Olive Leaf Extract for Hypertension

By Georges Ramalanjaona, MD, DSc, MBA, FACEP

Olive leaf extract (OLE) has been associated with many health-promoting benefits, including antihypertensive effects, for hundreds of years. However, successful identification of what appears to be the biological active component of OLE, oleuropein, has only been accomplished recently.1 Recent development in clinical investigations of OLE was due to the structural changes to the molecule, which overcame the bio-availability problems seen earlier in humans.

This article reviews the available scientific evidence on the hypotensive role of OLE.

Pharmacokinetics

Oleuropein, the biologic active component responsible for the hypotensive action of OLE, is derived from the olive’s leaves, buds, wood, fruit, and roots.2,3 OLE contains 60-90 mg per gram (dry weight) of oleuropein, which in turn is hydrolyzed to the major biologically active molecules such as oleuropein aglycone and elenolic acid.

Oleuropein, a bitter glycoside that belongs to the iridoid group, is water soluble and unstable against acid. It appears that oleuropein has other cardiovascular effects unrelated to hypotensive action, including antioxidant and antiarrhythmic properties, and improves coronary blood flow.4

Mechanism of Action

The specific pharmacological mechanisms of the cardiovascular effects of OLE remain unknown. Recently, Fehri et al demonstrated that OLE works on a bi-phasic mode (hypertensive and hypotensive) with two types of receptors: The first receptor has a high affinity for small concentrations of OLE, which leads to vasoconstriction, and the second receptor has a low affinity for high concentrations of OLE, which results in vasodilation.5

Phenolic compounds derived from leaves and olive trees have antioxidant properties. Recently, Le Tutour et al showed that extracts of olive tree leaf (containing 90% of oleuropein, 1.8 flavonoid glycosides) displayed more potent antioxidant activity than vitamin E.6

Animal Studies

Empirical data about the antihypertensive properties of OLE have been derived mainly from animal studies. This hypotensive action depends on the species of animal studied and dose of oleuropein used.

In a study of anesthetized cats, oleuropein at a dose of 30 mg/kg IV decreased blood pressure (BP) by an average of 36%; 20 mg/kg and 40 mg/kg doses decreased initial BP by 25% and 50%, respectively.7 A hypotensive effect was seen at a dose of 30 mg/kg; initial BP decreased by 36% (average values from seven experiments). BP returned to its pretreatment value in 1-2 hours. The difference in rate of BP decrease between pretreatment and post-treatment at various doses was statistically significant.

In dogs with induced hypertension, oleuropein at a dose of 10 mg/kg IV decreased the systolic pressure by 62% and the diastolic pressure by 68%.8 A three-fold increase in dose (30 mg/kg) decreased the systolic pressure by 61% and diastolic pressure by 73%. This difference in BP (systolic and diastolic) was statistically significant in both doses. Also, oleuropein given in successive days did not display any cumulative effect. Recovery of BP was seen in five hours.

Petkov et al observed that oleuropein at 3-50 mg/kg intraperitoneally (IP) caused a minimal increase in respiration rate in anesthetized cats.7 In another study, the same authors were unable to determine oleuropein LD50 in mice after a single dose ranging from 100 to 1,000 mg/kg IP; there were no deaths or side effects during seven days of post-treatment.

In conscious dogs with induced hypertension, a dose of 30 mg/kg IV of OLE for one month resulted in mild gastric irritation with gastric biopsy revealing small gastric erosion.8

Clinical Studies

Formal clinical trials of antihypertensive effects of OLE in humans are scarce. Most of the evidence of its clinical efficacy comes from case reports and clinical anecdotes provided by health practitioners and consumer letters received by manufacturers.9 A limited number of open (uncontrolled) clinical trials have been conducted with OLE; however, results from these trials have not been published.

In a recent uncontrolled clinical trial of 30 primary hypertensive patients (ages 40-66 years; 16 males), Cherif et al used OLE (7.2% oleuropein) 400 mg qid for three months following a 15-day placebo period.10 The investigators found a statistically significant decrease in both systolic and diastolic BP (P < 0.001) in the group with no prior treatment (n = 12) and the group with prior treatment (n = 18) when comparing initial values to post-treatment at days 30, 60, and 90. This effect began at 30 days post-treatment and BP steadily declined over a two-month period. Additionally, the authors did not report any side effect from OLE in either group.

Adverse Effects

In the sole clinical trial of OLE for hypertension treatment, authors did not find any side effects during a three-month period. Biological decrease of glycemia and calcemia were observed.

A "die-off" effect similar to the Herxheimer reaction is seen during OLE treatment of yeast infection.

Contraindications and Precautions

The effects of OLE in children and pregnant women are unknown. OLE can be irritating to the stomach and should be taken with meals. OLE can inactivate antibiotics and should not be taken concurrently with them. Patients who are taking warfarin should exercise caution when taking OLE since it may increase bleeding tendency.

Formulation and Dosage

Dried leaf extract containing 6-15% OLE is available commercially, but no standard formulation has been set. To make a tea infusion, 1 teaspoon of dry leaves is steeped in 1 cup of hot water for 10-15 minutes.

In the only human clinical trial for hypertension, OLE (7.2% oleuropein) was used at a dose of 400 mg qid for three months. The reported dosage of OLE in other unrelated trials was 500 mg PO tid.

Conclusion

Animal studies demonstrate the hypotensive effectiveness of OLE.

Preliminary data from a single recent human trial on OLE’s hypotensive action are encouraging. However, these results are insufficient to formulate a valid conclusion on its role as an antihypertensive agent at this time.

Recommendation

OLE cannot be recommended as an antihypertensive agent. Final recommendations will await the results of future controlled trials.

Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Education, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.

References

1. Panizzi L, et al. Isolation of oleuropein from olive leaf. Chim Ital 1960;90:1449-1451.

2. Zarzuelo A, et al. Vasodilator effect of olive leaf. Planta Med 1991;57:417-419.

3. Visoli F, Galli C. The effects of minor constituents of olive oil on cardiovascular disease; new finding. Nutr Rev 1998;56:142-147.

4. Petkov V. Plants with hypotensive, antiatheromatous and coronary-dilating action. Am J Chin Med 1970;7: 197-236.

5. Fehri B, et al. Hypotension, hypoglycemia and hypouricemia recorded after repeated administration of aqueous leaf extract of Olea europaea L. J Pharm Belg 1994;49:101-108.

6. Le Tutour B, et al. Antioxidative activities of Olea europaea leaves and related phenolic compounds. Phytochem 1992;31:1173-1178.

7. Petkov V, et al. Pharmacological analysis of iridoid oleuropein. Drug Res 1975;22:1476-1486.

8. Elliott GA, et al. Preliminary safety studies with calcium elemolate, an antiviral agents. Antimicrob Agents Chemother 1979:173-178.

9. Letters received from consumers by East Park Research, Inc., Hendersen, NV; August 1995-March 1996.

10. Cherif S, et al. A clinical trial of titrated oleo extract in the treatment of arterial hypertension. J Pharm Belg 1996;51:69-71.

11. Duarte J, et al. Vasodilatory effects of flavonoids in rat aortic smooth muscle. Biochem Pharmacol 1993;24: 857-862.