Herbal Products That May Contribute to Hypertension

Sir: The article “Herbal Products That May Contribute to Hypertension” by Jalili et al. 1 contains several questionable statements and conclusions. Under the section “Bitter orange (Citrus aurantium),” the authors state that bitter orange contains two adrenergic agents, synephrine and octopamine, and that bitter orange increases blood pressure when it is combined with caffeine and also increases systolic and diastolic blood pressure. This statement is clearly inconsistent with the current research literature regarding bitter orange and p-synephrine.2–4 Octopamine is absent in bitter orange extract or present in inconsequential trace amounts, whereas p-synephrine comprises 90 percent or more of the total protoalkaloids.2 Furthermore, p-synephrine poorly binds to cardioresponsive α, β1, and β2 adrenoreceptors as compared with ephedra and phenylephrine.3 As a consequence, increases in heart rate and blood pressure are not expected at common doses. The results of more than 20 human studies involving bitter orange–containing products have recently been reviewed.4 Five published and two unpublished studies reported no cardiovascular effects when consuming products that contained only bitter orange. Five published and five unpublished studies using p-synephrine with other ingredients reported no cardiovascular effects (total of 170 subjects). As noted by the authors,1 small cardiovascular effects have been reported for a study that involved a total of 20 subjects consuming p-synephrine alone or with caffeine.4 The results of this study have been questioned due to experimental design.4 At a dose of 46.9 mg, p-synephrine had no effect on blood pressure, but when p-synephrine was used in combination with 239 mg caffeine, an increase in systolic and diastolic blood pressures were observed that the authors attributed to the caffeine and not p-synephrine.1 An increase in heart rate 6 hours after p-synephrine but not before does not coincide with the pharmacokinetics of the p-synephrine (2- to 3-hour half-life), but can be related to the consumption of a meal 3 hours after administration of the p-synephrine.2,4 A more recent study reported that the administration of p-synephrine at a dose of approximately 49 mg twice a day (total of 98 mg per day) to healthy human subjects for 60 days did not result in any significant changes in systolic or diastolic blood pressures, heart rate, blood chemistries, or hematologic studies.5 The authors referred to an early Health Canada report regarding bitter orange,1 but they failed to mention a much more recent report by the Natural Health Products Directorate of Health Canada involving an extensive review of bitter orange and p-synephrine.6 The report released in May of 2011 is a 49-page health risk assessment of p-synephrine, p-octopamine, and caffeine that redefines the previous guidelines for the use of these three natural ingredients. This is the latest and most definitive statement on the subject by Health Canada, and previous statements should be discounted. Health Canada has approved the use of up to 50 mg per day of p-synephrine alone in healthy adults, and 40 mg per day or less of p-synephrine when it is combined with 320 mg per day or less of caffeine. These doses are higher than the amount of p-synephrine in most available products. According to the Health Canada Report, under these conditions, p-synephrine “is not likely to cause any adverse health consequences.”6 Health Canada is the equivalent of the U.S. Food and Drug Administration. Intertek Cantox, a global leader in scientific, toxicology, and regulatory services, conducted an in-depth literature review of bitter orange/p-synephrine and issued a report in September of 2012 that redefines its guidelines for their use.7 The report notes that “p-synephrine is unlikely to have significant effects on inotropy, vasoconstriction, or blood pressure.” The report further states that the following dosages are “not likely to cause adverse effects”: up to 60 mg of p-synephrine alone or 40 mg in combination with 320 mg of caffeine; and if taken as divided doses spaced over the course of the day, 70 mg of p-synephrine alone or 60 mg of p-synephrine in combination with 320 mg of caffeine.7 It should also be noted that various orange juices contain up to 25 to 40 mg of p-synephrine per 8-ounce glass.8 Millions of individuals unknowingly consume p-synephrine daily in juices and orange food products as marmalades and do so without adverse events. Furthermore, tens of millions of doses of bitter orange products have been consumed by millions of individuals without report of serious incidents.2 Finally, contrary to widely held beliefs, no serious adverse cardiovascular effects have ever been directly attributable to bitter orange extract or p-synephrine,2,4 although the possibility exists that someone may experience hypertension in response to p-synephrine. In summary, the assertions that bitter orange and p-synephrine cause hypertension and present serious health concerns are not supported by the current research data. DISCLOSURE The author has served as a consultant for Nutratech, Inc. (West Caldwell, N.J.), a company that markets bitter orange (Citrus aurantium) extracts. The author has no financial interest in any of the products, devices, or drugs mentioned in this communication. Sidney J. Stohs, Ph.D., F.A.C.N., C.N.S., A.T.S. 7068 Maumee Valley Court Frisco, Texas 75034 [email protected]

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