Citrus aurantium (bitter orange) extract: Safety assessment by acute and 14-day oral toxicity studies in rats and the Ames Test for mutagenicity

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine

“…For the sake of comparison, it should be noted that the oral LD50 of sodium chloride, common table salt, is about 3000 mg/kg. The oral administration of a 50% p-synephrine bitter orange extract at a dose of 2000 mg/kg to female rats for four consecutive days did not have any toxicological effects (Deshmukh et al, 2017a), while a dose of 1000 mg/kg for 90 days produced no deaths or serious adverse effects (Deshmukh et al, 2017b). The animals exhibited burrowing of the heads in the bedding material and piloerection, which disappeared by the end of the study.…”

“…There are no indications that p-synephrine adversely affects the heart, liver, kidneys, or thyroid at doses up to 100 mg per day (Stohs et al, 2012;Kaats et al, 2013;Shara et al, 2016;Kaats and Stohs, 2017), and as a consequence, there is no evidence supporting the proposed contraindications. Furthermore, studies have shown that no teratogenicity (Hansen et al, 2011) or mutagenicity (Morimoto et al, 1982;Kaefer, 2014;Deshmukh et al, 2017a) occurs in response to p-synephrine and bitter orange extracts. However, some cautionary statements regarding use of bitter orange extract and p-synephrine may be warranted and are subject to further discussions.…”

“…The potential mutagenicity of a bitter orange extract (Advantra Z ® ) containing 50% p-synephrine was assessed by using the bacterial Salmonella typhimurium reverse mutation assay (Ames Test; Deshmukh et al, 2017a). The assay was performed by the preincubation method by using the tester strains TA1535, TA97a, TA98, TA100, and TA102, each of which contains a different kind of mutation in the histidine operon.…”

Bitter orange ( Citrus aurantium L.) extract subchronic 90-day safety study in rats

“…Although bitter orange extracts are now extensively used in dietary supplements and p -synephrine occurs in various Citrus juices and food products, subchronic safety studies on this extract and p -synephrine have not been conducted. It has been previously shown that the oral LD50 of a bitter orange extract standardized to 50% p -synephrine exceeded 5000 mg/kg in female rats [4] , indicating a high degree of safety. Oral administration of this extract at 2000 mg/kg to female rats for four consecutive days did not produce any overt signs of toxicity [4] .…”

“…It has been previously shown that the oral LD50 of a bitter orange extract standardized to 50% p -synephrine exceeded 5000 mg/kg in female rats [4] , indicating a high degree of safety. Oral administration of this extract at 2000 mg/kg to female rats for four consecutive days did not produce any overt signs of toxicity [4] .…”