Safety evaluation of p‐synephrine following 15 days of oral administration to healthy subjects: A clinical study

Abstract

Extracts of bitter orange (BOE, Citrus aurantium L.) and its primary protoalkaloid p-synephrine are extensively consumed as dietary supplements. p-Synephrine is also present in foods and juices prepared from various Citrus species. The safety of p-synephrine has been questioned as a result of structural similarities with ephedrine. This study assessed the cardiovascular (stimulant) and hemodynamic effects of BOE (49 mg p-synephrine) daily given to 16 healthy subjects for 15 days in a placebo-controlled, cross-over, double-blinded study. A physical evaluation by a cardiologist, as well as heart rates, blood pressures, and electrocardiograms were determined, and blood samples were drawn at baseline, and Days 5, 10, and 15. Serum levels for caffeine and p-synephrine were measured at 1 and 2 weeks. Subjects completed a 10-item health and metabolic questionnaire at baseline and on Day 15. No significant changes occurred in heart rate, electrocardiograms, systolic blood or diastolic pressures, blood cell counts, or blood chemistries in either the control or p-synephrine treated groups at any time point. No adverse effects were reported in response to the bitter orange (p-synephrine). Caffeine consumed by the participants varied markedly. Under these experimental conditions, BOE and p-synephrine were without stimulant (cardiovascular) and adverse effects.

Acute cardiovascular effects of bitter orange extract (p‐synephrine) consumed alone and in combination with caffeine in human subjects: A placebo‐controlled, double‐blind study

“…Similar to the present study, they also reported no differences in the responses between habitual caffeine consumers and non‐consumers. In a follow‐up study by the same research group, 49 mg of p ‐synephrine consumed daily in capsule form for 15 days in male, and female subjects was shown to have no significant effects on ECG, HR, BP, and no adverse effects were reported (Shara, Stohs, & Smadi, ). Again, no differences were observed between caffeine consumers and non‐consumers.…”

Acute hematological and mood perception effects of bitter orange extract (p‐synephrine) consumed alone and in combination with caffeine: A placebo‐controlled, double‐blind study

“…Shara et al () examined consumption of 49 mg of p ‐synephrine over an 8‐hr period and reported no significant changes in any blood chemistry variable at 2‐ and 8‐hr postconsumption. In a follow‐up study, Shara et al () had male and female subjects consume a dose of 49‐mg p ‐synephrine daily in capsule form for 15 days and reported no significant effects on serum chemistries or blood cell counts. Jung et al () examined a dietary supplement (containing 284 mg of caffeine) with and without 20 mg of p ‐synephrine and reported no adverse effects on liver enzymes, kidney function, blood chemistries, or muscle enzymes.…”

“…Approximately 35% of the subjects consumed caffeine (up to 528 mg/day) in combination with p ‐synephrine (up to 104 mg/day). In addition to a lack of cardiovascular stimulation seen when p ‐synephrine was consumed alone, no significant differences were observed in blood chemistry panels (Kaats et al, ; Shara, Stohs, & Mukattash, ; Stohs & Shara, ; Shara, Stohs, & Smadi, ; Stohs et al, ).…”

Effects of <em>p</em>-synephrine in combination with caffeine: a review

“…29 In a follow-up placebo-controlled, double-blind, crossover study, BOE at a dose of 49 mg p-synephrine daily in capsule form for 15 days to eight male and eight female subjects was shown to have no significant effects on ECG, heart rate, blood pressure, serum chemistry, or blood cell count, and no adverse effects were reported or observed by any of the subjects. 30 Average blood levels of p-synephrine 4 hours after administration on days 7 and 14 were ~2.6 ng/mL. At this time point, blood caffeine levels averaged about 800 ng/mL, indicating that most subjects regularly consumed caffeinated beverages.…”

“…[54][55][56] Haller et al 55 reported maximum p-synephrine blood concentrations of ~3 ng/mL after a dose of 46.9 mg, with blood levels near baseline after four half-lives. Shara et al 30 observed blood concentrations of ~10 ng/mL and 2.6 ng/mL at 2 and 4 hours after consumption of 49 mg. Various effects on lipid metabolism, 10,24,25,57 metabolic rate, 52,58 sport performance, 4 and energy production 11 have been demonstrated at these doses, as well as higher doses of p-synephrine that do not produce cardiovascular effects.…”