Chemistry and Form

Policosanol contains a natural mixture of eight long-chain aliphatic primary alcohols extracted from the wax of sugarcane ( Saccharum officinarum L.). A similar complex of long-chain aliphatic alcohols can also be derived from rice bran and beeswax, although most of the existing clinical studies have been done with sugarcane-derived material. Octacosanol (18-carbon) is the predominant moiety, constituting approximately 60% of the mixture. Other important constituents include triacontanol (13%) and hexacosanol (6%). Minor components include tetracosanol, heptacocosanol, nonacosanol, dotriacontanol, and tetratriacontanol.

Physiology and Function

Policosanol decreases levels of cholesterol in serum as well as cholesterol content in various tissues, such as liver, heart, and fatty tissue. In numerous clinical trials, policosanol has demonstrated lipid-lowering efficacy comparable to statin drugs and offers the potential to suppress isoprenylation reactions much as statins do, without the attendant hepatotoxicity and other adverse effects typically associated with direct hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibition. Other trials have produced less positive findings. Policosanol appears to reduce low-density lipoprotein cholesterol (LDL-C) and total cholesterol by inhibiting hepatic cholesterol synthesis before the formation of mevalonate, between the formation of acetate and mevalonate, and downregulating cellular expression of, but not directly inhibiting, HMG-CoA reductase. It also lowers LDL by enhancing the binding, uptake, and degradation of LDL-C in the endoplasmic reticulum.

Nevertheless, scientific knowledge of the exact mechanisms of policosanol's lipid-lowering activity remains incomplete and uncertain. High doses of policosanol can alter prostaglandin synthesis, lower platelet aggregation induced by arachidonic acid (AA), and inhibit proaggregatory thromboxane A2(TXA2) generation induced by collagen; it does not inhibit and may increase levels of the antiaggregatory prostaglandin prostacyclin. Policosanol supports healthy endothelial function by preventing intimal thickening and smooth muscle cell proliferation while also preventing and possibly reversing atherosclerotic lesions and thrombosis. Policosanol may be active as an effective antioxidant in the cardiovascular system, particularly in preventing LDL oxidation, most likely by limiting microsomal lipid peroxidation.

Known or Potential Therapeutic Uses

Policosanol has primarily been proposed as part of a comprehensive approach to treating dyslipidemia. Some research suggests that it may be specifically effective in reducing elevated LDL-C and total cholesterol levels, particularly in type II hypercholesterolemia, including the IIa subtype (characterized by elevated total serum cholesterol and LDL-C levels), the IIb subtype (mixed hypercholesterolemia characterized by elevated total serum cholesterol, LDL-C, and triglyceride levels), and diabetes-related hypercholesterolemia. It also appears to increase levels of high-density lipoprotein cholesterol (HDL-C). Efficacy in the treatment of intermittent claudication is consistent with its known effects on platelet aggregation and endothelial function.

Historical/Ethnomedicine Precedent

Policosanol has not been used historically as an isolated nutrient.

Historical Note: Policosanol was largely developed in Cuba during the embargo that prevented access to many Western pharmaceuticals, and the initial laboratory and clinical research was done by Cuban scientists and physicians. Subsequent researchers and commentators, particularly after less successful trials, have suggested that politics may have played a role in earlier published findings of therapeutic efficacy.

Possible Uses

Dyslipidemia, hypercholesterolemia (type II), intermittent claudication, platelet aggregation.

Deficiency Symptoms

Not applicable.

Dietary Sources

Not applicable.

Dosage Forms Available

Capsule, tablet.

Source of Materials for Nutrient Preparations

Isolated constituents from sugarcane (Saccharum officinarum) wax; beeswax, rice bran.

Dosage Range

Adult

Dietary: Not applicable.

Supplemental/Maintenance: Not applicable.

Pharmacological/Therapeutic: 5 to 20 mg per day. A 6-month double-blind clinical trial found that daily dosages greater than 20 mg produce no significant additional cholesterol-lowering efficacy. ¹ Many practitioners experienced in nutritional therapeutics advise patients to take their once-daily dose of policosanol in the evening because hepatic synthesis of cholesterol usually occurs primarily during the night.

Toxic: None reported, even at equivalent of approximately 620 times higher than the maximal recommended therapeutic dose (20 mg/day). ²

Overview

Clinical trials of policosanol lasting up to 3 years indicate that it is well tolerated and safe for most individuals at usual dosage levels. ³ Policosanol has not been associated with increases in hepatic enzymes or creatine kinase.

Nutrient Adverse Effects

General Adverse Effects

Quantifiable adverse effects include weight loss (1.8% of patients), polyuria (0.7%), and headache (0.6%). Other reported adverse effects include insomnia, somnolence, nervousness, dizziness, excitability, hypotension, hypertension, polyphagia, nausea, epigastric pain, diarrhea, constipation, erythema, pruritus, skin rash, and bleeding from the nose and gums. ⁴ These symptoms have been recorded in people taking policosanol; causality linking policosanol and these symptoms has not been established.

Research with Swiss mice shows no evidence of policosanol-induced carcinogenicity. ⁵

Several animal studies, including rat model using doses up to 500 mg/kg, showed no evidence of significant reproductive or mutagenic toxicity. ^2,6-9

Adverse Effects Among Specific Populations

No dosage reduction is necessary in individuals with compromised hepatic function. No studies have been conducted involving individuals with compromised renal function. ⁴

Pregnancy and Nursing

As of this writing, no reported adverse effects have been related to fetal development during pregnancy or to breast-fed infants. However, use during pregnancy is generally contraindicated because cholesterol and associated metabolic products are required for healthy fetal development. Likewise, administration during lactation should be discontinued because little is known about whether the product or some active metabolite is excreted in breast milk.

Infants and Children

Adequate long-term research is lacking, but no adverse effects have been reported in relation to policosanol use by children.

Contraindications

Pregnancy, breastfeeding.

Precautions and Warnings

Although potentially beneficial, concurrent use of policosanol and HMG-CoA reductase inhibitors may be inappropriate given the current lack of knowledge of policosanol's mechanism of action.

Strategic Considerations

Data from long-term formal studies of drug interactions, additive toxicity, or integrative therapeutics involving policosanol in humans are generally lacking. Pharmacokinetic research suggests that policosanol does not interact with drug-metabolizing processes involving the cytochrome P450 microsomal system. ² Consequently, drug-to-drug interactions between policosanol and drugs metabolized through the cytochrome P450 hepatic system are not probable, although adverse pharmacodynamic drug-to-drug interactions cannot be excluded. Furthermore, the consistent lack of toxicity associated with sustained policosanol therapy and its proposed ability to shift lipid parameters positively and inhibit platelet aggregation significantly, without elevating liver enzymes or affecting coagulation parameters, suggest that therapeutic synergy is more likely to characterize potential interactions than is enhanced risk. Adjunctive therapies with a strong safety profile are much in demand given the wide range of uses emerging for statin medications and the widespread use of beta blockers, despite their known toxicities and risks. Thus, policosanol presents significant promise as a therapeutic agent in concert with statins, beta blockers, or other nutritional and botanical agents to treat dyslipidiemia and support lipid homeostasis and healthy cardiovascular function.

Even though largely undertaken by a relatively small number of researchers, mostly by a single research institute in Cuba, the initial positive evidence available on policosanol provides a substantial foundation for further large, well-designed clinical trials into its efficacy and interaction patterns. In contrast to data indicating that policosanol at 5 to 40 mg per day exerts lipoprotein-lowering effects comparable to statins, Berthold et al. ¹⁰ (2006) arrived at much less convincing findings. These investigators conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Germany involving 143 patients with “hypercholesterolemia or combined hyperlipidemia having baseline low-density lipoprotein cholesterol (LDL-C) levels of at least 150 mg/dL … and either no or one cardiovascular risk factor other than known coronary heart disease, or baseline LDL-C levels of between 150 and 189 mg/dL … and two or more risk factors.” After a 6-week initial open-label placebo and diet run-in phase, they randomized subjects into five groups receiving sugarcane-derived policosanol (10, 20, 40, or 80 mg daily) or placebo for a double-blind 12-week treatment phase. None of the subjects in the five treatment groups exhibited decreases in LDL-C levels more than 10% from baseline, and “no statistically significant difference between policosanol and placebo was observed.” Furthermore, after this relatively short treatment period, none of the secondary outcome measures—total cholesterol, HDL-C, very-low-density lipoprotein cholesterol (VLDL-C), triglycerides, lipoprotein(a), and ratio of total or LDL-C to HDL-C, exhibited any significant effects of policosanol. ¹⁰

In an 8-week, double-blind, randomized controlled trial, Dulin et al. ¹¹ reported that policosanol (20 mg/day) is “ineffective” in the treatment of “mild hypercholesterolemia.”

These conflicting findings indicate that long-term, well-designed studies of adequate size are warranted to determine the therapeutic efficacy of policosanol monotherapy and suggest whether its role as a component of a more comprehensive protocol may be more effective. It should be noted that Berthold's study ¹⁰ of 143 patients randomized into five groups is very small (<30 per group), particularly in comparison to statin trials, which typically involve many thousands of patients. Also, the experience with fish oil (omega-3 fatty acids) has shown more dramatic survival benefit than with statins in several trials, despite very modest changes in lipoprotein profiles. Given the earlier research with policosanol suggesting many mechanisms of action, it would seem premature to halt research with this agent after several small, negative clinical trials.

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