d-Limonene

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Limonene is a terpene that conveys a citrus aroma not only found in cannabis but also in the rinds of citrus fruits such as lemon, grapefruit, tangerine, orange and lime. Widely used as a food flavour and fragrance additive it is Generally Recognised as Safe (GRAS) and considered to have low toxicity. Plants produce limonene as a natural insecticide to ward off predators.

d-Limonene is an excellent solvent of cholesterol, and supports normal peristalsis, assisting to reduce reflux (1,2,3). It has also been shown to protect neurons from amyloid fibril-induced damage (21), and can assist with the absorption of other compounds (26).

Limonene has also been shown to elicit gastroprotective effects, reducing inflammation and protecting against gastric ulcers and inflammation (22,23,24,25).

D-Limonene has been shown to be effective in relieving occasional heartburn. In a double-blind, placebo-controlled study, 13 participants suffering from mild/moderate to severe heartburn/GERD were randomized to d-limonene or placebo. Seven participants in the d-limonene group received 1,000mg d-limonene once daily or every other day, while six participants received an identical capsule containing soybean oil (placebo). Each participant was asked to rate the frequency and severity of symptoms on a scale of 1-10, with 1 corresponding to complete relief and 10 corresponding to severe and/or painful symptoms that occur every day (4).

On day four, 29 percent of participants in the d-limonene group experienced significant relief of symptoms (severity rating=1-2), compared to no relief of symptoms in the placebo group. By day 14, 86 percent of participants achieved complete relief of symptoms, compared to 29 percent of participants in the placebo group (4).

d-limonene has also demonstrated antiproliferative effects in a range of tissues (1,5,6,7,8,9,10,11,12,13,14,15) via inhibition of protein isoprenylation. Many prenylated proteins regulate cell growth and/or transformation. Impairment of prenylation of one or more of these proteins might account for the anti-proliferative activity of d-limonene (16). This activity may also be linked to decreased DNA synthesis and ornithine decarboxylase activity in deleterious cells (17,18,19,20).

 Key references:

  • Liver protective (2,3)

  • Anti-proliferative (1,15,16,17,18,19,20)

  • Anti-reflux (4)
  • Anti-stress (27)
  • Anti-inflammatory (22)
  • Pain reducing (28)
  • Anti-bacterial (29)
  • Neuroprotective (21)
  • Reduced gut inflammation and oxidation (22,23,24,25)
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1 - Jidong Sun PhD 2007. D-limonene Safety and clinical applications. Alternative medicine review Volume 12, Number 3, 2007

2 - Igimi H, Hisatsugu T, Nishimura M. The use of d-limonene preparation as a dissolving agent of gallstones. Am J Dig Dis 1976; 21:926-939

3 - Igimi H, Tamura R, Toraishi K, et al. Medical dissolution of gallstones. Clinical experience of d- limonene as a simple, safe, and effective solvent. Dig Dis Sci 1991; 36:200-208

4 - Wilkins J Jr. Method for treating gastrointestinal disorder. U.S. Patent (642045). 2002.

5 - Elegbede JA, Elson CE, Quereshi A, et al. Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene. Carcinogenesis 1984;5:661-664

6 - Elson CE, Maltzman TH, Boston JL, et al. Anti-carcinogenic activity of d-limonene during the initiation and promotion/progression stages of DMBA-induced rat mammary carcinogenesis. Carcinogenesis 1988;9:331-332

7 - Maltzman TH, Hurt LM, Elson CE et al. The prevention of nitrosomethylurea-induced tumors by d-limonene and orange oil. Carcinogenesis 1989;10:781-783.

8 - Wattenberg LW. Inhibition of neoplasia by minor dietary constituents. Cancer Res 1983;43:2448S-2453S.

9 - Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr 1999; 129:775S-778S.

10 - Uedo N, Tatsuta M, Iishi H, et al. Inhibition by d-limonene of gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine in Wistar rats. Cancer Lett 1999; 137:131-136

11 - Yano H, Tatsuta M, Iishi H, et al. Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine in Wistar rats. Int J Cancer 1999; 82:665-668

12 - Dietrich DR, Swenberg JA. The presence of alpha 2u-globulin is necessary for d-limonene promotion of male rat kidney tumors. Cancer Res 1991;51:3512-3521.

13 - Wattenberg LW, Sparnins VL, Barany G. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes. Cancer Res 1989;49:2689-2692.

14 - Wattenberg LW,Coccia JB. Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone carcinogenesis in mice by d-limonene and citrus fruit oils. Carcinogenesis 1991;12:115-117.

15 - Vigushin DM, Poon GK, Boddy A, et al. Phase 1 and Pharmokinetic study of d-limonene in patients with advanced cancer. Cancer Research Campaign Phase 1&2 Clinical Trials Committee. Cancer Chemother Pharmacol 1998; 42:111-117.

16 - Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr 1999; 129:775S-778S.

17 - Uedo N, Tatsuta M, Iishi H, et al. Inhibition by d-limonene of gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine in Wistar rats. Cancer Lett 1999; 137:131-136

18 - Yano H, Tatsuta M, Iishi H, et al. Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine in Wistar rats. Int J Cancer 1999; 82:665-668

19 - Giri RK, Parija T, Das BR. D-limonene chemoprevention of hepatocarcinogenesis in AKR mic: inhibition of c-jun and c-myc. Oncol Rep 1999;6: 1123-1127

20 - Kaji I, Tatsuta M, Iishi H, et al. Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague- Dawley rats does not involve p21(ras)plasma membrane association. Int J Cancer 2001; 93:441-444.

21 - Shin, M., Liu, Q. F., Choi, B., Shin, C., Lee, B., Yuan, C., .& Cho, K. S. (2020). Neuroprotective effects of limonene (+) against Aβ42-induced neurotoxicity in a Drosophila model of Alzheimer’s disease. Biological and Pharmaceutical Bulletin, 43(3), 409-417.

22 - d'Alessio, P. A., Ostan, R., Bisson, J. F., Schulzke, J. D., Ursini, M. V., & Béné, M. C. (2013). Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life sciences, 92(24-26), 1151-1156.

23 - Yu, L., Yan, J., & Sun, Z. (2017). D-limonene exhibits anti-inflammatory and antioxidant properties in an ulcerative colitis rat model via regulation of iNOS, COX-2, PGE2 and ERK signaling pathways. Molecular medicine reports, 15(4), 2339-2346.

24 - Rozza, A. L., de Mello Moraes, T., Kushima, H., Tanimoto, A., Marques, M. O. M., Bauab, T. M., & Pellizzon, C. H. (2011). Gastroprotective mechanisms of Citrus lemon (Rutaceae) essential oil and its majority compounds limonene and β-pinene: Involvement of heat-shock protein-70, vasoactive intestinal peptide, glutathione, sulfhydryl compounds, nitric oxide and prostaglandin E2. Chemico-biological interactions, 189(1-2), 82-89.

25 - de Souza, M. C., Vieira, A. J., Beserra, F. P., Pellizzon, C. H., Nóbrega, R. H., & Rozza, A. L. (2019). Gastroprotective effect of limonene in rats: Influence on oxidative stress, inflammation and gene expression. Phytomedicine, 53, 37-42.

26 - Carvajal-Vidal, P., Mallandrich, M., García, M. L., & Calpena, A. C. (2017). Effect of different skin penetration promoters in halobetasol propionate permeation and retention in human skin. International journal of molecular sciences, 18(11), 2475.

27 - Lima, N. G., De Sousa, D. P., Pimenta, F. C. F., Alves, M. F., De Souza, F. S., Macedo, R. O., & de Almeida, R. N. (2013). Anxiolytic-like activity and GC–MS analysis of (R)-(+)-limonene fragrance, a natural compound found in foods and plants. Pharmacology Biochemistry and Behavior, 103(3), 450-454.

28 - Piccinelli, A. C., Santos, J. A., Konkiewitz, E. C., Oesterreich, S. A., Formagio, A. S. N., Croda, J., & Kassuya, C. A. L. (2015). Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model. Nutritional neuroscience, 18(5), 217-224.

29 - Hąc-Wydro, K., Flasiński, M., & Romańczuk, K. (2017). Essential oils as food eco-preservatives: Model system studies on the effect of temperature on limonene antibacterial activity. Food chemistry, 235, 127-135.