Ginkgo (Ginkgo biloba, Ginkgoaceae) is one of the most widely used medicinal plants throughout the world, and ginkgo leaf extract is used frequently to treat cognitive decline. There is extensive research evaluating the efficacy and safety of ginkgo. Clinical studies show that the rate of adverse events in patients treated with ginkgo is similar to those treated with placebo. However, a technical report published by the US National Toxicology Program concluded that high doses of ginkgo caused liver and thyroid cancer in rodents. The Committee on Herbal Medicinal Products of the European Medicines Agency reported that “there is no proof for an increased cancer risk in patients taking ginkgo folium medicinal products at their approved posology … .” Also, the International Agency for Research on Cancer “reported that there is inadequate evidence in humans for the carcinogenicity of Ginkgo biloba extract.” Despite the conclusions of international agencies, the safety of ginkgo needs to be further evaluated, according to the authors. Hence, the purpose of this multicenter, randomized, double-blind, placebo-controlled study was to evaluate the clinical and genomic safety of ginkgo in elderly patients.
Patients (n = 66, aged ≥ 65 years) living in nursing homes in the San Raffaele network (2 in Rome, Italy, and 1 in Latina, Italy) participated in the study, conducted between June and November 2015. Excluded patients had a history of increased bleeding tendency, were receiving anticoagulant or antiplatelet drugs, had cognitive impairment, or had a life expectancy of < 1 year. Patients received either 240 mg/day ginkgo tablets (IDN 5933/Ginkgoselect®Plus; Indena SpA; Milan, Italy), divided into 120-mg doses, or placebo tablets (also prepared by Indena SpA), administered twice daily for 6 months. IDN 5933/Ginkgoselect®Plus is obtained by extracting dried ginkgo leaves using ethanol:water (70:30 per volume), and contains 24.3% flavone glycosides and 6.1% terpene lactones (2.9% bilobalide, 1.38% ginkgolide A, 0.66% ginkgolide B, and 1.12% ginkgolide C).
At baseline and at study end, blood was drawn to evaluate liver injury by measuring levels of gamma-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase; DNA damage via the comet assay; and genomic instability via the micronucleus assay. A subgroup of 17 patients had additional assessments to evaluate the expression of c-myb, p53, and CTNNB1 (β-catenin) genes, which are modulated in early stages of liver carcinogenesis.
Nineteen patients were discontinued from the study due to death (n = 1), developing acute pancreatitis with pre-existing chronic renal failure and/or being discharged (n = 10), admission to a hospital (n = 4), and discontinuing treatment (n = 4). Of the patients who completed the study, 27 were treated with ginkgo and 20 were treated with placebo.
Baseline variables were similar between groups, and the baseline characteristics of those who discontinued versus completed the study were similar. One patient in the ginkgo group died due to acute pancreatitis. The medical staff concluded that the death was due to worsening of a multipathological condition and not ginkgo treatment. Neither group of patients reported specific symptoms that could be classified as adverse events resulting from this study.
The incidence of patients with pathological levels of liver enzymes was low, and the rates were the same at baseline and study end. There was no significant difference between groups in genomic instability according to the micronucleus assay, even after adjusting for confounding variables (P value not significant). There was no significant difference between groups in DNA damage according to the comet assay, even after adjusting for confounding variables (P value not significant). There was no significant difference between groups in gene expression (P value not significant).
The authors conclude that treatment with IDN 5933/Ginkgoselect®Plus did not have a higher risk than placebo in affecting genomic safety. This study used a variety of indexes that may predict the risk of developing cancer in subjects treated with a therapeutic dose of ginkgo. The authors used these indexes because it would be difficult to do an epidemiological analysis that would involve finding a population of long-term ginkgo users and monitoring hepatic cancer, which has long latency (time between exposure and symptoms), as a primary endpoint. This also explains why the study had a 6-month duration; the objective was to study early genomic risks, not cancer outcome. A limitation of this study is the relatively small sample size. However, the strengths of this study are that it used multiple endpoint measures, used an elderly population, and it was a randomized controlled study.
The study was funded by Indena SpA. One of the authors (Bonassi) was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC; Milan, Italy); this author also received consulting fees from Indena SpA. The institutions of 4 of the authors (Bonassi, Prinzi, Lamonaca, and Paximadas) have received research grant support from Indena SpA. One of the authors (Malandrino) is employed by Indena SpA.