Inositol Hexaniacinate: A Safer Alternative to Niacin Kathleen A. Head, N.D. Abstract Niacin has long been prescribed for the treatment of various cardiovascular con- ditions, particularly the hyperlipidemias. It has been proven effective at lowering VLDL, LDL, total cholesterol and triglyceride levels while raising HDL levels. The side effects of niacin which may occur at the dosages often required for therapeutic efficacy, rang- ing from flushing and pruritus to hepatoxicity and impaired glucose tolerance, often prove troubling for both patient and practitioner. The need for a safer approach to niacin supplementation has resulted in the investigation of niacin esters. One of the most widely studied of these is inositol hexaniacinate (IHN). In numerous trials it has been found to be virtually free of the side effects associated with conventional niacin therapy. Extensive research has found IHN to be effective in the treatment of hyperlipi- demia, Raynaud’s disease and intermittent claudication. A number of other conditions which respond favorably to niacin therapy such as hypertension, diabetes, dysmennorhea and alcoholism bear further investigation. (Alt Med Rev 1996;1(3):176-184.) Importance of Niacin to Human Health: Niacin (B3, nicotinic acid) is vital to cellular metabolism, principally through its role in the coenzymes, nicotine-adenine dinucleotide (NAD) and nicotine-adenine dinucleotide phosphatate (NADP), in oxidation-reduction reactions. Niacin is primarily metabolized in the liver to niacinamide (nicotinamide) and other derivatives. Niacinamide is, in turn, a precursor to NAD and NADP.1 Due to its vasodilatory effects, niacin (but not niacinamide) has, for decades, been prescribed by orthodox and alternative practitioners alike for the treatment of cardiovascular disease, particularly the hyperlipidemias.1-2 In addition, the use of niacin for the treatment of peripheral vascular disorders including Raynaud’s disease and intermittent claudi- cation has been widely studied.3-6 Besides the use of niacin in therapeutic doses, there are certain fractions of the general population that may be deficient in niacin, requiring supplemen- tation to prevent pellagra (the disease of niacin deficiency). These groups include alcoholics7 and the elderly.8 Adverse Effects of Niacin: Although niacin has numerous therapeutic benefits, it may also result in a considerable number of side effects both acute and chronic, subjective and objective. The acute, subjective symptoms include flushing, particularly of the face and neck with pruritis and burning skin, GI complaints and weakness.9 These effects are due to histamine release from the mast cells, starting approximately 20 minutes after ingestion and lasting from one to one and a half hours. Page 176 Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Inositol Hexaniacinate FIGURE 1. Side effects are often N rare.1 Coppola and minimized by the ad- Brady12 reported on N dition of aspirin N four cases of niacin- which may create CO induced hepatotoxic- further problems. O ity. All four were tak- Although there may OCO OCO ing sustained-release also be a reduction of niacin. Fulminant symptoms after sev- Esterase liver failure may oc- HO OCO eral days by increas- O cur with the use of ing the dose gradu- COOH high doses of sus- ally and by taking CO tained-release niacin the niacin with N as evidenced by the N meals, many people N case of a 44-year- discontinue its use NIACIN old male who devel- before ever reaching oped liver failure af- optimal therapeutic ter three days on 6 doses. Sustained-release niacin preparations grams daily of timed-release niacin, reported may minimize flushing but result in more gas- by Mullin et al.13 He had previously consumed trointestinal complaints, according to at least up to 6 grams daily of regular crystalline nia- one study.1 Chronic conditions may also re- cin. After 16 months on this regime his liver sult from the use of niacin. These may in- enzymes had remained normal. Gibbons et clude hepatoxicity, hyperuricemia, glucose al14 reported on the prevalence of side-effects intolerance, ocular effects, exacerbation of of both sustained-release and regular niacin peptic ulcer, postural hypotension, particularly in a clinical setting. 110 patients in 133 sepa- in patients taking antihypertensive agents, and rate trials were given nicotinic acid during a skin disorders including acanthosis nigricans.1-2 five year period. The results were that 43% of The ocular effects may include decreased vi- individuals given regular nicotinic acid and sion, cystoid macular edema, periorbital 42% of those receiving the sustained-release edema, loss of eyebrows or eyelashes and su- form were forced to discontinue treatment perficial punctate keratitis. These may occur because of side-effects.14 with the use of niacin in high doses and are 10 reversible if it is discontinued. Niacin com- Inositol Hexaniacinate: petes with uric acid for renal excretion with subsequent elevation of serum uric acid levels. Biochemistry and Metabolism On rare occasions, this may lead to the de- Because of the therapeutic importance velopment of gout or uric acid kidney stones.11 of this vitamin it is imperative that we explore The hepatotoxic effects are perhaps of safer and perhaps more effective forms of ad- the most concern to those administering this ministration. One such form, and probably therapy on a long-term basis. Abnormalities the most studied, is the hexanicotinic acid es- noted on liver function tests may include dose ter of meso-inositol, inositol hexaniacinate related increases in aspartate aminotransferase (IHN), also called inositol hexanicotinate or and alkaline phosphatase. Liver pathology inositol nicotinate. The compound consists of may include cholestasis, hepatocellular disar- six molecules of nicotinic acid and one mol- ray and nodular formation by fibrous tissue. ecule of inositol (See Figure 1).15 It is me- Severe liver toxicity with regular niacin is quite tabolized in the body into its component parts, Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 177 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission niacin and inositol (hexahydroxycyclohexane). Raynaud’s disease and intermittent claudica- In the United States it was first described by tion. Promising applications which bear fur- Badgett et al. in 1945.15 It appears that the ther investigation include its use for stasis ulcers, compound is slowly metabolized, not reach- dysmenorrhea, dermatitis herpetiformis, alcohol- ing maximum serum levels for approximately ism, diabetes, cancer prevention and hyperten- 10 hours after ingestion.15 When IHN is ad- sion. These will each be addressed below. ministered orally to humans, the result is a sustained increase in the level of free nicotinic Hyperlipidemia: acid in blood and plasma.16 Pharmacokinetic Numerous epidemiological studies, studies have indicated that these esters are, at both prospective and retrospective, have least in part, absorbed intact and hydrolyzed demonstrated that hyperlipidemia is a major in the body with release of free niacin and risk factor for the development of athero- inositol. The rise in niacin levels was more sclerosis. High levels of very low density than could be explained by observation of the lipoproteins (VLDL), low density lipopro- rate of hydrolysis of these esters in buffered teins (LDL), total cholesterol and triglycer- solutions of various pHs, designed to simu- ides correlate positively with an increased late the gastric and intestinal juices. There- risk for cardiovascular disease (CVD) while fore, it was assumed that another mechanism elevated levels of high density lipoproteins was involved. This was demonstrated by (HDL) convey cardioprotection.2,20 Harthon and Brattsand16 to be an active, en- Niacin, in doses up to 6 grams daily, zymatic hydrolysis in the bloodstream. has long been known to effectively reduce trig- lycerides, total cholesterol, and LDL choles- Safety of Inositol Hexaniacinate terol while at the same time elevating HDL IHN appears to be safe and free of side levels1,2,21,22 Supplemental niacin will also effects at doses up to 4 grams. Welsh and Ede reduce the risk of MI in patients with a previ- studied a group of 153 patients with a variety ous history.23 Niacin appears to effect blood of conditions ranging from Raynaud’s disease lipids by a number of different mechanisms. to psoriasis and reported not a single side ef- It lowers LDL and triglyceride levels by de- fect, with doses ranging from 600 to 1800 mg creasing VLDL synthesis in the liver. This daily. They compared this to patients with the decrease occurs as a chain reaction, beginning same conditions receiving nicotinic acid. Ap- with the activation of the enzyme, phosphodi- proximately 1/3 of them reported one or more esterase and inhibition of adenylate cyclase of the following symptoms: flushing, nausea, activity by nicotinic acid. This in turn inhib- vomiting, giddiness and weakness. Further- its cAMP production in adipocytes.. There is more, the IHN patients tolerated without side a subsequent decrease in release of free fatty effects dosages 3 or 4 times larger than the acids (FFA) from peripheral adipose tissue nicotinic acid group.15 Numerous other in- resulting in a decrease in FFA transport to the vestigators, studying the use of dosages of IHN liver followed by a reduction of VLDL forma- in the range of 4 grams daily, reported not a tion which results in a decrease in the LDL single adverse reaction.3,17-19 cholesterol fraction. The decrease in VLDL and LDL then leads to a decrease in serum trig- Therapeutic Applications of IHN lycerides, phospholipids and cholesterol which IHN has a fairly broad range of thera- generally combine with these lipoproteins.24 peutic applications. The most well researched Niacin also inhibits cholesterol synthe- conditions include the hyperlipidemias, sis from acetate in the liver and appears to Page 178 Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Copyright©1996 Thorne Research, Inc.