Analysis of bitter orange dietary supplements for natural and synthetic phenethylamines by LC–MS/MS

Abstract

Citrus aurantium, commonly known as bitter orange, is a popular dietary supplement ingredient sold worldwide. Bitter orange supplements are sold primarily as weight management and sports performance products and have gained popularity after Ephedra products were banned from the US market. Supplements containing synephrine are reported to exhibit adverse cardiovascular effects especially in the presence of caffeine. In this study, an LC–MS/MS method was established to quantify five natural amines (synephrine, octopamine, tyramine, N‐methyltyramine, and hordenine) and four synthetic phenethylamines (phenylephrine, methylsynephrine, etilefrine, and isopropyloctopamine) in dietary supplements sold in the US. The method was validated and found to have acceptable performance to accurately measure analytes in complex botanical products. The average recoveries from a blank matrix were 88–125% with an RSD of 0.5–7.0%. Fifty‐nine products labeled to contain bitter orange peel, extract, or its amines were purchased and their amine content was measured. Several products were found to contain higher amounts of amines than that expected from a typical bitter orange extract. Of the 23 products that made label claims for synephrine, only 5 products (22%) were within 80–120% of labeled synephrine content. The presence of synthetic amines, methylsynephrine (up to 240 mg/daily serving), and isopropyloctopamine (up to 76 mg/daily serving), whose effects in humans are not known, were detected in six products and one product, respectively. While the use of methylsynephrine and isopropyloctopamine are not permitted in dietary supplements, hordenine, N‐methyltyramine, and octopamine are currently listed on the FDA's Dietary Supplement Ingredient Advisory List.

Nine prohibited stimulants found in sports and weight loss supplements: deterenol, phenpromethamine (Vonedrine), oxilofrine, octodrine, beta-methylphenylethylamine (BMPEA), 1,3-dimethylamylamine (1,3-DMAA), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylbutylamine (1,3-DMBA) and higenamine

“…Dutch investigators in 2013 identified 19 mg to 39 mg deterenol combined with other stimulants in Dexaprine (iForce Nutrition) and found this product to be associated with a series of serious adverse events including nausea, vomiting, agitation, palpitations, chest pain and cardiac arrest [4]. Since 2018, three investigations have confirmed the presence of deterenol in supplements available in the US ranging in doses from 20 to 76 mg per serving [7][8][9]. One of these studies was performed by the FDA's analytic chemists [9]; nevertheless, we are not aware of any enforcement action by the agency to eliminate deterenol from dietary supplements or warn consumers of the stimulant's presence in supplements.…”

“…Since 2018, three investigations have confirmed the presence of deterenol in supplements available in the US ranging in doses from 20 to 76 mg per serving [7][8][9]. One of these studies was performed by the FDA's analytic chemists [9]; nevertheless, we are not aware of any enforcement action by the agency to eliminate deterenol from dietary supplements or warn consumers of the stimulant's presence in supplements.…”

“…In 2004, the US Food and Drug Administration (FDA) determined that deterenol is not permitted as an ingredient in dietary supplements [6]. Nevertheless, since 2018, deterenol has been detected in several brands of dietary supplements sold in the US [7,8], and FDA chemists have confirmed the presence of deterenol in supplements [9]. The FDA, however, has not advised manufacturers to remove deterenol from products nor warned consumers to avoid supplements labeled as containing deterenol.…”

Risk Associated with the Use of Selected Ingredients in Food Supplements

“…Octopamine and methylsynephrine are recognized not only as monitored substance but also as doping agents from the group S6 – Stimulants. An example of disqualification for unintended doping in 2013 was the female sprinter Sherone Simpson, as the anti‐doping tests performed on her showed the presence of methylsynephrine, which came from the food supplement she was using [211–213] …”

“…However, WADA specifies that ‘ and other substances with a similar chemical structure or similar biological effect(s) are also prohibited ’. As described in the following sections, the excessive use of certain substances present in dietary supplements by professional athletes has forced WADA to adapt and update its regulations to the current anti‐doping needs [13,211–213] …”