10. The Merck Manual. 16th edition. San Diego, CA: Merck Research Laboratories; 1992. p. 906-9.
11. Ballatori N, Lieberman MW, Wang W. N-acetylcysteine as an antidote in methylmercury poisoning. Environ Health Perspect
1998;106(5):267-71.
12. Flora SJ. Arsenic-induced oxidative stress and its reversibility following combined administration of N-acetylcysteine and meso 2,3-
dimercaptosuccinic acid in rats. Clin Exp Pharmacol Physiol 1999;26(11):865-9.
13. Kleinveld HA, Demacker PNM, Stalenhoef AFH. Failure of N-acetylcysteine to reduce low-density lipoprotein oxidizability in healthy
subjects. Eur J Clin Pharmacol 1992;43:639-42.
14. Healthnotes 2000. Healthnotes Inc. (www.healthnotes.com): Drug Interactions Summary for N-Acetylcysteine.
15. Brumas V, Hacht B, Filella M, Berthon G. Can N-acetylcysteine affect zinc metabolism when used as a paracetamol antidote? Agents
Action 1992;36:278-8.
16. Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci 1997;94:1967-72.
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Phosphatidylserine
General Features
Phosphatidylserine is the major phospholipid in the brain and plays a role in determining the integrity and fluidity of
nerve cell membranes (the outer skin of brain cells). The brain can manufacture Phosphatidylserine, but requires folic
acid, vitamin B12 and S-adenosylmethionine as cofactors (methyl donors) for its synthesis. Low levels of
Phosphatidylserine in the brain are associated with impaired cognitive function and depression in the elderly.1,11,12 In
Italy, Scandinavia and other parts of Europe Phosphatidylserine is widely used to help restore declining mental
function and depression in the elderly. As noted, the body makes its own Phosphatidylserine, but when required to
treat mental decline and memory loss, a therapeutic dosage is required from external sources.11,12
The serine portion of Phosphatidylserine can also be converted into choline and significantly improve acetylcholine
synthesis in the brain, aiding memory and reversing some age-related brain changes. Acetylcholine is the
neurotransmitter (brain chemical) required for memory.2,3,4 Thus, Phosphatidylserine may aid memory and cognitive
function via its participation as a vital phospholipid component of the nerve cell membrane and as a bioactive agent
that can increase brain levels of the memory chemical acetylcholine.1-4
Clinical Application and Mechanism of Action
Treatment of Depression and/or Impaired Mental Function in the Elderly
Numerous studies in elderly patients (65-93 yrs) with moderate to severe senility and depressed elderly patients have
demonstrated significant improvement in memory, behaviour, mood states and cognitive function with
Phosphatidylserine supplementation of 100 mg, three times daily.5-10 A number of double-blind studies, involving more
than 1,000 patients suggest that Phosphatidylserine supplementation improves behaviour and mental function in
patients with moderate to severe mental decline, including Alzheimer’s disease patients.12 This is largely at ributable
to the role that Phosphatidylserine plays within the nerve cell membrane, aiding the conduction of nerve impulses and
improving the movement of nutrients in and out of nerve cells. The serine fraction of Phosphatidylserine can also be
converted into choline within the brain and is used as substrate from which brain cells can synthesize acetylcholine,
the neurotransmitter required for memory function.1-4,11,12
Dosage Range
Age-Related Cognitive Decline (Age-Associated Memory Impairment), and Depression in the Elderly: 100 mg, three
times per day in the treatment of age-related cognitive impairment, senility and depression of the elderly has been
used successfully in a number of well designed clinical trials. Once improvement is noted (usually within 3-6 months),
the dosage can be reduced to 100 mg per day as a maintenance regime. Note that the above cited studies used
bovine (cow-brain)-derived Phosphatidylserine, a product that is no longer available (due to the possible risk of “mad
cow” disease, or more correctly Creutzfeld-Jacob disease). Most of the Phosphatidylserine available in the
marketplace today is derived from soy, but there have been only a limited number of studies using this source of
Phosphatidylserine in studies evaluating cognitive function. The use of Phosphatidylserine in the treatment of age-
related memory loss and depression is primarily based upon the positive results demonstrated by bovine-derived
Phosphatidylserine. Soy-derived Phosphatidylserine is a relatively new product by comparison. Soy and bovine-
derived Phosphatidylserine are not chemically identical; however, preliminary animal studies show that soy-derived
Phosphatidylserine does have ef ects on brain function similar to that of bovine-derived Phosphatidylserine.
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Nevertheless, human trials are necessary to confirm the clinical efficacy of soy-derived Phosphatidylserine for the
above-cited purposes.1-4,11,12
Adverse Side Effects and Toxicity
Phosphatidylserine is generally regarded as safe when used at recommended dosages. No significant side effects or
adverse reactions have been noted, other than mild gastrointestinal distress on rare occasions.1,11,12
Drug-Nutrient Interactions
There are no well known drug-nutrient interactions for Phosphatidylserine.1
1. Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 356-358.
2. Vannucchi MG, Casamenti F, Pepeu G. Decrease of acetylcholine release from cortical slices in aged rats: Investigations into its reversal
by phosphatidylserine. J Neurochem 1990;55:819-25.
3. Valzelli L, Kozak W, Zanotti A, Toffano G. Activity of phosphatidylserine on memory retrieval and on exploration in mice. Meth Find Extl
Clin Pharmacol 1987;9:657-60.
4. Nunzi MG, Milan F, Guidolin D, et al. Effects of phosphatidylserine administration on age-related structural changes in the rat
Comment [c40]: Couldn’t find the other authors
hippocampus and septal complex. Pharmacopsychiat 1989;22:125-8.
5. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: A double-blind, placebo-controlled multicenter study on efficacy
Comment [c41]: Couldn’t find the other authors.
of phosphatidylserine administration. Aging 1993;5:123-33.
6. Engel, RR, Satzger W, Gunther W, Kathmann N, Bove D, Gerke S, et al. Double-blind cross-over study of phosphatidylserine vs.
placebo in subjects with early cognitive deterioration of the Alzheimer type. Eur. Neuropsychopharmacol, 1992;2:149-55.
7. Crook T, Petrie W, Wells C, Massari DC. Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992;28:61-6.
8. Crook TH, Tinklenberg J, Yesavage J, Petrie W, Nunzi MG, Massari DC. Effect of phosphatidylserine in age-associated memory
impairment. Neurology 1991;41:644-9.
9. Funfgeld EW, Baggen M, Nedwidek P, Richstein B, Mistlberger G. Double-blind study with phosphatidylserine (PS) in parkinsonian
patients with senile dementia of Alzheimer’s type (SKAT). Prog Clin Biol Res 1989;317:1235-46.
10. Maggioni M, Picotti GB, Bondiolotti GP, Panerai A, Cenacchi T, Nobil P, et al. Effects of phosphatidylserine therapy in geriatric patients
with depressive disorders. Acta Psychiatr Scand 1990;81:265-70.
11. Healthnotes Online. Healthnotes Inc, 2000.
12. Natural Products Encyclopedia. www.consumerslab.com: Phosphatidylserine.
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Policosanol (Saccharum officinarum)
General Features
Policosanol is a natural compound derived from sugar cane wax, which has been shown to significantly reduce high
cholesterol in human and animal studies. It also has been shown to reduce platelet stickiness, improving blood flow
and aiding patients with intermittent claudication and non-insulin dependent diabetes mellitus. 1,2,3 The ef icacy, safety
and lack of toxicity of this natural health product makes it a very desirable supplement in the management of high
cholesterol as it has been shown to reduce cholesterol levels equally as well as many prescription medications, without
producing significant side effects. 4,5
Principle Active Constituents
Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane wax, whose main component is
octacosanol. Octacosanol is a long chain fat y alcohol (similar in structure to cholesterol, which is also an alcohol ).
Policosanol is a combination of octacosanol and several other long chain alcohols — hence the name poli-cosanol.
Keeping octacosanol together with other naturally occurring fat y alcohols makes it more stable and seems to enhance
the efficacy of this supplement. 1,4
Clinical Application and Mechanism of Action
1. Cholesterol Lowering - Policosanol has been shown to reduce high levels of blood cholesterol to a significant
degree (LDL-cholesterol reduction ~ 20%) in human and animal studies. Its mechanism of action is not completely
understood, but it is known to suppress cholesterol synthesis in the liver. This effect appears to be related to its
modulation of the HMG-CoA reductase enzyme, a rate-limiting enzyme in cholesterol synthesis. However, it is not
of icially considered to be an HMG-CoA reductase inhibitor, as are statin drugs. Nor does it produce the side ef ects
associated with the use of statin drugs, which include potential liver damage, muscle pain, fatigue, dizziness, skin
rash, diarrhea, heartburn, skin rash and male impotence. 4,6,30 Large trials over long periods have demonstrated
that Policosanol supplementation can lower and maintain blood cholesterol levels as well as most conventional
drugs, without producing untoward side ef ects. 1,4,7,8,9
Human Trials
A review of the clinical trials using Policosanol to lower cholesterol levels in humans appeared in the American
Heart Journal in 2002. A review of the available peer-reviewed journal publications revealed that Policosanol, at
doses of 10 to 20 mg per day lowers total cholesterol by 17% to 21% and low-density lipoprotein (LDL) cholesterol
by 21% to 29%, and raises high-density lipoprotein (HDL, the good cholesterol) cholesterol by 8% to 15%. The
researchers state that because higher doses have not been tested up to now, it can not be excluded that
ef ectiveness may be even greater. Daily doses of 10 mg of Policosanol have been shown to be equally ef ective in
lowering total and LDL cholesterol as the same dose of simvastatin or pravastatin (two widely prescribed
cholesterol-lowering statin drugs). Triglyceride levels are not influenced by Policosanol supplementation. At doses
of up to 20 mg per day, Policosanol is safe and well tolerated, as studies of greater than three years of therapy
indicate. 1
Postmenopausal Women - Policosanol has been shown to reduce elevated total and LDL-cholesterol levels in
postmenopausal women by 17.3% and 26.7%, respectively, in 56 women who showed no cholesterol lowering to a
6-week standard lipid-lowering diet that has been followed prior to the administration of Policosanol. This is of
great clinical significance as heart disease is the number one cause of death in postmenopausal women. After
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menopause the decline in estrogen levels is associated with a decrease in LDL-cholesterol receptors on the cell
surface. In turn, this reduces clearance of cholesterol from the bloodstream permitting blood levels of LDL-
cholesterol to rise, predisposing women to heart attack and ischemic stroke. 9
Type I Hypercholerterolemia - Patients with type I hypercholesterolemia are known to have a genetically based
defect that encourages lifelong elevation of blood cholesterol- a condition that is difficult to manage through diet
and exercise alone. Studies have shown in a convincing manner that Policosanol supplementation significantly
lowers cholesterol levels even in these more challenging patients. Total and LDL-cholesterol can be expected to
drop by up to 17.4% and 25.6%, respectively. HDL-cholesterol levels have been shown to rise by 15.5% to 28.4%
in these patients, which is a remarkable finding due to the fact that it is dif icult to raise HDL levels and that higher
HDL levels are known to significantly reduce risk of heart at ack. HDL-cholesterol collects the cholesterol that has
been deposited in the artery wall and transports it back to the liver where it can be cleared from the blood stream
and eliminated from the body via its conversion to bile acids. 10
Even in older patients with type I hypercholesterolemia presenting with more than one concomitant atherosclerotic
risk factor, the administration of Policosanol at 5 mg or 10 mg per day was shown to significantly reduce total and
LDL-cholesterol levels and raise HDL- levels by up to 29.1%. The 10 mg dose produced bet er results in all
cholesterol parameters compared to the 5 mg dose. 11
Head-To-Head Trials Against Statin Drugs - A study involving older patients with type II hypercholesterolemia
tested the ef icacy of the statin drug Pravastain against Policosanol, in a randomized, double-blind study. The
results showed that Policosanol was more ef ective than Pravastatin in reducing total and LDL-cholesterol and was
able to raise HDL-cholesterol by 18.4%, whereas Pravastatin showed no ef ect on HDL-cholesterol levels.
Policosanol also more ef ectively reduced platelet aggregation than did Pravastatin, another important risk factor in
cardiovascular disease. Patients receiving Pravastatin over the 6-week trial period experienced a rise in their
serum levels of alanine amine transferase enzyme, which indicates potential damage to liver cells. This did not
occur in the Policosanol group. Two patients dropped out of the Pravastatin group due to adverse side ef ects
(myocardial infarction and jaundice, likely due to liver damage). The researchers conclude “the ef ects of
Policosanol (10 mg per day) on lipid profile, platelet aggregation and endothelemia in older patients with type I
hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of
Pravastatin.” 12
A second study tested the ef icacy of Policosanol against Lovastatin and Simvastatin (two popular statin drugs).
The results showed that Policosanol reduced LDL-cholesterol by 24% on average compared to a 22% and 15%
reduction with Lovastatin and Simvastatin, respectively. HDL levels rose significantly in the Policosanol group and
no change was seen in the patients receiving Lovastain or Simvastatin. This was a 6- week trial involving patients
with an LDL-cholesterol level of over 160 mg/dl. 13
Used In Conjunction With Fibrate Drugs - A study combining the use of Bezafibrate and Policaosanol demonstrated
that these cholesterol and triglyceride-lowering agents can be used together to produce a positive outcome on
blood lipids with no untoward side ef ects. Fibrate drugs are often used to help lower triglyceride levels, an effect
that is not produced to a substantial degree by Policosanol. Thus, in patients with high cholesterol and high
triglycerides, the combination of both agents has been shown to be effective and safe. 14
Intermittent Claudication - Sixty-two patients with intermittent claudication were given either 10 mg of Policosanol,
twice per day or a placebo for 6 weeks. The Policaosanol group realized a significant improvement on treadmill
walking distance during the course of the study. No change was seen in the placebo group. 15
Improved Exercise ECG Results in Coronary Patients - Policosanol supplementation was tested in patients with
myocardial ischemia (severe blood flow restriction to the heart muscle) versus placebo. The results showed that
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after 20 months the Policosanol group experienced an incremental improvement in ECG exercise testing (aerobic
functional capacity percent) and a decline in blood cholesterol levels. The researchers state that Policosanol
treated patients with coronary heart disease showed improved clinical evolution, and exercise-ECG responses,
owing to the amelioration of myocardial ischemia. These results were even bet er when Policosanol was combined
with 125 mg of aspirin per day, indicating that the use of aspirin in conjunction with Policosanol may be of greater
benefit to certain heart patients than is aspirin alone. 16
Coronary Heart Disease Patients - A randomized single-blinded, placebo-controlled trial was conducted on 23
middle-aged outpatients with established coronary heart disease. The 12 patients given the Policosanol
demonstrated a significant reduction in blood cholesterol levels and exhibited a clinical tendency to improvement of
their coronary heart disease, in comparison to no improvement in these parameters in the placebo group. “ These
findings show the ef ectiveness of low dose of Policosanol lowering total cholesterol and LDL-cholesterol and
suggest a coronary heart disease improvement in middle-aged patients with primary or marginal hyperlipidemia.” 17
Diabetic Patients With High Cholesterol - In a study of non-insulin dependent diabetic patients with high cholesterol
levels, Policosanol supplementation at 10 mg per day was shown to reduce total cholesterol by 17.5% and LDL-
cholesterol by 21.8% compared with baseline and placebo. HDL-cholesterol levels rose by 11.3% and triglyceride
levels fell by 6.6% in the Policosanol group. None of these changes occurred in the placebo group. Moreover,
Policosanol did not adversely affect glucose levels or glycemic control. The researchers conclude “ Policosanol is
ef ective and safe in patients with non-insulin dependent diabetes mellitus and hypercholesterolemia.” 18