The German Federal Institute for Risk Assessment (BfR) has warned that products marketed as food or nutritional supplements that contain both caffeine and synephrine - a plant constituent which is found in bitter oranges - may not comply with article 14 (food safety) of General Food Law Regulation (EC) 178/2002 regulations due to potential risks on the cardiovascular system.
Both substances are known to influence the cardiovascular system, noted the BfR report, which also suggested that such effects may be synergistic if synephrine and caffeine are taken at the same time.
"Such products can contain caffeine and synephrine in pharmaceutically active doses in which they have cardiovascular effects and which significantly exceed the single doses in which they were or still are used in single agent drugs," the report states.
"This is all the more concerning, as it is to be expected that the two substances mutually reinforce each other’s effects on the cardiovascular system," it adds, noting that the combination of bitter orange extract and caffeine has potential to increase heart frequency, cardiac arrhythmia, and blood pressure.
Bitter orange (Citrus aurantium) is suggested to increase energy expenditure, facilitate the breakdown of fat and increase glucose uptake by muscles, and is widely used in weight management and sports nutrition supplements.
The ingredient’s profile increased following the US Food and Drug Administration (FDA) ban on ephedra in 2004 as it contains similar compounds and was favoured by dietary supplements manufacturers as an ephedra substitute.
Some suppliers have also reported a surge in enquires from manufacturers looking for alternatives to controversial ingredient DMAA in the wake of recent bans on the stimulant.
However there have been several concerns raised over the safety of bitter orange, and in particular the compound synephrine - with a recent FDA analysis suggesting multi-component extract of bitter orange may raise blood pressure and heart rate in lab animals.
However recent human safety data from Nutratech has suggested that the compound is safe for consumption.
The BfR assessment found that while there are 'very big differences' in the levels of both synephrine and caffeine in products between various products, there were several products in which both compounds were found at levels that may cause harm.
In addition it noted that other active ingredients contained in bitter orange extracts may also enhance cardiovascular effects of synephrine.
"BfR recommends that quantities of health-relevant components of Citrus aurantium ingested through such products should be limited to the intake levels from conventional foods such as oranges and bitter oranges," the report finds.
For synephrine, this means that no more than 6.7 milligrams per day should be consumed in the form of a food supplement, said the risk assessor - noting that such a limit would ensure even for frequent consumers that total intake of synephrine from both conventional foods and food supplements does not exceed 25.7 milligrams.
However, it noted that for some products currently available on the market, "there are, due to the dosage levels, sufficient reasons to suspect that the products do not meet the requirements of Regulation No. 14 (EC) 178/2002."
"For this reason, they are classified as unsafe."