Clinical Safety of Ephedrine Alkaloid-free Ephedra Herb Extract (EFE)
Ephedra (Ephedra sinica, E. equisetina, and E. intermedia; Ephedraceae) herb (primarily stem tissue) is used in Japanese Traditional Medicine (Kampo) formulations. Ephedra herb is defined in the Japanese Pharmacopoeia as stem material containing ˃0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). Ephedrine alkaloids (EAs) are thought to be responsible for the analgesic, anti-inflammatory, antipyretic, antitussive, and diaphoretic effects of ephedra. EAs stimulate adrenaline receptors and may induce adverse effects such as hypertension, heart palpitations, insomnia, and dysuria (painful urination). Due to deaths attributed to excessive intake or misappropriate use of ephedra, the US Food and Drug Administration (FDA) has prohibited the sale of supplements containing EAs. These authors have reported that ephedrine alkaloid-free ephedra extract (EFE) has analgesic, anti-influenza, and c-Met receptor inhibitory effects (the latter suppresses the metastasis of cancer cells). These findings suggest that the pharmacological effects of ephedra are not solely due to EAs, and EFE possibly could be used clinically to replace ephedra herb. In mice, EFE demonstrated low toxicity in a repeated-dose toxicity test; however, a preliminary two-week trial of EFE in seven healthy humans found elevated white blood cell counts in two participants. The purpose of this randomized, double-blinded, crossover study was to determine whether EFE has an inferior safety to ephedra herb extract (EHE).
Healthy men (n = 12, aged 20-45 years) participated in this study conducted at Kitasato University Hospital Clinical Trial Center in Tokyo, Japan (study commencement and end dates not reported). Included participants weighed ≥ 50 kg but < 100 kg, had a body mass index ≥ 18 kg/m2 but < 27 kg/m2; and an absence of any health problems, based on tests including medical examination, vital signs, clinical test values, and electrocardiogram findings. Exclusion criteria were as follows: current or history of respiratory disease, digestive disease, cardiovascular disease, renal disease, hematological disease, mental disease, neurological disease, or malignant tumors; prior digestive tract or renal surgery; infectious disease; current or history of hypertension, hyperthyroidism, or urinary disorders; history of epileptic seizures or brain disorders, or likelihood of epileptic seizures; food or drug allergies; pollen allergies or allergic rhinitis; smoking; positive test for hepatitis B, hepatitis C, HIV, or syphilis; positive urine drug tests or alcohol dependence; receipt of therapeutic drugs within four weeks before study commencement; participation in clinical trials within 12 weeks of study commencement; donation of ≥ 200 mL of blood within four weeks or ≥ 400 mL of blood within 12 weeks before study commencement; or study physician deemed the participant not eligible.
Participants received EFE or EHE twice daily, two hours after meals for six days. The daily dose of EFE and EHE was “equivalent to the amount extracted with hot water from 6 g of ephedra herb (crude drug).” Following a four-week washout, participants were crossed over to the alternate treatment. EFE and EHE were prepared by hot water extraction of Japanese Pharmacopoeia-grade E. Sinica herb. To prepare the EHE treatment, the bulk extract was sterilized, dextrin added as an excipient, and the mixture was freeze-dried. To prepare the EFE treatment, EAs were removed from the bulk extract via cation exchange column chromatography, the EFE extract was sterilized, dextrin added, and the mixture freeze-dried. Ephedrine and pseudoephedrine were confirmed to be undetectable in the EFE; the content in the EHE was 1.32% and 0.54%, respectively.
Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs and causality was appraised. The total number of AEs was determined; if the same participant experienced several different types of AE, each type of AE was counted. The incidence of each type of AE was determined for each treatment.
No participants discontinued from the study, and all complied with the study protocol. There were a total of 25 AEs. Of those, 11 were deemed to have a causal relationship with the treatment; eight AEs were associated with EHE treatment, and three AEs were associated with EFE treatment. Specifically, the EHE-related AEs were increased pulse rate (n = 4, 33%), insomnia (n = 3, 25%), and dysuria (n = 1, 8%). The EFE-related AEs were increased pulse rate (n = 1, 8%), insomnia (n = 1, 8%), and hot flashes (n = 1, 8%). There was no statistically significant difference between groups in the incidence of each type of AE. All AEs were mild and did not affect the activities of daily living.
The authors conclude the safety of EFE is not inferior to the safety of EHE. Acknowledged limitations of the study include the small sample size, relatively short duration, and restriction of the study population to young males. Further safety studies are needed to address these limitations and determine whether the safety of EFE is superior to that of EHE. The authors state the “next step toward the clinical application of EFE will be clinical research to establish EFE’s efficacy against pain, influenza virus infection, and metastatic cancer.”
Odaguchi H, Sekine M, Hyuga S, et al. A double-blind, randomized, crossover comparative study for evaluating the clinical safety of ephedrine alkaloids-free ephedra herb extract (EFE). Evid Based Complement Alternat Med. August 2018;2018:4625358. doi: 10.1155/2018/4625358.