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Ginkgo Biloba
Indications
There is no Food and Drug Administration (FDA)-approved indication, and there is insufficient evidence to support non-FDA-approved use of Ginkgo biloba.
Dementia/ Cognitive Impairment
Regarding treatment of existing dementia, data have been contradictory regarding the efficacy of Ginkgo biloba extract (EGb). A 52-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study of 309 patients in 1997 concluded that EGb was safe and, though modestly, appeared to stabilize and improve cognitive performance and social functioning in patients with dementia for 6 months to 1 year.[1] Similarly, another 24-week randomized controlled trial involving 410 outpatients found that treatment with EGb 761 at a once-daily dose of 240 mg was safe and demonstrated statistically significant improvements in cognition, psychopathology, functional status, and quality of life for patients and caregivers.[2]
On the other hand, a randomized controlled trial of 513 outpatients with mild to moderate dementia of the Alzheimer type did not support the efficacy of ginkgo extract.[3] A systematic review of 36 trials in 2009 and another review of 38 trials in 2018 demonstrated that Ginkgo biloba was relatively safe, but did not support its clinical benefit for patients with cognitive impairment and dementia.[4][5] Conversely, a 2015 systematic review of 9 trials concluded that EGb761 at 240 mg/day slowed declines in cognition, function, behavior, and global change at 22 to 26 weeks in patients with dementia, particularly among those with neuropsychiatric symptoms.[6] A 2017 study of 12 systematic reviews also suggested that at doses greater than 200mg/day for at least 5 months, EGb may have beneficial effects in patients with dementia.[7]
In terms of preventing dementia, there is also insufficient evidence to support the use of ginkgo. The Ginkgo Evaluation of Memory (GEM) Study showed that Ginkgo biloba at 120 mg twice daily was not effective in reducing all-cause dementia incidence or Alzheimer dementia incidence in elderly patients with normal cognition or mild cognitive impairment.[8] Similarly, the GuidAge clinical trial was conducted in patients aged 70 years or older who spontaneously reported memory complaints to their primary care physician in France.
This trial randomized patients with either 120 mg standardized Ginkgo biloba extract or a matching placebo and did not support the benefit of long-term use of standardized EGb in reducing the risk of progression to Alzheimer disease throughout five years.[9] A meta-analysis of two trials involving 5889 participants showed no significant difference in the rate of dementia development between Ginkgo biloba and placebo in late life.[10] A 2012 meta-analysis found no evidence supporting the use of Ginkgo biloba to enhance cognitive function in healthy adults.[11]
Cardiovascular disease (CVD)/ Cardiovascular Risk Factors Reduction
Effects of ginkgo on cardiovascular disease and risk factors, including hypertension and diabetes, have been the topic of many studies. However, there has been a lack of large, evidence-based, well-designed randomized controlled trials to support its use in treating or preventing cardiovascular disease. Though Ginkgo biloba extract has often been an option in the treatment of acute ischemic stroke in China, a systematic review in 2005 did not show the benefit of improving mortality or neurological recovery in the post-stroke period.[12]
On the other hand, a randomized, open-label, blinded, controlled clinical trial in 2018 suggested that ginkgo, in combination with aspirin treatment lessened cognitive and neurological impairment after acute ischemic stroke without increasing the incidence of vascular events.[13] A small randomized controlled trial of 80 patients with coronary artery disease showed that EGb use was associated with increased left anterior descending coronary artery blood flow, as measured by Doppler echocardiography, increased nitric oxide, and decreased endothelin-1 levels.[14]
A randomized controlled trial in 2010 that monitored CVD as a prespecified secondary outcome of the GEM study showed no evidence that ginkgo reduced CV mortality or CVD events, though it reported fewer peripheral vascular disease events in the ginkgo arm.[15] A systematic review, however, suggested that Ginkgo biloba provided no statistically or clinically significant benefit to patients with peripheral arterial disease.[16] Data from the GEM study also demonstrated that EGb did not reduce blood pressure or the incidence of hypertension in elderly patients with a mean age of 79 years.[17]
Ginkgo biloba research has also shown it to decrease plasma lipoprotein(a) levels, a known risk factor for atherosclerotic diseases.[18] A small randomized controlled trial in 2018 showed that adjunct use of EGb along with metformin was more effective than metformin alone in improving outcomes in patients with type 2 diabetes mellitus as measured by blood HbA1c, fasting glucose, insulin level, BMI, waist circumference, and visceral adiposity index without negatively affecting the liver, kidney, or hematopoietic functions.[19] Overall, due to the lack of strong evidence, the use of Ginkgo biloba extract is not indicated at this point for treatment or prevention of CVD.
Psychiatric disorders:
Studies have examined the role of Ginkgo biloba in treating depression and other psychiatric disorders. A small randomized controlled trial with 136 subjects suggested that EGb, as an adjunctive treatment along with citalopram, could improve depressive symptoms and cognitive function as measured by Hamilton Depression Rating Scale (HAMD) and Wisconsin Card Classification Test (WCST), respectively; it also decreased the expression of serum S100B, a marker of brain injury.[20] A randomized controlled trial of 157 patients with DSM-IV-diagnosed schizophrenia and tardive dyskinesia (TD) suggested EGb could help reduce the symptoms of TD.[21] A meta-analysis of four trials involving 1628 patients showed treatment with EGb improved behavioral and psychological symptoms of dementia and also caregiver distress associated with such symptoms.[22]
Sexual Dysfunction
Many small studies have explored the role of EGb in treating sexual dysfunction. A triple-blind, placebo-controlled trial of 24 patients with sexual dysfunction due to antidepressant drugs showed no statistically significant differences in responses and side-effect profiles between the EGb group and the placebo group.[23] A randomized controlled trial of 108 patients showed that a nutritional supplement containing L-arginine, ginseng, ginkgo, damiana, multivitamins, and minerals increased sexual desire in premenopausal, perimenopausal, and postmenopausal women compared with placebo.[24]
Vertigo
A multicenter, double-blind, randomized controlled trial that followed 70 patients for 3 months showed that Ginkgo biloba extract reduced the intensity, frequency, and duration of vertigo syndrome (47% in the EGb group versus 18% in the placebo group).[25] Another randomized controlled trial in 2014 showed no statistically significant difference in vertigo treatment outcomes between the Ginkgo biloba and betahistine groups, although EGb had a better tolerability profile.[26] Again, due to the lack of strength of the evidence, more studies are necessary to establish the efficacy of Ginkgo biloba in treating vertigo.
Tinnitus
A Cochrane review in 2013, which included four trials with a total of 1543 participants, found no evidence that Ginkgo biloba was effective in patients with a primary complaint of tinnitus.[27] Similarly, a 2018 study that extracted data from systematic reviews concluded that Ginkgo biloba did not alleviate tinnitus severity or improve patients' quality of life.[28]
Vitiligo
A double-blind, placebo-controlled trial in 52 patients with vitiligo showed that Ginkgo biloba treatment was associated with a statistically significant cessation of active depigmentation.[29] Despite such a promising result, more studies are needed to validate Ginkgo's role as a potential therapy of choice for vitiligo.
Macular Degeneration
A 2012 systematic review identified one study of 20 patients with macular degeneration conducted in France, randomly allocated to Ginkgo biloba extract EGb 761 80 mg twice daily or placebo, and another study of 99 patients performed in Germany randomly assigned to two different doses of Ginkgo biloba extract EGb 761 (240 mg per day and 60 mg per day). Researchers followed the patients for 6 months in both trials. Their results could not be pooled, but both experiments demonstrated some beneficial effects of Ginkgo biloba on vision.[30]
Glaucoma
A 2019 systematic review suggested that flavonoids, often found in Ginkgo biloba, had a beneficial effect on glaucoma, particularly by increasing ocular blood flow and potentially halting the progression of visual field loss.[31] More high-quality research is warranted to determine the role of Ginkgo biloba in the treatment of glaucoma.
Altitude Sickness
The Prevention of High Altitude Illness Trial (PHAIT), which followed 614 healthy Western trekkers, showed that ginkgo was not effective in preventing acute mountain sickness compared with placebo.[32] Additionally, a 2017 systematic review demonstrated that Ginkgo biloba, whether used alone or as an adjunct to acetazolamide, was beneficial for altitude sickness.[33]
Mechanism of Action
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Mechanism of Action
Ginkgo biloba has 2 primary active ingredients at varying concentrations: terpene lactones (most notably ginkgolides and ginkgolides A and B) and ginkgo flavone glycosides (most notably ginkgetin, bilobetin, and sciadopitysin).[34] Most studies investigating the effects of ginkgo extract use the standardized Ginkgo biloba extract (EGb) 761. Ginkgo biloba extract has been shown to affect several neurotransmitter pathways and brain structures, mostly in animal studies.
EGb761 limits stress-induced corticosterone hypersecretion by reducing peripheral benzodiazepine receptor numbers in the adrenal glands of rats.[35] Ginkgo extract appears to have reversible inhibitory effects on rat brain monoamine oxidase by inhibiting the uptake of serotonin and dopamine.[36][37] EGb761 also has modest anticholinesterase inhibitory activity, thereby increasing cholinergic transmission in the brain.[38]
Several studies have suggested the neuroprotective effects of Ginkgo biloba extract. Long-term use of EGb761 appears to improve the short-term memory of middle-aged rats, likely by reducing free radical production in the prefrontal cortex.[39] It also protects against age-related changes in the mouse hippocampus.[40] Additionally, Ginkgo biloba extract acts as a free radical scavenger and protects neurons from oxidative damage and apoptosis, which have been observed prominently in cerebral ischemia and Alzheimer's disease.[41][42][43]
The effects of ginkgo on the cardiovascular system are widely studied and are generally considered protective. Ginkgo's roles include those of a metabolic regulator, a membrane stabilizer, and a vasodilator.[44] In the arterial endothelium, ginkgo biloba extract triggers the release of endogenous relaxing factors, such as endothelium-derived relaxing factor and prostacyclin.[45]
Under tissue-damaging inflammatory conditions such as ischemia, it can also moderate nitric oxide production and exert vasorelaxation properties.[46][47] Also, terpene lactones are potent antagonists of the platelet-activating factor.[48] Ginkgo extract also demonstrates fibrinolytic effects.[49]
Administration
Ginkgo biloba extract is administered orally. Most ginkgo extract is available as EGb 761. EGb 761 is standardized to include 6% terpenoids and 24% flavonoid glycosides.[50] Standard dosages of EGb 761 used in most studies and recommended by manufacturers are 40 mg three times per day, or 80 mg twice daily.
Adverse Effects
In general, Ginkgo biloba is safe and well-tolerated. The maximum recommended dose for ginkgo extract is 240 mg/day.[51] Mild adverse effects include headache, heart palpitations, gastrointestinal upset, constipation, and allergic skin reactions.[34] Although a systematic review and meta-analysis found no significant effect of ginkgo on prothrombin time, activated partial thromboplastin time, and platelet aggregation, several case reports have described a temporal association between ginkgo use and bleeding events, including severe intracranial bleeding.[52][53]
Contraindications
Use of ginkgo in patients with bleeding disorders or those who take nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet, or anticoagulant therapies requires caution. A case report described spontaneous bleeding from the iris into the anterior chamber of the eye in an elderly patient who took both aspirin and ginkgo.[54] A 2015 study in a large Veterans Administration Population demonstrated that coadministration of warfarin and ginkgo correlated with an increase in the risk of a bleeding event.[55]
There has been insufficient evidence about the perioperative risk of ginkgo use. One study recommended that clinicians discontinue ginkgo at least 36 hours before a planned surgical procedure.[56] There has been no existing data on the safety and efficacy of ginkgo in pregnant women, nursing mothers, or infants, so recommendations are against ginkgo use in these populations.[34] In epileptic patients or in patients who are prone to seizures, physicians should also be cautious with the administration of ginkgo, as ginkgo toxin, mostly found in ginkgo seeds but still present in ginkgo leaves, could lower the seizure threshold.[57][58]
Monitoring
It is worth noting that dietary supplements such as Ginkgo biloba do not require extensive pre-marketing approval from the Food and Drug Administration. On multiple occasions, nutritional supplements may contain several ingredients, and a discrepancy between labeled and actual ingredients or their amounts may occur. So physicians should be cautious regarding the safety or effectiveness of a dietary supplement.
Research has noted several interactions between Ginkgo biloba and other medications and dietary supplements. EGb doses higher than the recommended ones may lead to a weak induction of CYP2C19-mediated omeprazole 5-hydroxylation and a weak inhibition of CYP3A4-mediated midazolam 1'-hydroxylation; however, the clinical implications of these findings are unclear. Overall, as long as the maximum daily consumption of EGb 761 does not exceed 240 mg, pharmacokinetic herb-drug interactions remain within acceptable limits.[51]
As discussed above, physicians should be aware of the increased risk of bleeding when Ginkgo biloba is co-administered with agents that may increase bleeding risk (NSAIDs, antiplatelet agents, anticoagulant therapies, garlic, ginger, ginseng). Due to its properties as monoamine oxidase inhibitors,[36] ginkgo can precipitate serotonin syndrome in patients that are on other antidepressant medications. Also, ginkgo has an elevating effect on blood sugar, so if patients have diabetes and take ginkgo, closely monitoring of blood glucose levels is recommended.[59]
Toxicity
Raw ginkgo seeds contain potentially toxic cyanogenic glycosides.[34] Contact or ingestion of ginkgo seeds can be poisonous. It can cause a serious allergic skin reaction such as acute generalized exanthematous pustulosis and also convulsions.[60][61] As discussed in this review, bleeding, seizure, and serotonin syndrome could be potential consequences of ginkgo toxicity. There is no antidote for ginkgo. Treatment includes discontinuation of ginkgo and appropriate symptom control depending on the manifestation of each toxication case.
Enhancing Healthcare Team Outcomes
Ginkgo is one of the most commonly used dietary supplements in the United States. Healthcare providers often overlook inquiries about the use of herbal medicine. Due to ginkgo's several side effects and extensive interactions with other medications, it is important to educate the healthcare team (nurse practitioner, pharmacist, primary care provider, nursing staff) to incorporate the habit of asking patients about over-the-counter supplements and keep toxicity/interactions of these supplements with the patient's other medications as potential causes of the patient's presentation in their differentials.
Patients should be educated by the team, including the clinician, nurse, and pharmacist, about the possible side effects and interactions of ginkgo, and encouraged to share this information with their healthcare providers. The pharmacist should also review their medication profile and caution the patient's clinician and/or nurse if there are any potential interactions. Such an interprofessional healthcare team approach to ginkgo, or any supplement, can contribute to optimal patient outcomes if all providers are involved and communicate a consistent message.
References
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