Adverse Effects
General:
Orally, ginkgo leaf extract is well tolerated in typical doses. It can cause mild gastrointestinal (GI) upset, headache, dizziness, palpitations, constipation, and allergic skin reactions . Large doses can cause restlessness, diarrhea, nausea, vomiting, lack of muscle tone, and weakness. Spontaneous bleeding is one of the most concerning potential side effects associated with ginkgo, although several large-scale clinical trials and a meta-analysis show that the incidence of bleeding in patients taking ginkgo is not significantly higher than in those taking placebo .
Topically, ginkgo fruit and pulp can cause severe allergic skin reactions and irritation of mucous membranes and the gastrointestinal tract. Cross-reactivity is possible with ginkgo fruit in individuals allergic to poison ivy, poison oak, poison sumac, mango rind, and cashew shell oil.
Tell patients to avoid crude ginkgo plant parts; which can exceed concentrations of 5 ppm of the toxic ginkgolic acid constituents, and can cause severe allergic reactions.
Cardiovascular:
Frequent nocturnal episodes of paroxysmal atrial fibrillation have been reported for a 35 year-old women taking ginkgo extract 240 mg/day orally for 2 months. Following discontinuation of ginkgo, arrhythmias ceased. In one clinical trial, the rate of ischemic stroke and transient ischemic attacks was significantly higher in patients taking ginkgo extract orally compared to placebo.
Dermatologic
Orally, ginkgo leaf extract can cause allergic skin reactions in some patients. In one case, a patient developed acute generalized exanthematous pustulosis 48 hours after taking a single-ingredient ginkgo product. The rash resolved within 10 days after discontinuing ginkgo. There is also a case of Stevens-Johnson syndrome following a second administration of a preparation containing ginkgo leaf extract, choline, vitamin B6, and vitamin B12.
Topically, ginkgo fruit and pulp can cause severe allergic skin reactions and irritation of mucous membranes. Cross-reactivity is possible with ginkgo fruit in individuals allergic to poison ivy, poison oak, poison sumac, mango rind, and cashew shell oil.
Gastrointestinal
Orally, ginkgo extract may cause mild gastrointestinal discomfort or pain, nausea and vomiting, diarrhea, dry mouth, and constipation. However, post-market surveillance suggests that the incidence of these events is relatively low, occurring in <2% of patients.
Fresh ginkgo seeds can cause stomachache, nausea, vomiting, or diarrhea. Ingesting roasted seeds in amounts larger than the normal food amounts of 8-10 seeds per day, or long-term, can also cause these same adverse reactions.
Genitourinary
Blood in the urine has been reported for one patient taking ginkgo extract orally.
Hematologic
Spontaneous bleeding is one of the most concerning potential side effects associated with ginkgo. There are several published case reports linking ginkgo to episodes of minor to severe bleeding; however, not all case reports clearly establish ginkgo as the cause of bleeding. In most cases, other bleeding risk factors were also present including taking other medications or natural medicines, old age, liver cirrhosis, recent surgery, and other conditions. In most cases, bleeding occurred after several weeks or months of taking ginkgo. Large-scale clinical trials and a meta-analysis evaluating standardized ginkgo leaf extracts show that the incidence of bleeding in patients taking ginkgo is not significantly higher than in those taking placebo. There are several case reports of intracerebral bleeding. Some of these cases resulted in permanent neurological damage and one case resulted in death.
There are at least 4 cases of ocular bleeding including spontaneous hyphema (bleeding from the iris into the anterior part of the eye) and retrobulbar hemorrhage associated with ginkgo use.
There are also cases of surgical and post-surgical complications in patients using ginkgo. Retrobulbar hemorrhage (bleeding behind the eye) during cataract surgery has been associated with ginkgo use. Excessive postoperative bleeding requiring transfusion has also occurred following laparoscopic surgery in a patient who had been taking ginkgo leaf extract. There have also been two cases of excessive bleeding during surgery and post-surgical hematoma in patients undergoing rhytidoplasty and blepharoplasty. In another case, an elderly woman taking ginkgo experienced excessive postoperative bleeding following total hip arthroplasty. In another case, use of ginkgo following liver transplantation surgery was associated with subphrenic hematoma requiring evacuation by laparotomy. The patient also subsequently experienced vitreous hemorrhage, In another case, an elderly woman who had taken ginkgo chronically experienced excessive post-operative bleeding following an ambulatory surgical procedure.
In another case, an elderly man experienced nose bleeds and ecchymosis following use of ginkgo. One case of diffuse alveolar hemorrhage in a woman taking ginkgo and ginseng for over one year has been reported. These instances of bleeding stopped when ginkgo was discontinued, and recurred when the patient started taking ginkgo again.
Persistent bleeding has also occurred following dental surgery and laparoscopic cholecystectomy. Nosebleed has also been reported as an adverse effect in a clinical trial.
Musculoskeletal
Edema has been reported for three patients treated with ginkgo extract 40 mg orally three times daily. In one case, systemic edema and severe arthralgia was reported after contact with a ginkgo tree nut and manifested as multifocal lymphadenopathy on PET/CT scan imaging associated with an allergic reaction.
Neurologic/CNS
Orally, ginkgo extract may cause headache, dizziness, increased desire to sleep, and sedation in some patients.
Fresh or roasted ginkgo seeds in amounts larger than the normal food amounts of 8-10 seeds per day, or long-term, can cause restlessness, seizure, loss of consciousness, or shock. The fresh seeds contain large amounts of ginkgotoxin, which can cause seizures and death. Ginkgo leaf and ginkgo leaf extract contain small amounts of ginkgotoxin, which is unlikely to cause these more serious effects. However, there are anecdotal reports of seizure occurring after use of ginkgo leaf preparations both in patients without a history seizure disorder and in those with previously well-controlled epilepsy.
Ocular/Otic
Orally, ginkgo extract may cause tinnitus is some patients, although the incidence is rare. Topically, eye drops containing ginkgo extract and hyaluronic acid may cause stinging sensations in some people.
Psychiatric
Orally, ginkgo has been associated with a single case of mood dysregulation. A 50-year-old female with schizophrenia developed irritability, difficulty controlling anger, and agitation after one week of taking ginkgo 80 mg twice daily. The mood changes resolved within 2-3 days of discontinuation. When ginkgo was re-trialed at a later date, the same symptoms reappeared, and again dissipated after discontinuation of the ginkgo product. The relationship between ginkgo and mood dysregulation was considered to be “probable” based on the Naranjo adverse drug reaction probability scale; however, the exact mechanism by which ginkgo may have affected mood regulation is unknown.
Toxicology
There is some concern about toxic and carcinogenic effects seen in rats and mice exposed to a ginkgo leaf extract containing 31.2% flavonoids, 15.4% terpenoids, and 10.45 ppm ginkgolic acid, in doses of 100 to 2000 mg/kg five times per week for 2 years. There were dose-dependent increases in rates of liver problems including cancer, hypertrophy, hyperplasia, hepatocyte fatty changes, and bile duct hyperplasia. There were also dose-dependent increases in thyroid problems such as cancer and hypertrophy, nasal hyperplasia and epithelial atrophy, and gastric problems including inflammation, hyperplasia, hyperkeratosis, and ulcers. However, the doses studied are much higher than those typically used by humans, since a single dose of 50 mg/kg in rats is estimated to be equivalent to a single dose of about 240 mg in humans. Therefore, the clinical relevance for these adverse effects in humans is unclear.