Limonene

Last Updated: September 28 2022

D-Limonene is a molecule that is found in high levels in lemons (where it derives its name) but also most citrus foods. It holds promise as an anti-cancer agent, and for some reason is marketed as a fat burner despite minimal evidence of fat burning effects. Can be consumed via pulpy lemon juice.

Limonene is most often used for




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    1.

    Sources and Structure

    1.1

    Sources

    Limonene has its name derived from 'Lemon', the food source that is most abundant in limonene and among the first sources discovered. It is found in:

    • Lemons (as well as limes)[1]
    • Essential oils from Orange where it acts as an aroma[2]
    • Oils from mandarin and grapefruit[1]
    • Teas derived from Phlomis (Lamiaceae)[3]
    • Cardamom[4]
    • Japanese Catnip[5]

    1.2

    Structure

    Limonene is known as a monoterpene molecule (having one isoterpene in its structure) as well as a cyclic terpene (having a six-carboned ring structure).[6] Alongside Limonene, a well-researched compound is its metabolite 'Perillyl Aldcohol'.

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    2.

    Limonene pharmacology

    Limonene is colourless hydrocarbon compound that smells of oranges. Despite the scent, it is at highest levels in the rinds of lemons, where it acquires its name from.[1]

    Limonene is rapidly and almost wholly absorbed in the GI tract after ingestion, and then gets divided to various body tissues after first pass metabolism in the liver[7] where it may be subject to metabolism into carveol metabolites or perillyl metabolites by CYP2C enzymes[8] of which inter-species differences exist.[9]

    After a 1.6g dose, between 52-83% of the dose is excreted in 48 hours[10] and no build up of the compound is seen 21 days after cessation.[11] The half-life of D-limonene in humans is estimated to be between 12 and 24 hours.[11]

    The primary metabolites of limonene in humans are perillic acid, dihydroperillic acid, and limonene-1,2-diol.[12] These metabolites are glucuronidated by the liver and excreted via the urine.

    3.

    Limonene from food sources

    Serum limonene and metabolite levels are able to be elevated via food consumption. A 30-40 oz. serving of 'Mediterranean Style' lemonade (made with the whole lemons) contains 447-596mg limonene. [13] The termination half-life of perillic acid is shorter than that of D-limonene (in the range of 0.82-1.84 hours) and spiked serum levels of perillic acid 2.08 to 13.98 μM.

    Standard Citrus juices in western nations (made without the rind) contain up to 100mg per litre of juice, whereas juices made with the rind included contain up to 1027mg per litre.[14][13]

    4.

    Limonene and liver health

    In those with Non-alcoholic Fatty Liver disease (onset by diet), supplementation with D-limonene has been shown (in rats) to reverse the hepatic fatty acid buildup as well as downstream effects caused by the hepatic impairment.[15]</di|authors=Victor Antony Santiago J, Jayachitra J, Shenbagam M, Nalini N|journal=Eur J Nutr]

    5.

    Limonene and body fat

    At this moment in time, no scientific consensus exists on D-limonene's role in adipocytes. Select anecdotes, however, suggest it may induce weight loss in high doses.

    It, as well as the metabolite perillic acid, do build up in adipocytes over time[16][17], which ensures it can actually get to fat cells. Beyond that, it might exert fat-burning effects via suppression of insulin secretion in response to nutrients at pancreatic cells[18] or perhaps vicariously through possibly being an adenosine A(2A) agonistic ligand.[19]

    6.

    Limonene and Cancer

    Dietary D-Limonene, as a monoterpene structure, is an anti-carcinogenic agent in various models of cancer including; skin, kidney, lung, forestomach, and mammary models.[20][21][22][13]

    It seems to exert most carcinogenic effects by prevention of protein prenylation[23] at advanced stages of tumorogenesis, and by increasing levels of glutathione in the earlier stages as a preventative measure.[24] Some Phase 1 enzymes of the liver are also affected positively.[25]

    7.

    Safety

    Limonene is a fairly safe compound to supplement, and has a Generally Recognized as Safe (GRAS) listing for being a food additive.[1]

    It has no significant toxicity in humans. Past research indicated it may accelerate formation of tumors, however this result was found in rats and has since been shown to be of no significance to human metabolism.[26]

    References
    1.^Sun JD-Limonene: safety and clinical applicationsAltern Med Rev.(2007 Sep)
    2.^Perez-Cacho PR, Rouseff RLFresh squeezed orange juice odor: a reviewCrit Rev Food Sci Nutr.(2008 Aug)
    3.^Limem-Ben Amor I, Boubaker J, Ben Sgaier M, Skandrani I, Bhouri W, Neffati A, Kilani S, Bouhlel I, Ghedira K, Chekir-Ghedira LPhytochemistry and biological activities of Phlomis speciesJ Ethnopharmacol.(2009 Sep 7)
    6.^Hyatt DC, Youn B, Zhao Y, Santhamma B, Coates RM, Croteau RB, Kang CStructure of limonene synthase, a simple model for terpenoid cyclase catalysisProc Natl Acad Sci U S A.(2007 Mar 27)
    7.^Crowell PL, Elson CE, Bailey HH, Elegbede A, Haag JD, Gould MNHuman metabolism of the experimental cancer therapeutic agent d-limoneneCancer Chemother Pharmacol.(1994)
    11.^Vigushin DM, Poon GK, Boddy A, English J, Halbert GW, Pagonis C, Jarman M, Coombes RCPhase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials CommitteeCancer Chemother Pharmacol.(1998)
    16.^Miller JA, Hakim IA, Chew W, Thompson P, Thomson CA, Chow HHAdipose tissue accumulation of d-limonene with the consumption of a lemonade preparation rich in d-limonene contentNutr Cancer.(2010)
    17.^Miller JA, Hakim IA, Thomson C, Thompson P, Chow HHDetermination of d-limonene in adipose tissue by gas chromatography-mass spectrometryJ Chromatogr B Analyt Technol Biomed Life Sci.(2008 Jul 1)
    19.^Park HM, Lee JH, Yaoyao J, Jun HJ, Lee SJLimonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptorsBiochem Biophys Res Commun.(2011 Jan 7)
    20.^Crowell PLMonoterpenes in breast cancer chemopreventionBreast Cancer Res Treat.(1997 Nov-Dec)
    22.^Tsuda H, Ohshima Y, Nomoto H, Fujita K, Matsuda E, Iigo M, Takasuka N, Moore MACancer prevention by natural compoundsDrug Metab Pharmacokinet.(2004 Aug)
    23.^Gelb MH, Tamanoi F, Yokoyama K, Ghomashchi F, Esson K, Gould MNThe inhibition of protein prenyltransferases by oxygenated metabolites of limonene and perillyl alcoholCancer Lett.(1995 May 8)