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Will usnic acid be banned next?

The tenacity with which some nutraceutical formulators and marketers search for novel weight loss-inducing agents is striking. One of the more recent illustrations is the inclusion of usnic acid, as a sodium salt or the free acid, in dietary supplements claiming to have anti-obesity effects. The Food and Drug Administration has its sights set on it as a candidate for market removal, following the fate of ephedra and, potentially, bitter orange and aristolochic acid. (Bitter orange was discussed on this page in the April issue, and aristolochic acid will be discussed next month.)

Its start as a supplement
Usnic acid (UA) is a polyphenol expressed by a variety of lichens. Additionally, UA has been described in hops resin and Kombucha tea.1,2

The genesis of UA?s positioning as a weight-loss nutraceutical appears to emanate from a single paper employing in vitro assessments of UA as an ?uncoupling agent? in mouse liver mitochondria.3

Uncoupling agents effectively render the process of aerobic metabolism in mitochondria—which couples oxidation of metabolic fuels to the attachment of phosphate groups to ATP precursors, yielding ATP, the axial molecule of bioenergetics—less efficient and thus energy is ?leaked? out. This manifests as heat and an increase in metabolic rate, known as thermogenesis.

In this in vitro study, UA was shown to be more potent than an infamous uncoupler, 2,4-dinitrophenol (DNP). DNP was sold as a drug in the 1930s in the United States, the product of studies at Stanford University showing a relationship between dose, metabolic rate increase and weight loss.4

In these studies, weight loss (without any dietary control) averaged 7.8kg without any apparent effects on food consumption. Hypertensive subjects also experienced significant decreases in blood pressure. However, the widespread use of DNP eventually led to its procurement without medical supervision, and the sharp dose-dependent relationship on metabolic rate led to some individuals being ?cooked to death,? which led to its subsequent removal from the market.

Effects on the liver
In the above study comparing UA to DNP, UA was about 50 times more potent an uncoupler. This single in vitro study, despite the absence of any in vivo studies examining UA?s effect upon thermogenesis or body weight, fostered a number of dietary supplements incorporating pure UA or its sodium salt. Most notable was a product called LipoKinetix, which was associated with severe chemical hepatitis (elevated liver enzymes in blood, jaundice, vomiting) in seven previously healthy men and women.5 The duration of use in this cohort ranged from 10 days to 12 weeks. LipoKinetix was comprised of phenylpropanolamine, sodium usnate, a thyroid hormone precursor, diiodothyronine, yohimbine and caffeine. Thus, attributing the acute hepatotoxicity to UA alone is unfounded. Notably, after each of the subjects ceased using this product, their liver enzyme profiles normalised.

Recent research has subjected mouse liver cells to UA in vitro and found both oxidative stress and toxicity, which could be prevented by the pre-addition of a fat-soluble antioxidant like alpha-tocopheryl succinate (vitamin E).6 Interestingly, DNP also showed similar oxidative and toxic effects, which were in fact not mitigated by vitamin E.

Another study found high-dose (200mg/kg) injections of UA for five days had no significant effect on blood liver enzymes but a demonstrable effect on liver cell size and shape, indicative of a toxic effect.7

One area of promising use for UA in hepatology is with an inherited metabolic defect called tyrosinemia I, an often-fatal fibrotic liver disease marked by disordered collagen metabolism. Recent investigations suggest that UA, which inhibits the plant form of the deranged enzyme characteristic of this disease, may indeed be a candidate for clinical therapy.8,9

Anthony Almada is president and chief scientific officer of IMAGINutrition Inc.

1. Stevens R. The chemistry of hop constituents. Chem Rev 1966;67:19-71.
2. Blanc PJ. Characterization of the tea fungus metabolites. Biotech Lett 1996;18:139-42.
3. Abo-Khatwa AN, et al. Lichen acids as uncouplers of oxidative phosphorylation of mouse-liver mitochondria. Nat Toxins 1996;4:96-102.
4. Tainter ML, et al. Dinitrophenol in the treatment of obesity: final report. J Am Med Assoc 1933;101:322-36.
5. Favreau JT, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002;136:590-5.
6. Han D, et al. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Biochem Pharmacol 2004;67:439-51.
7. Pramyothin P, et al. Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. J Ethnopharm 2004;90:381-7.
8. Hanauske-Abel HM, et al. Tyrosinemia I, a model for human diseases mediated by 2-oxoacid-utilizing dioxygenases: hepatotoxin suppression by NTBC does not normalize hepatic collagen metabolism. J Pediatr Gastroenterol Nutr 2002;35:73-8.
9. Romagni JG, et al. The phytotoxic lichen metabolite, usnic acid, is a potent inhibitor of plant p-hydroxyphenylpyruvate dioxygenase. FEBS Lett 2000;480:301-5.

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