormone, as compared with placebo.32
Another dimension of GPC's importance to brain vitality is its contribution to acetylcholine's transmitter action. This is reflected in GPC's improvement of the EEG (electroencephalograph) profile, seen even in healthy young subjects.33
Important for its protective properties in the water phase, GPC is also on the main metabolic pathway to PC, the key building block for nerve cell membranes. Unlike phospholipid preparations, GPC is stable in water, but is limited in the solid phase because it readily absorbs moisture. GPC's fast access to the human brain and its capacity to sharpen mental performance also makes it suitable for drink formulations.
Mixtures Benefit Circulation
Impaired blood cholesterol regulation continues to be a health issue in Western populations. But mixtures of soy phospholipids containing PC and smaller amounts of other phospholipids were shown through 12 double-blind trials to consistently reduce blood cholesterol levels. The degree of lowering of total and LDL cholesterol by dietary lecithins was clinically useful.
Soy phospholipid mixtures also can improve blood flow and reduce the risk of clot formation in blood circulation.34,35 These preparations offer the promise of cost-effective circulatory improvement, as well as the emulsification, dispersibility and surfactant characteristics necessary for free-flowing and instantised shake mixes or chewy bars.
Future Phospholipid Nutraceuticals
Consistent positive outcomes from controlled trials, backed by scores of clinical studies and many more experimental studies, establish PS, PC, GPC and mixed phospholipids' nutraceutical benefits for the brain, liver and circulation. The nutraceutical phospholipids are well tolerated and pose no toxic threat, as predictable from their orthomolecular status. PC's emulsifier and surfactant properties are valuable to homeostasis, and preclinical research in dogs indicates PC can be co-administered with aspirin to protect the intestinal lining from the latter's notorious toxicity.7
The natural tendency of phospholipids to form ultrafine molecular dispersions in water should be further explored to improve the bioavailability of non-phospholipid nutrients, especially those that are costly and poorly absorbed. Monomolecular nutrient dispersion using phospholipids also will improve the physical characteristics of the phospholipid-nutrient combinations, such that the resulting functionalised product becomes considerably more convenient and effective for the consumer.
This combined phospholipid-nutrient approach is suited toward producing chewable tablets, confections, cookies, granulates, spreads, bars, emulsified or purely aqueous-phase beverages, even liquid sprays. However, systematic comparator studies in humans, using exclusively phospholipid delivery systems and non-phospholipid systems, and showing demonstrable benefits with the former, appear to be lacking at present.
Further product value comes from the health benefits of the phospholipids being combined with the benefits of the selected nutrients; one prime combination would be phospholipids with omega-3 fatty acids.
Their safety record and well-documented array of health benefits qualify PS, PC and GPC as first-rate nutraceuticals. Their unique physico-chemical characteristics make them premier functional foods constituents, with a diverse potential market of both young and elderly consumers.
Parris M. Kidd, PhD, is a nutrition educator and technical consultant on phospholipids to Lipoid USA LLC, marketer of phospholipids.
1. Kidd PM. Dietary phospholipids as anti-aging nutraceuticals. In:Klatz RA, Goldman R, eds. Anti-Aging Medical Therapeutics, Vol. IV. Chicago, IL:Health Quest Publications;2000:282-300.
2. Pauling, L. Orthomolecular psychiatry. Science 1968;160:265-71.
3. Bretscher MS. The molecules of the cell membrane. Sci Am 1985;253:100-8.
4. Gobley M. Examen comparatif du jaune d'oeufe et de al matiere cerebrale. J Pharm Chim 1847;11:409.
5. Niederau C, et al. Polyunsaturated phosphatidylcholine and interferon alpha for treatment of chronic hepatitis B and C:a multicenter, double-blind, placebo-controlled trial. Hepatogastroenterol 1998;45:797-804.
6. Kidd PM. Phosphatidylcholine (Monograph). Alt Med Rev 2002;7:150-4.
7. Anand BS, et al. Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects. Am J Gastroenterol 1999;94:1818-22.
8. Carlson SE, et al. Lower incidence of necrotizing enterocolitis in infants fed a preterm formula with egg phospholipids. Ped Res 1998;44:491-8.
9. Wood JL, Allison RG. Effects of consumption of choline and lecithin on neurological and cardiovascular systems. Fed Proc 1982;41, 3015-121.
10. Crook TH, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-9.
11. Crook TH, et al. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull 1992;28:61-6.
12. Ryser CA, Kidd PM. Manuscript in preparation;2002.
13. Fahey T, Pearl M. The hormonal and perceptive effects of phosphatidylserine administration during two weeks of resistive exercise-induced overtraining. Biol Sport 1998;15:135-42
14. Gindin J, et al. The effect of plant phosphatidylserine on age-associated memory and mood in the functioning elderly. Kaplan Hospital, Rehovoth, Israel, 1995.
15. Crook TH. Treatment of age-related cognitive decline: effects of phosphatidylserine. In, Klatz RA, Goldman R, eds. Anti-Aging Medical Therapeutics, Volume II. Chicago, IL:Health Quest Publications;1998.
16. Alberts B, et al (eds.). Molecular Biology of the Cell. New York:Garland Publishing; 2000.
17. Jorissen BL, et al. The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment. Nutr Neurosci 2001; 4:121-34.
18. Crook TH. Personal communication. Oxford, MD; 2002.
19. Benton D, et al. The effects of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci 2001;4:169-78.
20. Monteleone P, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinol 1990;52:243-8.
21. Monteleone P, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Clin Pharmacol 1992;41:385-8.
22. de Moliner P, et al. Pharmacokinetics of choline alphoscerate in the healthy volunteer. Le Basi Razionali della Terapia 1993;23:75-80.
23. Burg MB. Molecular basis of osmotic regulation. Am J Physiol 1995; 268:F983-F996.
24. Parnetti L, Amenta F, Gallai V. Choline alfoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mechs Ageing Development 2001;122:2041-55.
25. Holmes-McNary MQ, et al. Choline and choline esters in human and rat milk and in infant formulas. Am J Clin Nutr 1996;64:572-6.
26. Infante JP. Defective synthesis of polyunsaturated phosphatidylcholines as the primary lesion in Duchenne and murine muscular dystrophies. Med Hypoth 1986;19:113-6.
27. Canal N, et al. Effect of L-a-glyceryl-phosphorylcholine on amnesia caused by scopolamine. Intl J Clin Pharmacol Ther Toxicol 1991;29:103-7.
28. Canal N, et al. Comparison of the effects of pretreatment with choline alfoscerate, idebenone, aniracetam and placebo on scopolamine-induced amnesia. Le Basi Razionali della Terapia 1993; 23:102-7.
29. Moglia A, Bergonzoli S, de Moliner P. Effect of aGFC in brain mapping changes in patients with age associated memory impairment (AAMI). Le Basi Razionali della Terapia, 1990;20:83-9.
30. Sicurella L, et al. Changes in VEP in subjects treated with alphaGFC. Preliminary study. Le Basi Razionali della Terapia 1990;20(3 Suppl. 1):91-3.
31. Barbagallo Sangiorgi G, et al. Alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. Ann NY Acad Sci 1994;717:253-69.
32. Ceda GP, et al. Alpha-glycerylphosphorylcholine administration increases the GH responses to GHRH of young and elderly subjects. Horm Metabolic Res 1991;24:119-21.
33. Locatelli M, et al. Neurophysiological evaluation of a GFC (choline alfoscerate) by means of computerized electroencephalogram (CEEG). Le Basi Razionali della Terapia 1990;20:79-82.
34. Schneider J. Experimental and clinical effects of polyenoyl phosphatidylcholine on erythrocytes and platelets. In:Ricci G, et al, ed. Therapeutic Selectivity and Risk/Benefit Assessment of Hypolipidemic Drugs. New York, NY:Raven Press;1982:263-8.
35. Schneider J, et al. Influence of essential phospholipids on human platelet aggregability. In: Peeters H, ed. Phosphatidylcholine. New York, NY:Springer-Verlag;1976:244-8.
Parris Kidd, Ph.D., earned his doctorate in cell biology-zoology from the University of California, Berkeley. Beginning in 1984, while a National Institutes of Health (NIH)-funded research investigator at the University of California San Francisco (UCSF) Medical Center, he published authoritative texts on antioxidants that launched him into nutritional medicine. In 1994, Kidd helped establish phosphatidylserine (PS), then glycerophosphocholine (GPC). His brain formulas have earned awards from the dietary supplement industry. Kidd is chief science officer and director of quality for BrainMD Health. He collaborates with the Amen Clinics to develop clinically validated products for memory, mood, behavior and healthy aging.
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