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Olive Leaf

Scientific Name(s): Olea europaea L.
Common Name(s): OLE, Olive leaf, Olive leaf extract

Clinical Overview

Use

Interest in olive leaf use centers on antioxidant and antiviral activity, as well as its possible role in diabetes and cardiovascular conditions. However, clinical trials do not support its use for any indication.

Dosing

Traditional dosages of olive leaf include 7 to 8 g of dry leaf in 150 mL water. In 1 clinical trial, patients with stage 1 hypertension were administered 500 mg of olive leaf extract twice daily for 8 weeks. A clinical trial in overweight men used oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks.

Contraindications

Contraindications have not been identified. Caution may be warranted in hepatic disease.

Pregnancy/Lactation

Information regarding safety and efficacy during pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

None well documented. Diabetic patients should be supervised carefully because of potential hypoglycemic effects.

Toxicology

Information is limited. Moodiness and aggressive behavioral changes likely related to olive leaf extract have been reported in an elderly woman at a dose of 85 mg/kg.

Botany

The olive tree (O. europaea) is an evergreen that grows to approximately 10 m in height. Native to Mediterranean regions, olive trees also are cultivated in similar climate zones in the Americas. The small, leathery leaves are gray-green on top, and the underside contains fine, white, scale-like hairs. The leaves are gathered throughout the year.1, 2, 3

History

The olive tree was cultivated in Crete, where the leaves were used to clean wounds as early as 3500 BC. The leaves were worn by athletes in ancient Olympic Games, and the olive branch has traditionally been a symbol of peace. In the 1800s, the plant was used to treat malaria.2, 3, 4, 5

Chemistry

Olive leaf contains the iridoid oleuropein (up to 240 mg per gram of dry leaves).6 Other secoiridoids include demethyloleuropein, esters of oleoside, ligustroside, oleuroside, and unconjugated secoiridoid aldehydes. Triterpenes and flavonoids, including luteolin and related glucopyranosides, tyrosol and hydroxytyrosol, apigenin, rutin, and diosmetin, are also present. Other compounds found in the leaves are oleasterol, leine, choline, cinconine, olivine, tannin, calcium, phosphorus, carbohydrates, fat, and fiber.7, 8, 9, 10, 11, 12

Uses and Pharmacology

Antidiarrheal

A study in mice with castor oil–induced diarrhea suggested that olive leaf extract reduced the number of diarrheal episodes and could affect gastric transit time.68

Antioxidant activity

Animal data

In vitro studies have demonstrated the antioxidant activity of olive leaf extracts.9, 10, 13, 14, 15, 16, 17, 18

Studies in rodents have shown antioxidant activity in brain tissue injury, gentamicin-induced nephrotoxicity, reperfusion injury, major organ injury, and induced gastric ulceration, as well as in other conditions.19, 20, 21, 22, 23, 24, 25, 26, 27, 28 In a model of Parkinson disease, olive leaf extract inhibited adrenal pheochromocytoma cell damage via antioxidant and antiapoptotic activity.29

Clinical data

The oral bioavailability of olive leaf extract and associated antioxidant biomarkers was evaluated in pre- and postmenopausal women. The findings suggest that postmenopausal status increases the production of olive leaf extract metabolites.30 In young healthy volunteers (N = 45), supplementation with olive leaf extract did not alter oxidative status, and wide interperson variability was seen.31

Anti-inflammatory

Animal data

In rat, mice, and rabbit studies, olive leaf extract decreased the production of proinflammatory cytokines. Studies have included models of osteoarthritis, colitis, wound healing, and gout (xanthine oxidase inhibition).17, 32, 33, 34, 35, 36

Clinical data

A small (N = 25) clinical study evaluated the effect of olive leaf extract (equivalent to 10 mg/day hydroxytyrosol) administration for 4 weeks versus placebo in osteoarthritis of the knee. Improved scores on pain rating scales were achieved.37 A crossover clinical study evaluated olive leaf extract in the form of a mouth rinse for efficacy in oral mucositis caused by chemotherapy in 25 patients. At 2 weeks, a difference in the rate and severity of mucositis was found, as well as a down-regulation of tumor necrosis factor and interleukin-1 beta.38

Antimicrobial activity

Animal data

Animal experiments and in vitro studies suggest that olive leaf extracts possess antiviral activity.5, 39 In an in vitro experiment, cell-to-cell transmission of HIV was inhibited in a dose-dependent manner, and HIV-1 replication was inhibited.5 In vitro activity against rotavirus has been demonstrated.40 Oleuropein has been patented in the United States for antiviral activity against viral diseases, including herpes, mononucleosis, and hepatitis.41 In vitro studies demonstrate activity against a range of human pathogens,16, 42, 43 as well as against Leishmania species.44

Clinical data

There are no clinical data regarding the antimicrobial use of olive leaf extract.

Cancer

Animal data

In vitro studies have demonstrated growth inhibition against human cancer cell lines, as well as cell membrane disruption and apoptosis.45, 46, 47, 48, 49, 50, 51 In 1 study in mice, activity against melanoma was demonstrated. When olive leaf extract was combined with different chemotherapeutics, antagonism and synergy were found.52

Clinical data

Clinical studies do not support the use of olive leaf extract as a chemotherapeutic agent.

Cardiovascular effects

Animal data

Experiments in rabbit and rat tissue preparations found that oleuropein had a hypotensive effect, possibly via direct action on smooth muscle. Oleuropein also may exert vasodilator activity. In another study in rats with metabolic syndrome, olive leaf extract had no effect on blood pressure, despite improving the lipid profile and glucose tolerance.53 Olive leaf extracts may also possess antispasmodic, vasodilator, and antiarrhythmic properties.54, 55 In a model of stroke in rats, pretreatment with olive leaf for 30 days attenuated the biochemical effects induced by brain ischemia.56 In rabbits pretreated with olive leaf extract for 8 weeks, the prothrombin time was prolonged and the morphology of induced thrombi differed from that of untreated animals. Activated partial prothrombin time was unaffected.57

Clinical data

A randomized clinical trial among patients with stage 1 hypertension compared the effectiveness of olive leaf extract with that of captopril in reducing systolic blood pressure. A dosage of 500 mg of olive leaf extract taken twice daily over 8 weeks achieved a reduction of 11.5 +/− 8.5 mm Hg, compared with a reduction of 13.7 +/− 7.6 mm Hg by captopril (P = 0.098). Triglycerides were also reduced, but no other biochemical indices were altered by the treatment.58

CNS

A dose-dependent analgesic effect has been demonstrated in rats,69 and the same group of researchers demonstrated that olive leaf extract prevented morphine tolerance in rats.70 Another study in rats demonstrated decreased neuropathic pain.71

Diabetes

Animal data

Studies in rodents consistently report decreased blood glucose levels.53, 59, 60 In addition, reduced triglycerides and cholesterol have been found.61, 62 In rats fed a high-fat diet, olive leaf extract positively modulated adipogenesis and thermogenesis.63 Suggested mechanisms include potentiation of glucose-induced insulin release and increased peripheral uptake of glucose.20, 64, 65

Clinical data

In patients with type 2 diabetes (N = 79), 500 mg of olive leaf extract daily significantly decreased glycated hemoglobin (HbA1c) and fasting plasma insulin levels over placebo; however, it had no effect on postprandial plasma insulin.66 A crossover study conducted among overweight men (N = 46) found a 15% increase (P = 0.024) in insulin sensitivity with olive leaf extract (oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks) versus placebo. In addition, increased pancreatic beta-cell responsiveness was found. No effect on the lipid profile, blood pressure, body composition, or liver function was reported.67

Thyroid activity

An aqueous extract of olive leaf administered to rats for 14 days increased triiodothyronine levels and reduced circulating thyroid-stimulating hormone levels, possibly via a feedback mechanism.72

Dosing

Traditional dosages of olive leaf include 7 to 8 g of dry leaf in 150 mL water.73 Many commercial preparations of olive leaf and its extracts are available and vary in strength. The 500 and 750 mg capsules contain approximately oleuropein 20 mg per capsule. In 1 clinical trial, patients with stage 1 hypertension were administered 500 mg of olive leaf extract twice daily for 8 weeks.58 A crossover study of overweight men used oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks.67

Based on studies with healthy volunteers, olive leaf extracts appear to be more bioavailable in liquid than in capsule or tablet form, with wide individual variation.6

Pregnancy / Lactation

Information regarding safety and efficacy during pregnancy and lactation is lacking.

Interactions

Based on a study in mice, olive leaf extract should be used with caution with concomitant chemotherapy because both antagonism and synergy were found.52 In a study in rabbits, increased prothrombin times were demonstrated,57 whereas another clinical study demonstrated no effect on platelets.58

Adverse Reactions

None well documented. Diabetic patients should be supervised carefully because of potential hypoglycemic effects. Hepatotoxicity has been demonstrated in 1 animal study. (See Toxicology.)74

Toxicology

The potential toxicity of olive leaf is not well documented. In mice fed 0.5% to 0.75% olive leaf extract ad libitum for 14 weeks, increased liver enzymes, hyperplasmia of the bile ducts, cholestatis, and hepatic fibrosis and necrosis were found.74

Oleuropein in dosages up to 1 g/kg body weight was not lethal in albino mice.7 At 1 mg/mL, an extract of olive leaf was not toxic to human cells.5 Olive leaf extract has an estimated oral median lethal dose of more than 3,000 mg/kg in mice.73, 74 However, unusual symptoms in mood and aggression reported in a 67-year-old female was suspected to be a result of excessive olive leaf extract from a dose of 85 mg/kg body weight. The authors hypothesized that hydroxytyrosol, a constituent of olive leaf extract that is structurally similar to dopamine, could have caused changes in synaptosomal dopamine levels.75

References

1. Olea europaea L. USDA, NRCS. 2006. The PLANTS database (http://plants.usda.gov, 6 September 2006). National Plant Data Center, Greensboro, NC 27401-4901 USA. Accessed May 1, 2015.
2. Chevallier A. The Encyclopedia of Medicinal Plants. New York, NY: DK Publishing; 1996: 239.
3. Weiss RF. Herbal Medicine. Meass AR, trans. Beaconsfield, England: Beaconsfield Pub Ltd; 1988: 160-161.
4. Bruneton J. Pharmacognosy, Phytochemistry, Medicinal Plants. Paris, France: Lavoisier Publishing; 1995:487-489.
5. Lee-Huang S, Zhang L, Huang PL, Chang YT, Huang PL. Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. Biochem Biophys Res Commun. 2003;307(4):1029-1037.12878215
6. de Bock M, Thorstensen EB, Derraik JG, Henderson HV, Hofman PL, Cutfield WS. Human absorption and metabolism of oleuropein and hydroxytyrosol ingested as olive (Olea europaea L.) leaf extract. Mol Nutr Food Res. 2013;57(11):2079-2085.23766098
7. Petkov V, Manolov P. Pharmacological analysis of the iridoid oleuropein. Arzneimitteiforschung. 1972;22(9):1476-1486.4678608
8. Meirinhos J, Silva BM, Valentão P, et al. Analysis and quantification of flavonoidic compounds from Portuguese olive (Olea europaea L.) leaf cultivars. Nat Prod Res. 2005;19(2):189-195.15715265
9. Benavente-Garcia O, Castillo J, Lorente J, Ortuno A, Del Rio JA. Antioxidant activity of phenolics extracted from Olea europaea L. leaves. Food Chem. 2000;68:457-462.
10. Briante R, Patumi M, Terenziani S, Bismuto E, Febbraio F, Nucci R. Olea europaea L. leaf extract and derivatives: antioxidant properties. J Agric Food Chem. 2002;50(17):4934-4940.12166985
11. Kontogianni VG, Gerothanassis IP. Phenolic compounds and antioxidant activity of olive leaf extracts. Nat Prod Res. 2012;26(2):186-189.22060136
12. Duke JA. Handbook of Biologically Active Phytochemicals and Their Activities. Boca Raton, FL: CRC Press, Inc.; 1992.
13. Visioli F, Poli A, Gall C. Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev. 2002;22(1):65-75.11746176
14. Caturla N, Pérez-Fons L, Estepa A, Micol V. Differential effects of oleuropein, a biophenol from Olea europaea, on anionic and zwiterionic phospholipid model membranes. Chem Phys Lipids. 2005;137(1-2):2-17.16002058
15. Türkez H, Toğar B. Olive (Olea europaea L.) leaf extract counteracts genotoxicity and oxidative stress of permethrin in human lymphocytes. J Toxicol Sci. 2011;36(5):531-537.22008529
16. Lee OH, Lee BY. Antioxidant and antimicrobial activities of individual and combined phenolics in Olea europaea leaf extract. Bioresour Technol. 2010;101(10):3751-3754.20106659
17. Koca U, Süntar I, Akkol EK, Yilmazer D, Alper M. Wound repair potential of Olea europaea L. leaf extracts revealed by in vivo experimental models and comparative evaluation of the extracts' antioxidant activity. J Med Food. 2011;14(1-2):140-146.21128831
18. De Marino S, Festa C, Zollo F, et al. Antioxidant activity and chemical components as potential anticancer agents in the olive leaf (Olea europaea L. cv Leccino.) decoction. Anticancer Agents Med Chem. 2014;14(10):1376-1385.25102361
19. Zaslaver M, Offer S, Kerem Z, et al. Natural compounds derived from foods modulate nitric oxide production and oxidative status in epithelial lung cells. J Agric Food Chem. 2005;53(26):9934-9939.16366677
20. Al-Azzawie HF, Alhamdani MS. Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits. Life Sci. 2006;78(12):1371-1377.16236331
21. Wang Y, Wang S, Cui W, He J, Wang Z, Yang X. Olive leaf extract inhibits lead poisoning-induced brain injury. Neural Regen Res. 2013;8(22):2021-2029.25206510
22. Seddik L, Bah TM, Aoues A, Slimani M, Benderdour M. Elucidation of mechanisms underlying the protective effects of olive leaf extract against lead-induced neurotoxicity in Wistar rats. J Toxicol Sci. 2011;36(6):797-809.22129743
23. Turkez H, Togar B, Polat E. Olive leaf extract modulates permethrin induced genetic and oxidative damage in rats. Cytotechnology. 2012;64(4):459-464.22262123
24. Tavafi M, Ahmadvand H, Toolabi P. Inhibitory effect of olive leaf extract on gentamicin-induced nephrotoxicity in rats. Iran J Kidney Dis. 2012;6(1):25-32.22218116
25. Dekanski D, Selaković V, Piperski V, Radulović Z, Korenić A, Radenović L. Protective effect of olive leaf extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in Mongolian gerbils. Phytomedicine. 2011;18(13):1137-1143.21757330
26. Çoban J, Öztezcan S, Doğru-Abbasoğlu S, Bingül I, Yeşil-Mizrak K, Uysal M. Olive leaf extract decreases age-induced oxidative stress in major organs of aged rats. Geriatr Gerontol Int. 2014;14(4):996-1002.24854676
27. Alirezaei M, Dezfoulian O, Neamati S, Rashidipour M, Tanideh N, Kheradmand A. Oleuropein prevents ethanol-induced gastric ulcers via elevation of antioxidant enzyme activities in rats. J Physiol Biochem. 2012;68(4):583-592.22581435
28. Al-Attar AM, Abu Zeid IM. Effect of tea (Camellia sinensis) and olive (Olea europaea L.) leaves extracts on male mice exposed to diazinon. Biomed Res Int. 2013;2013:461415.23691503
29. Pasban-Aliabadi H, Esmaeili-Mahani S, Sheibani V, Abbasnejad M, Mehdizadeh A, Yaghoobi MM. Inhibition of 6-hydroxydopamine-induced PC12 cell apoptosis by olive (Olea europaea L.) leaf extract is performed by its main component oleuropein. Rejuvenation Res. 2013;16(2):134-142.23394606
30. García-Villalba R, Larrosa M, Possemiers S, Tomás-Barberán FA, Espín JC. Bioavailability of phenolics from an oleuropein-rich olive (Olea europaea) leaf extract and its acute effect on plasma antioxidant status: comparison between pre- and postmenopausal women. Eur J Nutr. 2014;53(4):1015-1027.24158653
31. Kendall M, Batterham M, Obied H, Prenzler PD, Ryan D, Robards K. Zero effect of multiple dosage of olive leaf supplements on urinary biomarkers of oxidative stress in healthy humans. Nutrition. 2009;25(3):270-280.18947980
32. Cvjetićanin T, Miljković D, Stojanović I, Dekanski D, Stosić-Grujicić S. Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice. Br J Nutr. 2010;103(10):1413-1424.20025835
33. Flemmig J, Kuchta K, Arnhold J, Rauwald HW. Olea europaea leaf (Ph.Eur.) extract as well as several of its isolated phenolics inhibit the gout-related enzyme xanthine oxidase. Phytomedicine. 2011;18(7):561-566.21144719
34. Fakhraei N, Abdolghaffari AH, Delfan B, et al. Protective effect of hydroalcoholic olive leaf extract on experimental model of colitis in rat: involvement of nitrergic and opioidergic systems. Phytother Res. 2014;28(9):1367-1373.24590915
35. Gong D, Geng C, Jiang L, Wang L, Yoshimura H, Zhong L. Mechanisms of olive leaf extract-ameliorated rat arthritis caused by kaolin and carrageenan. Phytother Res. 2012;26(3):397-402.21796704
36. Gong D, Geng C, Jiang L, Wang L, Yoshimuram H, Zhong L. Olive leaf extract facilitates healing of experimental cartilaginous injuries in rabbits. J Med Food. 2011;14(3):268-275.21182446
37. Takeda R, Koike T, Taniguchi I, Tanaka K. Double-blind placebo-controlled trial of hydroxytyrosol of Olea europaea on pain in gonarthrosis. Phytomedicine. 2013;20(10):861-864.23746949
38. Ahmed KM. The effect of olive leaf extract in decreasing the expression of two pro-inflammatory cytokines in patients receiving chemotherapy for cancer. A randomized clinical trial. Saudi Dent J. 2013;25(4):141-147.24371380
39. Micol V, Caturla N, Pérez-Fons L, Más V, Pérez L, Estepa A. The olive leaf extract exhibits antiviral activity against viral haemorrhagic septicaemia rhabdovirus (VHSV). Antiviral Res. 2005;66(2-3):129-136.15869811
40. Knipping K, Garssen J, van't Land B. An evaluation of the inhibitory effects against rotavirus infection of edible plant extracts. Virol J. 2012;9:137.22834653
41. Fredrickson WR, Inventor; F & S Group, Inc., assignee. Method and composition for antiviral therapy with olive leaves. US patent 6 117 884. September 12, 2000.
42. Bisignano G, Tomaino A, Lo Cascio R, Crisafi G, Uccella N, Saija A. On the in-vitro antimicrobial activity of oleuropein and hydroxytyrosol. J Pharm Pharmacol. 1999;51(8):971-974.10504039
43. Markin D, Duek L, Berdicevsky I. In vitro antimicrobial activity of olive leaves. Mycoses. 2003;46(3-40):132-136.12870202
44. Sifaoui I, López-Arencibia A, Martín-Navarro CM, et al. Activity of olive leaf extracts against the promastigote stage of Leishmania species and their correlation with the antioxidant activity. Exp Parasitol. 2014;141:106-111.24662269
45. Anter J, Fernández-Bedmar Z, Villatoro-Pulido M, et al. A pilot study on the DNA-protective, cytotoxic, and apoptosis-inducing properties of olive-leaf extracts. Mutat Res. 2011;723(2):165-170.21620995
46. Belščak-Cvitanović A, Durgo K, Bušić A, Franekić J, Komes D. Phytochemical attributes of four conventionally extracted medicinal plants and cytotoxic evaluation of their extracts on human laryngeal carcinoma (HEp2) cells. J Med Food. 2014;17(2):206-217.24325458
47. Cabarkapa A, Zivković L, Zukovec D, et al. Protective effect of dry olive leaf extract in adrenaline induced DNA damage evaluated using in vitro comet assay with human peripheral leukocytes. Toxicol In Vitro. 2014;28(3):451-456.24389114
48. Elamin MH, Daghestani MH, Omer SA, et al. Olive oil oleuropein has anti-breast cancer properties with higher efficiency on ER-negative cells. Food Chem Toxicol. 2013;53:310-316.23261678
49. Samet I, Han J, Jlaiel L, Sayadi S, Isoda H. Olive (Olea europaea) leaf extract induces apoptosis and monocyte/macrophage differentiation in human chronic myelogenous leukemia K562 cells: insight into the underlying mechanism. Oxid Med Cell Longev. 2014;2014:927619.24803988
50. Tezcan G, Tunca B, Bekar A, et al. Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating miRNA expression. Am J Cancer Res. 2014;4(5):572-590.25232498
51. Tunca B, Tezcan G, Cecener G, et al. Olea europaea leaf extract alters microRNA expression in human glioblastoma cells. J Cancer Res Clin Oncol. 2012;138(11):1831-1844.22722712
52. Mijatovic SA, Timotijević GS, Miljkovic DM, et al. Multiple antimelanoma potential of dry olive leaf extract. Int J Cancer. 2011;128(8):1955-1965.20568104
53. Poudyal H, Campbell F, Brown L. Olive leaf extract attenuates cardiac, hepatic, and metabolic changes in high carbohydrate-, high fat-fed rats. J Nutr. 2010;140(5):946-953.20335636
54. Zarzuelo A, Duarte J, Jiménez J, González M, Utrilla MP. Vasodilator effect of olive leaf. Planta Med. 1991;57(5):417-419.1798793
55. Khayyal MT, el-Ghazaly MA, Abdallah DM, Nassar NN, Okpanyi SN, Kreuter MH. Blood pressure lowering effect of an olive leaf extract (Olea europaea) in L-NAME induced hypertension in rats. Arzneimittelforschung. 2002;52(11):797-802.12489249
56. Rabiei Z, Bigdeli MR, Rasoulian B, Ghassempour A, Mirzajani F. The neuroprotection effect of pretreatment with olive leaf extract on brain lipidomics in rat stroke model. Phytomedicine. 2012;19(10):940-946.22796433
57. Dub AM, Dugani AM. Antithrombotic effect of repeated doses of the ethanolic extract of local olive (Olea europaea L.) leaves in rabbits. Libyan J Med. 2013;8:20947.23702352
58. Susalit E, Agus N, Effendi I, et al. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with captopril. Phytomedicine. 2011;18(4):251-258.21036583
59. Kontogianni VG, Charisiadis P, Margianni E, Lamari FN, Gerothanassis IP, Tzakos AG. Olive leaf extracts are a natural source of advanced glycation end product inhibitors. J Med Food. 2013;16(9):817-822.24044491
60. Park JH, Jung JH, Yang JY, Kim HS. Olive leaf down-regulates the oxidative stress and immune dysregulation in streptozotocin-induced diabetic mice. Nutr Res. 2013;33(11):942-951.24176234
61. El-Amin M, Virk P, Elobeid MA, et al. Anti-diabetic effect of Murraya koenigii (L) and Olea europaea (L) leaf extracts on streptozotocin induced diabetic rats. Pak J Pharm Sci. 2013;26(2):359-365.23455208
62. Liu YN, Jung JH, Park H, Kim H. Olive leaf extract suppresses messenger RNA expression of proinflammatory cytokines and enhances insulin receptor substrate 1 expression in the rats with streptozotocin and high-fat diet-induced diabetes. Nutr Res. 2014;34(5):450-457.24916559
63. Shen Y, Song SJ, Keum N, Park T. Olive leaf extract attenuates obesity in high-fat diet-fed mice by modulating the expression of molecules involved in adipogenesis and thermogenesis. Evid Based Complement Alternat Med. 2014;2014:971890.24624222
64. Gonzalez M, Zarzuelo A, Gamez MJ, Utrilla MP, Jimenez J, Osuna I. Hypoglycemic activity of olive leaf. Planta Med. 1992;58(6):513-515.1484890
65. Cumaoğlu A, Rackova L, Stefek M, Kartal M, Maechler P, Karasu C. Effects of olive leaf polyphenols against H2 O2 toxicity in insulin secreting β-cells. Acta Biochim Pol. 2011;58(1):45-50.21383995
66. Wainstein J, Ganz T, Boaz M, et al. Olive leaf extract as a hypoglycemic agent in both human diabetic subjects and in rats. J Med Food. 2012;15(7):605-610.22512698
67. de Bock M, Derraik JG, Brennan CM, et al. Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, placebo-controlled, crossover trial. PLoS One. 2013;8(3):e57622.23516412
68. Amabeoku GJ, Bamuamba K. Evaluation of the effects of Olea europaea L. subsp. africana (Mill.) P.S. Green (Oleaceae) leaf methanol extract against castor oil-induced diarrhoea in mice. J Pharm Pharmacol. 2010;62(3):368-373.20487221
69. Esmaeili-Mahani S, Rezaeezadeh-Roukerd M, Esmaeilpour K, et al. Olive (Olea europaea L.) leaf extract elicits antinociceptive activity, potentiates morphine analgesia and suppresses morphine hyperalgesia in rats. J Ethnopharmacol. 2010;132(1):200-205.20713147
70. Zare L, Esmaeili-Mahani S, Abbasnejad M, et al. Oleuropein, chief constituent of olive leaf extract, prevents the development of morphine antinociceptive tolerance through inhibition of morphine-induced L-type calcium channel overexpression. Phytother Res. 2012;26(11):1731-1737.22422486
71. Kaeidi A, Esmaeili-Mahani S, Sheibani V, et al. Olive (Olea europaea L.) leaf extract attenuates early diabetic neuropathic pain through prevention of high glucose-induced apoptosis: in vitro and in vivo studies. J Ethnopharmacol. 2011;136(1):188-196.21540099
72. Al-Qarawi AA, Al-Damegh MA, ElMougy SA. Effect of freeze dried extract of Olea europaea on the pituitary-thyroid axis in rats. Phytotherapy Res. 2002;16(3):286-287.12164280
73. Duke JA, Bogenschutz-Godwin MJ, duCellier J, Duke PK. Handbook of Medicinal Herbs. 2nd ed. Boca Raton, FL: CRC Press; 2002.
74. Arantes-Rodrigues R, Henriques A, Pires MJ, et al. High doses of olive leaf extract induce liver changes in mice. Food Chem Toxicol. 2011;49(9):1989-1997.21609751
75. Shaw IC. Possible toxicity of olive leaf extract in a dietary supplement. NAMJ. 2016;129(1432):86-87.21609751

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