Policosanol

Policosanol is a term that refers to a mixture of fatty acid alcohols, and is sometimes referred to as 'Cane Sugar Extract' or 'Cane Sugar Wax' due to its first discovered source being Cuban Cane Sugar. It can also be extracted from Rice Bran, Wheat Germ, and Beeswax by solvent extraction and saponification.^[1][2]

Policosanol can also be found in:

• Perilla Seeds (Perilla frutescens), alongside Rosmarinic Acid and the gamma forms of Vitamin E^[3] in approximately the same ratios as in Cane Sugar^[4] In Perilla oil, the content is 427.83mg/kg oil (10mg Policosanol per 23.4g oil)^[5]
• Wheat and Wheat Germ^[6]
• Peanuts^[7]
• Rice (Orzya species only such as Gamma Oryzanol)^[8] and Rice Bran Oil^[5] at 171.17mg/kg oil (10mg Policosanol per 58.4g oil)
• Pomegranate seeds^[9]
• Grape seed oil, at 245.15mg/kg oil (10mg Policosanol per 40.8g oil)^[5]
• Corn, Sesame, and Soybean oil in minute quantities^[5]
• Switchgrass (Panicum virgatum)^[10]
• Guduchi (Tinospora cordifolia)^[11]

Found mostly in seeds and the waxy coating of Cane Sugar, but is seen in a variety of unique sources

As 'Policosanol' is a term used to refer to a mixture of fatty acid alcohols, there are several molecules and structures associated with the term. The Fatty Acid alcohols in question are all long-chained, with the most prominent fatty acid alcohols being between 26-32 carbons in length and all fatty acid alcohols being between 20-34 in length.

The fatty acid alcohols in question (with their carbon length designated as Cxx), and their approximate quantities, are:

• C20, Eicosanol at less than 0.1%^[12]
• C22, Docosanol at less than 0.1%^[12]
• C23, Tricosanol at less than 1%^[12]
• C24, Tetracosanol at approximately 2%^[12]
• C26, Hexacosanol at approximately 6%^[12] but standardized to the 3-10% range
• C27, Heptacosanol at less than 1%^[12]
• C28, Octacosanol at approximately 66%^[12] but standardized to the 60-70% range
• C29, Nonacosanol at less than 0.1%^[12]
• C30, Triacontanol at approximately 17%^[12] and standardized to the 10-15% range usually
• C32, Dotriacontanol at approximately 5%^[12] and standardized to the 5-10% range at times
• C34, Tetratriacontanol at less than 1%^[12]

The bolded terms are those that are in highest amounts. Octacosanol is seen as the primary bioactive fatty alcohol whereas Triacontanol is seen as a significant source of bioactivity as well; the others should be noted as their bioactivity may be relevant.

For all intents and purposes, 'Policosanol' is a term used to refer to a collection of fatty acid alcohols

In two studies on 5-10mg capsules of Policosanol, it was found that the product was stable for up to 9 months under ambient storage conditions; some degradation was noted into fatty acid esters from the alcohol form of the molecules, such as octacosanol to octacosanoyl ester.^[13][14]

Using cane sugar policosanols in a CaCo-2 cell line, up to 86% of the octosanol was absorbed after 48 hours of incubation yet was not detected on the basolateral (post-absorptive) side of the membrane, theoretically due to oxidation.^[15] Octosanol did not appear to change into other fatty acid alcohol in these tests.^[15] When comparing the absorption of policosanols derived from 'authentic' Cuban Cane Sugar against an assortment of alternative sources that were matched for octacosanol content, it was found that no significant difference existed.^[16]

Policosanol appeared to enhance cholesterol ester and free fatty acid uptake into intestinal cells, without affecting triglyceride or phospholipid uptake; cholesterol ester retention in these cells was enhanced, while free fatty acids could not be determined.^[15] However, when tested in hypercholesterolemic individuals cholesterol absorption rates do not appear to be significantly affected.^[17] The omega-6 content of the intestinal cells appeared to increase relative to control.^[15]

Interestingly, it was found that 1.14ug/mL Policosanol inhibited growth of the CaCo-2 cells, whereas half the concentration (0.57ug/mL) had no effect.^[15]

Absorbed fairly well and in vitro is rapidly metabolized, does not appear to prevent a large deal of cholesterol uptake

After intra-gastric administration of 60mg/kg policosanol in water, hepatic (liver) levels were a C_max of 68.4ng/g Octacosanol (used as biomarker) and 331.6ng/g Octacosanoic Acid, the fatty acid metabolite of Octacosanol; both of these C_max values were attained at the T_max of 30 minutes.^[18] The levels in circulation were lower, with the C_max of octacosanol still occurring at 30 minutes but at 30.4ng/mL (44.4% of the liver value) and octacosanoic acid not reaching T_max during the 100 minute testing period, instead gradually increasing concentration in the blood until 19.51ng/mL was recorded at 90 minutes, the time where Octacosanoic Acid's ascending curve passed Octacosanol's descending curve.^[18]

Similar results were seen in Macaca arctoides monkeys fed 10mg/kg bodyweight Policosanol, with the T_max of Octacosanol at 1 hour (when fed via a banana) with a C_max of approximately 500ng/mL, and Octacosanoic Acid reaching a similar C_max at the T_max of 2 hours.^[18]

After oral administration of carbon-labelled octacosanol, it was found that 9.5% of the oral dose accumulated in the liver while 8.2% and 3.5% accumulated in the intestinal organs and the skeletal muscle; respectively.^[19]

In vitro studies suggest that Octacosanol (main fatty alcohol of Policosanol) can be metabolized into Octacosanolic Acid, its fatty acid, in a time-dependent manner in cultures.^[18] Another undetermined metabolite of Octacosanol was noted in cellular medium.

Octacosanoic acid may be able to be partially metabolized for energy similar to other fatty acids, as one study using carbon labelling on Octacosanol noted that some carbon left as breath carbon dioxide.^[20]

Policosanol has been reported to activate AMPK in liver cells by 2-2.5 fold after intragastric dosing and after incubation (15-25ug/mL), respectively, in rats. The increases seen in vitro were comparable to the active controls of Metformin and AICAR.^[12] Oral doses of 10 and 100mg/kg bodyweight failed to influence AMPK and HMG-CoA, while doses of 25 and 50mg/kg were successful.^[12] This activation may be downstream of other kinases, in particular CAMKKβ^[12][21] and possibly LKB1 (although the study investigating policosanol's influence on this did not reach statistical significance).^[12]

This inhibition of AMPK may reduce cholesterol synthesis, and in isolated rat cells has been shown to reduce synthesis by up to 30%.^[22] This phosphorylation occurs at Thr172.^[22][23] Policosanol has also been demonstrated to influence (inhibit) HMG-CoA Reductase, the regulatory step in cholesterol synthesis.^[12] Policosanol does not directly modify this enzyme expression or content,^[22] but seems to be secondary to the influences of AMPK^[22] and it has been noted before that higher AMPK activation in liver cells phosphorylates HMG-CoA at Ser872^[24][25] and in vitro complete phosphorylation inhibits 70-80% of cholesterol synthesis.^[26] The suppression of cholesterol seems to be most related to the fatty acid triacontanol.^[22] The discrepancy between policosanol's cholesterol inhibition (30% or so) and the aforementioned 70-80% may be due to policosanol being inable to activate AMPK in intestinal cells, which can account for up to 25% of circulating cholesterol levels.^[12]

All the previous mechanisms have been replicated in vitro in human fibroblasts.^[27][28] When tested in vivo, suppression of cholesterol synthesis has been noted twice with rats^[29] and rabbits^[30] and has not been demonstrated in two studies using hamsters.^[31][32]

The mechanisms appear to exist for policosanol to reduce cholesterol synthesis, via AMPK acting as the main lever but the true activation probably occurring more upstream of that. Ultimately, it is an indirect inhibition of HMG-CoA (rate limiting step of cholesterol synthesis) which is credited

Interestingly, policosanol fatty acid alcohols appear to work mostly through their metabolites; the fatty acids. Elimination of peroxisomal metabolism (converting alcohols to acids) eliminates influence on HMG-CoA and halves the influence on AMPK, but coincubation with acetate preserved this.^[12] Interestingly, despite similar in vitro potencies between policosanol and Metformin, Metformin was not influenced by peroxisomal elimination.^[12]

Possible lifestyle interactions here, where the liver must be 'burning fat' in order for conversion to the active molecules to occur

At least in regards to literature on policosanol, there appears to be a schism of sorts when it comes to studies conducted in Cuba on the efficacy of Policosanol compounds. Studies that are conducted in Cuba are listed here, and those that show benefit^{[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]} significantly outweigh those that show negative or null effects, of which none can be found.

Going on the assumption that the above studies are valid, the range of improvement in blood lipids tends to be quite reliably in the range of 20+/-5% reductions in LDL cholesterol, 10+/-5% reductions in total cholesterol, and 15+/-10% increases in HDL cholesterol (numbers approximations). Studies range from 6-12 weeks^[38][41] to 12^[33] to 24 months^[37] and tend to have similar overall reductions. Doses used tend to be 5-20mg taken in two divided doses daily, and studies investigating varying dosages usually find no significant differences between lower and higher doses.^[34]

The only study originating from Cuba painting Policosanols in a bad light is a comparative study that was testing out a product called D-003, which is a purified form of Policosanols.^[49] However, if these studies are true then 5-20mg of Policosanol daily is about as effective as statin therapy in reducing cholesterol levels

For studies conducted outside of cuba, ones that show benefit are conducted in Chile,^[50] and Mexico,^[51] with a study from Croatia showing mixed benefits^[52]; studies from Italy,^[53][54], the Netherlands,^[55] Germany,^[56] South Africa,^[57] Canada,^[58][17] and the USA^{[59][60][61][62]} note no effects on circulating cholesterol or triglyceride levels, and some studies do make note that they use 'authentic' Cuban Cane Sugars.^[58][54] When assessing non-Cuban studies for possible conflicts of interest, none are reported and only 3 studies report external funding; all from companies not directly involved with statin or pharmaceutical distribution.^[56][61][57]

These possible publication bias shows in studies on LDL oxidation, where a Cuban study reported benefit^[63] while a study conducted in Montreal, Canada reported no such effect.^[64] It is possible that studies on blood flow are also subject to this, as although there is a multitude of research originating from Cuba showing benefits on platelet aggregation^{[65][66][67][68][69][70]} physical performance secondary to blood flow (intermittent claudation or heart disease)^[71][72] and adverse effects reduction related to heart disease.^[33] Counter-evidence to this point is minimal, but the only study conducted outside Cuba on blood clotting (Croatia) noted no effects^[73] and an Australian study noted no interactions with Warfarin efficacy (a blood thinner).^[74]

Not to sound all conspiracy theorist like, but the chances of the above occurring by pure chance are next to nothing and 'true' Policosanols are derived from Cuban Cane Sugar; this discord in the evidence undermines a lot of the beneficial studies on the subject matter, and despite the large body of evidence there really is not much quality evidence if we assume the Cuban studies are undermined

A 100% success rate is seen with studies conducted in Cuba while the success rate for every other location combined is 2 out of 14 (14.2%). The possibility that Policosanol is ineffective in treating cholesterol levels but suffers from a large degree of publication bias cannot be ruled out

When looking at studies that are both conducted within Cuba and those that find benefit, some are seen using the step I NCEP (National Cholesterol Education Program) diet found here.^[75] and these studies include the following.^{[76][34][33][40]} Other studies specified a lipid-lowering diet,^[43][35][42] while some a cholesterol-lowering diet.^[45][38][44] and some unspecified but present.^[36][47][46] Several studies using diets do include a 2-6 week 'run-in' period where diet is adapted to and made routine before the intervention is conducted.

Two studies have been conducted in Cuba on persons who do not appear to respond to dietary interventions,^[37][41] neither study specified whether dietary control was continued, but both studies found non-responsiveness to the NCEP dietary intervention as well as improvements with policosanol. The one study noted that did not have dietary interventions was a retrospective cohort study of the elderly population and policosanol.^[48]

When looking at studies conducted outside of Cuba that found positive effects of policosanol, all three studies used a modified diet but not the specified NCEP diet.^[50][51][52]

When looking at the studies that found no effects of policosanol on blood lipids (all conducted outside of Cuba), one used controlled cholesterol lowering diets such as 55/15/20 carbohydrate/protein/fat with under 300mg cholesterol^[57] and another used the NCEP diet;^[56] most of the others used no controlled dietary intervention (just measuring intake post-intervention to see if any significant differences existed).^{[17][62][61][55][58]} Beyond that, one study measured food intake via questionnaire to see if any changes that could have influenced results existed,^[59] and another controlled for calories but permitted standard lifestyle food intake.^[53] One study specifically investigated persons who, using an NCEP intervention prior to the study, failed to have any reduction of cholesterol by the diet; they were instructed to continue with their current lifestyle diets but were controlled for calories.^[54]

Of those, two studies used the dietary 'lead-in' period of accustomizing persons to a lifestyle change diet before introducing policosanol intervention. A study from Croatia^[8] can back with a reduction of total cholesterol (down to 94% of baseline) and no significant influence on LDL-C or HDL-C between groups and a study from Germany^[56] found no significant effects and no patients reporting more than a 10% drop in LDL-C regardless of statistical significance.

The notion that policosanol's efficacy is reliant on a controlled diet is a plausible counter-hypothesis that has not yet been ruled out, and may play some importance given the 2011 in vitro study suggesting fatty acid metabolism is mandatory for fatty acid alcohols to become effective. This is the only significant difference between Cuban studies and non-Cuban studies that persists, and the differences can be explained currently by either location or dietary intervention

One study in karate athletes found that fish oil at 2.25g daily paired with 10mg policosanol found that after 21 days of supplementation that the combination was able to reduce reaction time and increase mood, with the increased mood persisting 21 days after cessation of supplementation while reaction time returned to normal.^[77] These effects have been seen with isolated policosanol compounds at 3.6mg daily in as short as a week^[78] Both studies were carried out on otherwise healthy and youthful persons, although the degree of improved speed is minor; the study in athletes noted decreased reaction time from approximately 860milliseconds (ms) to 840ms (data extracted from graphs, approximately a 2% decrease)^[77] whereas in healthy sedentary persons the decreases range from 90% of baseline values to 94% of baseline depending on the manner of testing.^[78]

May increase reaction time in humans after ingestion, but aside from being relatively understudied the effects do not seem overly potent. Kava Kava or Vinpocetine may be better options

A single rat study on policosanol noted that it had a small effect on enhancing the apparent acetylcholine release, possibly through interaction with acetylcholinesterase.^[79]

A study in rats noted that policosanol at 50 and 200mg/kg bodyweight was able to preserve some bone mass during a model of menopausal bone loss, theoretically via the same mechanisms that reduce cholesterol.^[80] With indirect inhibition of HMG-CoA comes decreased production of Mevalonate, which is a cholesterol precursor that can influence production of osteoclasts that may act as pro-osteoporotic.^[81]

Warfarin is a blood thinning pharmaceutical, and adverse reactions with nutraceuticals and Warfarin can cause excessive blood thinning resulting in death in some persons using Warfarin.

When policosanol and Warfarin were investigated alongside each other, Policosanol dosed at 10mg and taken twice daily did not influence the effects of Warfarin (25mg) and was deemed safe in this preliminary investigation; study conducted in otherwise healthy subjects.^[74]

A study in rats using D-003 (the fatty acids of policosanol) did note synergism, however, and suggests that the combination may confer much greater anti-platelet activity than Warfarin and D-003 in isolation.^[82]

May interact adversely with Warfarin, possibly mediated through the active metabolites

The formulation of D-003, which is the fatty acids of policosanol rather than the fatty alcohols, appears to be synergistic with Aspirin in both positive and negative manners; the combination of D-003 (50mg/kg) and Aspirin (3mg/kg) synergistically enhanced bleeding time from preventing platelet aggregation (negative) but the combination enhanced a 33% survival rate seen with the isolated treatments in response to a blood clotting stimuli to 88% survival with combination therapy.^[83]

May work synergistically with Aspirin

Policosanol has been investigated with fish oil, as Policosanol has evidence for benefitting lipoproteins with minimal influence on triglycerides while fish oil can reduce triglycerides while possible raising LDL-C. One Cuban trial done into this combination in hypercholesterolemic patients^[76] found that combination therapy led to LDL-C decreases of 21.1-26.2% at 5-10mg daily, although the fish oil only group had a decrease of 2.1% (possibly due to following a NCEP cholesterol reduction diet); Triglycerides decreased by 13% in the fish oil group at 2g daily (44% EPA, 37% DHA), and the addition of policosanol did not significantly influence the triglyceride reduction.^[76]

Preliminary evidence that they can nicely compliment each other, although no synergism has been demonstrated

CoQ10 is a vitamin-like compound that becomes important to ingest or supplement when using statin drugs, as endogenous synthesis of CoQ10 is reduced when the HMG-CoA enzyme is inhibited; synthesis normally occurs to sustain CoQ10 levels and mitochondrial function, and the decrease may lead to myopathies and increased fatigue.

As the mechanisms of policosanol are ultimately mediated via HMG-CoA, a long-term deficiency of CoQ10 could be suspect. This has not been reported in chronic studies with Policosanol currently (1-2 years) when dosed at 10-20mg, but has not been ruled out either.

Possible interaction with these two based on the mechanisms of Policosanol, under the assumption that it works

Red yeast extract is an extract from rice that has been fermented by the bacteria Monascus purpureus, and appears to have additive effects when paired with policosanols in reducing cholesterol levels (according to one study conducted in rabbits).^[84]

No significant adverse events have been reported with policosanol in the dosage range of 5-20mg daily in all currently conducted trials, regardless of region of origin, up to 2 years of usage. And the opposite of this (high dose, small time frame) has demonstrated that doses up to 80mg daily for 12 weeks have been tested with no adverse events reported.^[56] 40mg for 6 months also appears to be well tolerated^[34] and over the short term does not adversely affect platelet function.^[67]

A 1 year study of the toxicological effects of policosanol in beagle dogs with doses ranging between 30 or 180mg/kg bodyweight, with no toxicity reported in either group.^[67] The latter dose is approximately 620 times higher than the recommended dose of 20mg daily.^[67] Doses of 50mg/kg bodyweight in rats^[85] (172.4 fold higher than the recommended dose), 500mg/kg in rats^[86][87][85] (1,724 fold higher) and 5,000mg/kg in rats^[88] (17,240 fold higher) also appeared to be free of side-effects, with the latter study being conducted over a period of 6 months^[88] and the former study being conducted starting 15 days after pregnancy onset and continuing during pregnancy to after lactation.^[87] This study on maternal supplementation has been replicated with 1,000mg/kg and in two species (rats and rabbits) with the same null results.^[89]

A study in monkeys, the most repesentative animal model to humans, was found to be safe and not affect any measured parameter adversely at doses of 35mg/kg bodyweight for just over 1 year of supplementation.^[90]

No differences between groups have been noted in rats fed 500mg/kg in regards to tumor growth, suggesting policosanol may not influence cancer metabolism.^[85] This study was replicated and extended 6 months (from 18 to 24) and a lack of effects was again noted.^[91]

Independent of whether it works or not, Policosanol appears to be quite a safe supplement to ingest and has not been linked to side-effects currently