p‐Synephrine, ephedrine, p‐octopamine and m‐synephrine: Comparative mechanistic, physiological and pharmacological properties

Abstract

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p ‐synephrine and p ‐octopamine relative to ephedrine and m ‐synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p ‐synephrine and p‐ octopamine as related to ephedrine and m ‐synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p ‐Synephrine and p‐ octopamine exhibit little binding to α‐1, α‐2, β‐1 and β‐2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m ‐synephrine. As a consequence, the effects of ephedrine and m ‐synephrine cannot be directly extrapolated to p ‐synephrine and p ‐octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.

Effects of p-Synephrine during Exercise: A Brief Narrative Review

“…Specifically, the absence of adrenergic receptor binding of p -synephrine provides the explanation for its lack of production of harmful cardiovascular effects as compared to m -synephrine. Hence, while m -synephrine can be considered as an alkaloid with a potent cardiovascular effect [ 12 ], p -synephrine or Citrus aurantium intake are normally not associated to harmful cardiovascular events [ 13 ].…”

Risk Associated with the Use of Selected Ingredients in Food Supplements

“…methylsynephrine shows greater α‐adrenergic receptor activity than synephrine. Octopamine and synephrine have similar affinity to α‐adrenergic receptor, but octopamine shows greater activity toward the β‐adrenergic receptor than synephrine [211,212] …”

“…C. aurantium /synephrine was demonstrated to be the most popular substitute replacing ephedrine, which was withdrawn from use in food supplements. C. aurantium /synephrine use in combination with other stimulants such as caffeine has been associated with many adverse reactions in the cardiovascular system [211,212] …”

Current Evidence to Propose Different Food Supplements for Weight Loss: A Comprehensive Review

“…Bitter orange, the fruit of the Citrus aurantium, is rich in p-synephrine, a primary protoalkaloid which has been widely used for weight-loss management as suppressor of appetite and stimulator of energy expenditure and lipolysis [144,145]. P-synephrine has some structural similarity to ephedrine, from which it differs by the presence of a hydroxyl group in the para position on the benzene ring [146].…”