Ginkgo Biloba

Ginkgo biloba (of the family Ginkgoaceae) is a medicinal plant from traditional chinese medicine that is commonly called 'Maidenhair tree', and the name of the genus comes from the german common name for this plant (Ginkobaum).^[1] The tree is also commonly called a 'living fossil', as the order of Ginkgoales which contains the family ginkgoaceae only consists of this plant, as the other members of the order that existed 190 million years ago have since become extinct.^[1] It is claimed (with little evidence to support it) that buddhist monks preserving ginkgo biloba trees in their gardens is the reason for their existence currently.^[2]

Ginkgo biloba is used in traditional chinese medicine and the fruits and seeds were first used (and referred to as Bai-guo^[1]) they more recently (1505 AD) included leaf extracts^[2] which consist of the majority of sold dietary supplements. It is further considered a phytopharmaceutical (similar to Boswellia serrata) as it has drug status in some countries such as Germany.^[3][4]

The compounds that are thought to be unique to ginkgo biloba include:

• The basic terpene trilactone Bilobalide, totalling 2.6-3.4% dry weight^[5] and 2.6-3.2% of the EGb-761 extract^[6]
• Gingkolides A, B and C (collectively totalling 3-3.6% dry weight of the leaves)^[7][5] as well as Ginkgolide J,^[8] K (0.3-0.6% dry weight^[5]) as well as M,^[9][10] Q,^[11] and P^[11]
• The carboxylic acids known as Ginkgolic acids^[6] which are usually seen as somewhat toxic^[12] and thus limited to 5-10ppm in many standardizations of ginkgo biloba^[13]
• Other carboxylic acids such as ginkgols (cardols)^[13] and shikimic acid^[14]

Bilobalide and the ginkgolides are thought to be the main bioactive constituents that are unique to ginkgo biloba supplementation

Other bioactive molecules that have been detected in the ginkgo biloba herb include:

• Procyanidins^[6] at 7% of an EGb-761 extract^[13] and 4-12% of the dry leaf extract^[13][15] which are mostly comprised of the dimers of procyanidin and prodelphinidin^[15][16]
• Quercetin^[6] and Isorhamnetin^[6] mostly as glycosides of α-L-rhamnosyl-β-D-glucosyl^[13]
• Kaempferol^[6][17] and its α-L-rhamnosyl-β-D-glucosyl glycoside^[13]
• Biflavone structures (two flavone skeletons bound to each other) including amentoflavone, bilobetin, sequojaflavone, ginkgetin, isoginkgetin, and sciadopitysin^[13] with total concentrations between 0.047-1.68% dry weight of the leaves;^[13][18] they may exist as glycosides^[19]
• D-Glucarate^[6]
• Chlorophyll^[20]
• Chitin binding protein^[21] which is not thought to be biologically relevant to supplementation^[13]

Various other common phenolic compounds are also found in the ginkgo biloba plant

EGb-761 (sometimes also called GBE-761,^[22][23] Tanakan, Tebonin, or Rökan) is a standardized extract of ginkgo biloba that is produced from the leaves and standardized to 24% flavone glycosides (specifically, a range of 22-27%^[24]) and 6% terpene lactones (range of 5-7%^[24][6]); this includes a 2.8-3.4% content of ginkgolides A-C and 2.6-3.2% bilobalide^[6] and while procyanidin compounds are preserved at around 7%^[13] the ginkgolic acids are kept below 5ppm (5µg/g dry weight).^[24] Although other components are not though to be significantly active in EGb-761, it is also somewhat standardized for total catechin (2%), carboxylic acids (13%), and non-flavonol glycosides (20%)^[13] where 4.5% of EGb-761 by weight (almost a fifth of all flavone glycosides) consist of the two specific acetylated glycosides of 3-O-(2’’-O-(6’’’-O-(p-hydroxy-trans-cinnamoyl)-β-D-glucosyl)-α-L-rhamnosyl)quercetin and its kaempferol equivalent (2.4–2.6% and 1.8-2.2%, respectively).^[25]

This extract is also commonly called a 50:1 concentrated extract, as 300mg of EGb-761 appears to be equivalent to 15g of the leaves dry weight when looking at the amount of ingested flavone glycosides and terpene lactones.^[23][24]

EGb-761 is an extract of ginkgo biloba that is commonly used in studies to standardize the terpenoid and flavonoid composition of the plant. It has a low ginkgolic acid content

Kaveri (LI1370) is a dietary supplement that appears to be standardized for 25% flavone glycosides only^[26] while a mixture known as Cp202 is standardized not for flavonoids but for the exclusion of terpene trilactones.^[27] Similar to LI1370, GINKOCER is another extract that is around 24% flavone glycosides.^[28]

BN52063 is a standardized extract of ginkgo biloba that contains terpenoid structures but is free of flavonoid structures^[27] and another extract known as P8A (also known as TTL) which contains a 70% terpene trilactone content.^[8]

Some other extractions concentrated either the flavonoid component of ginkgo or the terpene trilactone component

There is a tincture of ginkgo biloba with the brand name of Geriaforce.^[29]

This is a 65% ethanolic extract with a 1:9 drug:extract ratio, and 1mL of the tincture is thought to be bioequivalent to 920mg of the fresh leaves; the active dose of the tincture (2.73mL) is then equivalent to around 2,500mg of the leaf extract.^[29]

The extract contains 236.97μg/mL bilobalide, 109.21μg/mL ginkgolide A, and 54.01μg/mL ginkgolide B^[29] and supplementation of 90 drops of this tincture (2.73mL) results in significantly less systemic exposure to these terpene trilactones than does 120mg EGb-761 and even the fresh plant extract (360mg fresh plant extract).^[29]

Geriaforce is a tincture of ginkgo biloba, and while it does contribute the bioactive terpenes to the body following oral ingestion the exposure of terpenes is significantly lower than both EGb-761 and the basic leaf extract

The bioavailability has been detected for ginkgolidea A (80%), ginkgolide B (88%), and bilabolide (79%).^[24]

The terpenoids also appear to be absorbed from oral supplementation, with bilobalide and ginkgolide A and B being detected in plasma (not so much ginkgolide C) and having half-lifes of 1.8, 2.2 and 2.3 hours respectively.^[24]

The C_max of these terpenoids is reached within one hour, with 80-240mg oral supplementation of reaching plasma peaks of 15.2-42.9ng/mL (ginkgolide A), 6.53-18.11ng/mL (ginkgolide B), and 30.2-58.6ng/mL (bilobalide) all of which were dose-dependent.^[24] Supplementation of EGb-761 has elsewhere been noted to reach plasma levels of 26.85ng/mL (bilobalide), 16.44ng/mL (ginkgolide A), and 9.99ng/mL (ginkgolide B) with 120mg of EGb-761, which was a higher plasma concentration than that seen with ginkgo tinctures or fresh leaves (250mg).^[29]

Following oral ingestion of Ginkgo biloba, the ginkgolides and bilobalide appear to be present in the blood in the low nanomolar range

Supplementation of 36mg/kg EGb-761 to rats is able to increase plasma concentrations of quercetin (12µg/mL), kaempferol (7µg/mL), and isorhamnetin (50µg/mL)^[30] and higher concentrations may be reached if the solution is more water soluble (the AUC increased from 4.2μg/h/mL to 7.9μg/h/mL) which is also seen with the terpenoids (154.6-162.1% of control^[31]).

The flavonoids in ginkgo biloba appear to be absorbed to the low micromolar range

When taken with a meal relative to a fasted state, the AUC of ginkgo biloba bioactives is similar although the T_max and C_max attenuated to around 50-66% of the fasted state.^[24]

There is not too significant of an effect of ingesting ginkgo fasted relative to fed, although the speed of absorption may be attenuated when taken with a meal

Following oral administration of LI1370 (flavone extract), the urinary metabolites of 4-hydroxybenzoic acid, hippuric acid, 4-hydroxyhippuric acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid and vanillic acid are detected.^[24] These are mostly metabolites of flavonoids quercetin and kaempferol.^[32]

A fairly large degree of terpenoids (72.3% of ginkgolide A and 41.4% of B, as well as 31.2% of bilobalide) are eliminated in the urine without any apparent conjugation.^[24]

Ginkgo biloba has been noted to activate the pregnane X receptor (PXR), which is due to the Ginkgolide A content.^[33] 600μg/mL of the extract has been noted to activate PXR about 22 to 38-fold in vitro (which was less potent than the reference drug pregnenolone 16α-carbonitrile at 10μM)^[33] while 30-100μg/mL was ineffective; isolated Ginkgolide A is active at a concentration of 4.4μg/mL.^[33]

When looking at isolated compounds, bilobalide has been noted to increase activity of CYP2E1, CYP2B1/2, CYP3A1, and aromatase^[34] while ginkgolides A and B increased aromatase but not CYP3A1.^[34] The EGb-761 extract influenced the same enzymes that its components influenced, and was confirmed to not influence CYP2D2, CYP2C11, nor CYP2C7.^[34]

Ginkgo biloba may activate PXR, which causes an increase in drug metabolizing enzymes. This is thought to cause excessive metabolism of drugs and thus lower bodily exposure following coingestion of the drug with ginkgo

Ginkgo has been investigated for interactions with raltegravir (an antiretroviral), and there has been a failure for the two to interact in a clinically relevant manner^[35] although the antiretroviral efavirenz has been noted to interact with ginkgo (300mg) in case studies.^[36][37] Efavirenz is known to be metabolized by primarily CYP2B6 and CYP3A4, and due to these case studies noting subtherapeutic levels of efavirenz paired with the known ability of ginkgo biloba to induce CYP enzymes^[33] it is thought that ginkgo is accelerating metabolism of efavirenz.

Ginkgo has been noted in a few case studies to reduce circulating levels of the antiretroviral known as efavirenz, although raltegravir appears unaffected

Atorvastatin (a statin drug) has its serum concentrations slightly reduced by supplemental ginkgo biloba, but the degree of reduction is too small to influence the cholesterol lowering properties of the statin.^[38]

When investigating the interactions between ginkgo and anti-platelet or blood thinning drugs, ginkgo does not appear to adversely interact with ticlopidine nor alter its pharmacokinetic profile^[39][40] and the pharmacokinetics of warfarin appear to be unaffected.^[41][42]

Isolated bilobalide at 0.8µg/mL (800ng/mL) is able to preserve mitochondrial function and cytochrome C activity during oxidative insults and secondary to preserving the functioning of the electron transport chain ATP is preserved.^[43] Although the aforementioned study was in neurons, this protective effect has been noted in endothelial cells^[44] and liver cells^[45] with comparable potency (nanomolar range of bilobalide or 200-800µg/mL EGb-761), and has been confirmed to be protective against H₂O₂, β-amyloid proteins, and antimycin (complex III inhibitor).^[46]

In vivo studies note that oral ingestion of isolated bilobalide (8mg/kg) or EGb-761 extracts can attenuate the reduction seen in complex I and complex III activity associated with hypoxia/ischemia^[43][47][48] and the age-related increase in mitochondrial oxidative damage appears to be attenuated.^[49]

The antioxidant properties of ginkgo biloba, particularly that of bilobalide, appear to be active at the level of the mitochondria and thus this plant can act as a mitochondrial protective agent

Ginkgo is an inhibitor of the platelet activating factor (PAF) receptor, which is a mechanism underlying its anti-thrombic effects and improvements in circulation.^[50] Interestingly, PAF is also a neuromodulator that enhances presynaptic glutamate release and aids in long-term potentiation (LTP) although in situations where neuronal damage is present it may exacerbate damage (glutamate and inflammatory cytotoxicity).^[51]

Ginkgo has been noted to reduce the increase in PAF seen in hypoxia when fed to rats.^[52]

The ability of ginkgo to reduce the activity and levels of platelet activating factor (PAF) appear to extend to neurology, and this mechanism may underlie some neuroprotective effects

Monoamine oxidase (MAO) enzymes are known to be inhibited in vitro by ginkgo biloba extracts^[17][53][54] although they do not appear to be influenced by oral supplementation of ginkgo biloba, as a mouse study has confirmed no significant alterations^[55] and studies that measure increases in some monoamines (a natural consequence of inhibiting MAO enzymes) have failed to find a concomitant decrease in the monoamine metabolites.^[56][25] When the potency is measured, IC₅₀ values on inhibiting MAO-A is 170+/-37μg/mL while MAO-B is above 1mg/mL.^[55]

Ginkgo biloba likely does not influence MAO enzymes

Some other gene products that appear to be influenced with supplementation of ginkgo biloba include transthyretin mRNA, which is increased in the hippocampus^[57][58] associated with the terpene fraction.^[58] This hormone is associated with the transportation of the T4 thyroid hormone in serum^[59] and can sequester β-amyloid proteins in vitro^[60] suggesting a possible protective role.

The increase in some gene products, mostly transthyretin, may play a role in the neuromodulatory effects of ginkgo biloba

A single oral dose of 100-300mg/kg (but not 30mg/kg) EGb-761 in rats does not appear to influence extracellular catecholamines^[56] although a 2 week daily preload increases extracellular dopamine when measured 40-180 minutes after oral ingestion to 85-134% above baseline.^[56] This seems to be more related to the flavonoid component of EGb-761^[56] and a later study feeding rats only 72mg/kg of the flavonol glycosides found the same effects which were deemed to be due to the acylated flavonoid glycosides.^[25]

Oral ingestion of ginkgo biloba subchronically appears to increase dopamine concentrations in the prefrontal cortex, which seems to be related to the flavonoids rather than terpenoids

There appears to be a minor increase in dopamine in the striatum,^[56] and cells isolated from the striatum do not experience an increase in dopamine uptake with EGb-761 in vitro.^[61]

Dopamine and its metabolite (DOPAC) are increased in the nuclear accumbens and PVN following 50mg/kg EGb-761 to rats for 15 days.^[62]

Dopamine turnover may be increased in the brain of rats fed EGb-761, although dopamine uptake into neurons does not appear to be significantly altered

In the paraventicular nuclei (PVN) and nuclear accumbens (NAc), dopaminergic neurons are increased in count (more or less a doubling) after 15 days supplementation of 50mg/kg EGb-761 to rats.^[62]

In vitro, ginkgo biloba appears to reduce the oxidative damage to neurons that results in less dopamine secretion^[63] secondary to preserving membrane fluidity.^[64]

The neurotrophic and neuroprotective effects of ginkgo may extend to dopaminergic neurons

Ginkgo biloba has been found to inhibit the noradrenaline transporter (NET) in vitro at 100μg/mL, and oral intake of 100mg/kg EGb-761 in mice by 30%.^[55]

Extracellular concentrations of noradrenaline appear to be increased alongside the increases in dopamine seen with 14 days preloading of 100-300mg/kg EGb-761 in the prefrontal cortex.^[56]

The serotonin transporter (SERT) appears to be somewhat inhibited in vitro at 100µg/mL, but feeding 100mg/kg to mice has failed to show any inhibition.^[55]

Supplementation of EGb-761 at 100mg/kg in rats for 14 days was unable to increase serotonin concentrations in the prefrontal cortex.^[56]

Serotonin concentrations in the brain do not appear to be significantly affected by oral feeding of ginkgo biloba

Synaptosomal serotonin uptake has been noted to be enhanced in vitro by up to 23% between the concentrations of 4-16µg/mL,^[61] and this was associated with the flavonoids of ginkgo biloba.^[61]

There may be an increased uptake of serotonin into neurons, and this occurs at a concentration which likely applies to orally ingested ginkgo biloba

The age-related decline in 5-HT_1A receptors^[65] appears to be attenuated with chronic ingestion of ginkgo biloba, with no inhernet effect on young rats^[66] unless they experience a stress-related decline in receptor levels.^[67] As 5-HT_1A receptors are known to positively influence acetylcholine release in the hippocampus,^[68][69] it is thought that this protective effect may underlie some cognitive enhancing properties in older subjects.

Bilobalide and ginkgolide B are known to interact with the picrotoxin binding site on 5-HT_3A receptors (5-HT₃ receptors being a class of five receptors involved mostly in nausea^[70]), and can inhibit serotonin signalling at a concentration of 470-730μM^[71][72] without affecting binding of ligands (such as granisetron) to the serotonin binding site.^[71]

Although the ginkgolides and bilobalide technically inhibit the serotonin 5-HT_3A receptor, this may occur at too high a concentration to be relevant following oral supplementation. The 5-HT_1A receptor appears to have its activity preserved in instances where it would normally be decreased

The amnesia induced by scopolamine (cholinergic antagonist) appears to be reduced with oral ingestion of 30-50mg/kg EGb-761 in rats^[73][74] alongside reductions in scopolamine induced apoptosis^[75][76] while the suppression of acetylcholine release from β-amyloid is attenuated with isolated Ginkgolide B (1µM).^[77]

The general protective effects of ginkgo biloba on brain tissue may cause a preservation of acetylcholine signalling and its function. This is likely an indirect effect due to the protection rather than a per se influence on acetylcholine

Isolated 3-O-(2''-O-(6'''-O-(p-hydroxy-trans-cinnamoyl)-β-D-glucosyl)-α-L-rhamnosyl)quercetin (acetylated flavonoid at 2.2-2.6% of EGb-761 by weight) is known to increase acetylcholine concentrations in the medial prefrontal cortex to 181+/-16% within 90 minutes following oral ingestion, with the kaempferol equivalent being slightly less active.^[25]

Acylated flavonoid glycosides in EGb-761 appear to increase acetylcholine concentrations in the prefrontal cortex, and occur at a concentration low enough that it is probably relevant to oral supplementation of EGb-761

When looking at the acetylcholinesterase enzyme (its inhibition causing an increase in acetylcholine levels^[78]), ginkgo biloba at 300mg/kg does not appear to affect mRNA levels of this enzyme in the cortex or hippocampus of mice^[58] while an infusion of EGb-761 has been noted to inhibit acetylcholinesterase activity with an IC₅₀ of 268.33μg, significantly more potent than bacopa monnieri, and oral intake of 30-60mg/kg in rats (but not 15%) caused an approximately 20% reduction in acetylcholinesterase activity.^[28]

Ginkgo biloba does not appear to significantly infleunce the mRNA levels of the acetylcholinesterase enzyme, but may directly inhibit it. This has been noted with oral supplementation of EGb-761, although the amount of inhibition (20%) was fairly minor

Bilobalide appears to be a GABA_A receptor (α1β2γ2L) competitive antagonist with an IC₅₀ value of 4.6+/-0.5µM.^[79]

Histamine (particularly H1 receptors) are involved in learning and memory formation^[80][81] and reduced in Alzheimer's disease alongside a reduction in histidine decarboxylase, the biosynthetic enzyme for histamine^[82] and a reduction in receptor content.^[83]

30-50mg/kg ginkgo biloba extract (similar to EGb-761) is able to reduce the amnesiac effects of pyrilamine and diphenhydramine (H1 receptor antagonists).^[73]

Isolated bilobalide at 5-15µM is able to increase hippocampal cell proliferation by 55-80% (most efficacy at 10µM), with significantly more potency than 10µM Rolipram and 10µM Quercetin.^[84] This appears to be associated with an increase in BDNF that is not associated with CREB phosphorylation (an upstream regulator of BDNF^[85][86]) and has also been noted to proliferate dendrites^[84] and peripheral neurons in vitro.^[87] Ginkgolide A and B do not appear to be capable of proliferating neurons.^[84]

At least in rats, bilobalide (100-200µM)^[88] and injections of EGb-761^[89] have been found to enhance neuronal regenesis following sciatic nerve injury.

In vitro, bilobalide appears to promote neuronal proliferation with a potency greater than that of rolipram and this may apply to all neurons (of the CNS and PNS). Beyond possible cognitive enhancing effects, this may also underlie benefits in nerve repair

Ginkgo Biloba has also been implicated, in a rat model, with neuronal proliferation of AChE and NOS positive neurons in the forebrain.^[90]

Supplementation of EGb-761 is able to increase hippocampal neuronal proliferation in both young and older mice.^[91]

Dopaminergic neurons in the nuclear accumbens (NAc) and paraventricular nuclei (PVN) are proliferated following oral ingestion of 50mg/kg EGb-761 for 15 days in rats.^[62]

Several studies have noted cell proliferation in the brain following oral administration of ginkgo biloba

Supplementation of 240mg EGb-761 has been confirmed to elevate plasma concentrations of BDNF in schizophrenics suffering from tardive dyskinesia^[92] with more efficacy in Val/Val polymorphism in BDNF persons relative to Val66Met polymorphisms (the latter associated with impaired BDNF release^[93]).

Oral supplemenation of ginkgo biloba may increase plasma concentrations of BDNF

The EGb-761 extract seems to, in mouse models, to alleviate cognitive damage and excitotoxicity if preloaded before the insult; which is due to bilobalides and ginkgolides.^[94][95] This neuroprotection is mediated wholly through heme-oxygenase 1^[96] which is upregulated in a dose and time dependent manner in cells with no apparent toxicity level.^[97]

Ginkgo appears to have antioxidative effects, and may protect neurons from oxidative cell death

Neuronal losses induced by β-amyloid protein is fully prevented by 1µM bilobalide in vitro^[84] and EGb-761 has been noted to reduce oligomer formation in vitro^[98] and in vivo with 100mg/kg EGb-761 in mice.^[91]

There appear to be neuroprotective effects against β-amyloid proteins, which is of interest to the pathology of Alzheimer's disease

Ginkgo biloba appears to be used for anxiety reduction^[99] and has been noted to reduce symptoms of anxiety that is secondary to dementia whenever other behavioural symptoms are reduced.^[100]

Animal studies have noted a reduction in anxiety and stress with 100mg/kg EGb-761 in mice subject to an elevated plus maze and cold water stress test^[101] while antistress effects have been noted elsewhere with discrimination tests.^[102]

Ginkgo biloba appears to have basic anxiolytic actions in research animals, and for the treatment of dementia a 'side-effect' of treatment may be a reduction in anxiety

In young persons with generalized anxiety disorder (GAD) given 240mg or 480mg EGb-761 daily for four weeks, symptom reduction as assessed by HAMA was reduced to a larger degree with ginkgo (12.1-14.3 point reduction in a dose dependent manner) rather than placebo (7.8 point reduction) although it took four weeks for the benefits to occur; no significant improvement was noted at week 2.^[103]

Supplementation of EGb-761 appears to be able to reduce symptoms of anxiety in youth, although it may require a few weeks to work optimally

The antistress effects of EGb-761 have been noted to be associated with an attenuation of corticosterone relative to control^[102] and elsewhere ingestion of 50-100mg/kg EGb-761 daily for 2 weeks is able to reduce basal corticosterone levels thought to be related to Ginkgolide B.^[104]

In humans, supplementation of 120mg EGb-761 acutely before a stress test has been noted to attenuate the subsequent spikes in cortisol and blood pressure.^[105]

There appear to be antistress effects associated with ginkgo biloba supplementation, and due to these percieved effects as well as the ability to reduce corticosterone it is likely that ginkgo biloba is an adaptogen

5-10mg/kg injections of EGb-761 for 17 days prior to a forced swim test is associated with a 41% reduction in immobility in mice at the most effective dose (10mg/kg) which was similar to imipramine at 15mg/kg whereas 20-40mg/kg EGb-761 was ineffective.^[106]

Antidepressant effects have been associated with a preserved serotonin and dopamine turnover,^[106] antioxidant effects,^[106]

60mg/kg Egb-761 in rats is comparable (29%) to 40mg/kg bacopa monnieri (25%) in increasing cerebral blood flow over eight weeks of oral administration.^[107]

Ginkgo has been noted to increase cerebral blood flow in rat studies, with comparable potency

The addition of 40mg EGb-761 to 75mg aspirin (combination taken thrice daily) is associated with significant improvements in cerebral blood flow in persons who previously suffered from a cerebral infarct; this increased blood flow was noted in the middle cerebral artery (54.5%) and anterior cerebral artery (51.4%) but not in the vertebral, basilir, nor posterior cerebral arteries.^[108]

Elsewhere, 120mg EGb-761 over four weeks in elderly persons was associated with a slight increase in cerebral blood flow to the left parietal–occipital region, and overall improvements in blood flow reached 15% and 13% in white and grey matter respectively^[109] and other studies in a similar cohort using a slightly higher dose (240mg EGb-761) have noted changes in blood flow in the left frontal, frontoparietal, and parietal and right frontal and parietal lobes.^[110]

There appears to be an enhancement of blood flow associated with EGb-761 supplementation in humans, although the studies that note improvements in cerebral blood flow don't seem to have much consistency in what brain regions experience an increase

Oral ingestion of ginkgo biloba to gerbils prior to ischemic injury is able to reduce the subsequent edema in brain tissue and markers of damage^[111] which is thought to be related to the ginkgolide content as they are inhibitors of platelet activating factor.

In rats subject to middle cerebral artery occulation (MCAO), an experimental model of stroke, supplementation of 4-8mg/kg of isolated Ginkgolide K is able to reduce infarct size and damage induced by MCAO injury with a potency slightly greater than Ginkgolide B (6mg/kg).^[112]

Both the antioxidant effects and the inhibition of PAF signalling are thought to underlie protective effects against hypoxic injury from ginkgo biloba, thought to be due to the ginkgolides

In patients of cerebral infarcts, the addition of 40mg EGb-761 alongside the standard therapy of 75mg aspirin to be taken thrice daily noted that combination therapy was significantly more effective than both aspirin alone as well as placebo on the parameters of executive ability, attention, abstract, deferred memories, orientation force and the total score (assessed by Montreal cognitive assessment).^[108]

In isolated trials, ginkgo appears to have some potential benefit in persons who have previously had a stroke and are since recoverin from it

When looking at the risk of developing stroke over a period of time, ginkgo supplementation over a median 6.1 years in older persons at 240mg EGb-761 does not appear to confer significant reductions in risk relative to placebo.^[113]

A meta-analysis of trials conducted on ginkgo and stroke noted that while overall the evidence seems to show a positive effect of ginkgo on stroke, that the largest and most well conducted trial failed to note a significant effect; the authors concluded that there is not enough evidence to support the use of ginkgo for stroke.^[114]

The meta-analysis on the topic noted that the studies confirming the effects of ginkgo tended to be lower quality than the most well controlled study, and deemed insufficient evidence to support the role of ginkgo in the therapy of strokes

Improvements in 'speed of attention' appear to be somewhat suppressed with 120mg of ginkgo biloba (a dose effective at improving working memory) while it is enhanced at 240-360mg.^[115][116]

There are interactions with attention processing in otherwise healthy young adults

The usage of complementary medicine to treat ADHD is fairly widespread^[117] and due to the general popularity of ginkgo biloba supplements for this purpose^[118] it is investigated for its potential role in ADHD.

Supplementation of EGb-761 thrice daily at a cumulative dose of 80-120mg for six weeks in youth with ADHD is able to reduce symptoms as assessed by Parent and Teacher Rating Scale scores, although it appears to be about half as effective as 30mg methylphenidate.^[119] This appears to be the only relevant study, as others are either equivalent to case studies^[120] or confounded with the inclusion of other herbs such as panax quinquefolium.^[121]

When looking at reviews^[122] and meta-analyses^[123] suggest that, overall, ginkgo seems to be either ineffective for the treatment of ADHD or that there is insufficient evidence to draw good conclusions from; however, both of these studies only assessed the aforementioned comparative study with methylphenidate.

There is very limited evidence for the role of ginkgo biloba in the treatment of ADHD in children, and while it does appear to have a benefit it is significantly less effective than the standard dose of methylphenidate (Ritalin)

In a small sample of young persons with migraines without aura, supplementation of 80mg Ginkgolide B (alongside some other nutrients such as CoQ10 and Magnesium at 20mg and 300mg respectively) twice daily with meals for three months (followed by 9 months of followup) was associated with less symptoms of migraine^[124] which has been noted elsewhere with the same confounds.^{[125][126][127]}

There is some poorly structured evidence to 'support' the usage of ginkgo biloba in treating migraine. Overall, the evidence doesn't seem to be well structured enough to recommend this supplement for this purpose

A single acute dose of 120mg EGb-761 in otherwise healthy young volunteers has failed to influence short term memory^[105] and a trial in healthy adults over the age of 60 with 120mg Ginkgo daily for 26 months failed to find a difference between treatment and placebo.^[128] This is the same dose (120mg) that was found to be ineffective at improving working memory and mood, but increased pattern-recognition memory and attention.^[129] However, other studies do note benefits to working memory at this dose in healthy persons^[130] with the exact reason for the differential effects not known.

Word recollection appears to be more beneficially affected at a once taken dose of 120mg rather than 240mg or thrice daily lower dosages^[131] although in older but cognitively well persons 240mg EGb-761 appears effective^[132] and doses up to 600mg have shown efficacy acutely.^[133]

Overall a systematic review on the effects of ginkgo biloba and nootropic usage in otherwise healthy adults has concluded that in this population supplementation is no more effective than placebo, in part due to most of the long term studies coming back negative while overall studies had some probles with methodology.^[134]

In otherwise healthy youth, supplementation of ginkgo biloba has at times showed promise with 120mg of the EGb-761 extract but it is quite unreliable. Reviews on the topic suggest that it is not a good nor reliable cognitive enhancer in this population

In middle-aged persons (45-56yrs), 240mg EGb-761 once daily for a period of six weeks was able to improve memory recall as assessed by simulated appointment keeping while it was ineffective in promoting navigation skills.^[132]

In elderly persons not currently diagonsed with dementia or Alzheimer's disease, supplementation of EGb-761 appears to be associated with improved cognitive performance over the course of 12 weeks with some efficacy noted by week four.^[135] Elsewhere, persons in the same age bracket (55-86yrs) that are given a 180mg EGb-761 dosage for a period of six weeks noted improvements in memory retention as well as processing speed, with no significant influence on processing accuracy^[136] and improvements in delayed recall and recognition has been noted with 180mg in persons above the age of 60.^[137] This is also noted with 180mg of the basic leaf extract, where cognition via SF-12 and memory are improved relative to placebo.^[138]

A 70% ethanolic extract of the leaves (0.20mg/mL total flavones and 0.34mg/mL ginkgolides) daily for 24 weeks at either 1.9mL thrice daily (5.7mL) or a third this dose noted improvements in visual short-term memory retention but no improvements in working memory nor cognitive decline.^[139]

In older adults that are experiencing cognitive impairment and memory decline associated with aging but are not yet diagnosed with neurodegenerative disorders such as Alzheimer's or other variants of dementia, the standard recommended doses of ginkgo and EGb-761 appear to be therapeutic and aid in memory formation

In adults over 70 reporting spontaneous memory impairment (associated with being 'at risk' for dementia^[140]) then given 120mg of EGb-761 twice daily, supplementation over the course of five years failed to reduce the risk of developing Alzheimer's Disease (Hazard ratio of 0.84 and a nonsignificant 95% confidence interval of 0.60–1.18).^[141] The risk of developing general dementia has elsewhere been found to not be affected by ginkgo supplementation at 120mg EGb-761 twice daily, with a hazard ratio of 1.12 (95% confidence interval of 0.94-1.33)^[142] and basic cognitive decline in older adults with mild cognitive decline at the start of a study using 240mg EGb-761 also appears unaffected.^[143]

The risk of developing Alzheimer's Disease over a period of five years with the standard dosage of ginkgo does not appear to be significantly influenced, suggesting no major protective effect

24 weeks of EGb-761 (240mg) in persons currently diagnosed with dementia (multi-infarct or Alzheimer's origin) noted that supplementation was associated with a greater frequency of response to treatment (assessed by improved cognitive performance and memory) than placebo^[144] which has been replicated elsewhere^[145][146] and a later study with half the dose (120mg EGb-761) daily for the course of a year in persons already diagnosed with dementia had improvements in cognitive performance as assessed by ADAD-cog and GERRI relative to placebo^[147] and an analysis at the half-way point (26 weeks) showed efficacy within this time frame^[148] although a very similar trial (in regards to dosing and rating scales) over 24 weeks has come back null;^[149] this latter study has been criticized for being underpowered.^{[150][151][152]}

A trial which found that 240mg EGb-761 for 24 weeks was effective in reducing symptoms of persons diagonsed with dementia from either Alzheimer's or vascular origin^[153] was assessed further to note that both possible causes for dementia are equally benefitted with supplementation,^[154] and this has also been replicated elsewhere.^[146]

The degree of improvement on cognitive performance has been noted to be significant enough to be noticed by caretakers,^{[147][148][145]} and the magnitude of benefit seen with 240mg EGb-761 appears to be comparable to 10mg Donepezil.^[155]

In persons already experiencing cognitive decline, ginkgo appears to have some therapeutic benefit in improving cognitive performance. While not overly potent, it appears to be practically significant

Some trials have investigated the combination of EGb-761 daily with other drugs for the treatment of Alzheimer's, and the addition of EGb-761 (240mg) to donepezil (5-10mg) noted that while they were individually comparable that the combination outperformed either treatment in isolation.^[155]

Supplementation of Ginkgo biloba appears to be additive to some other drugs against cognitive decline such as Donepezil

An LI1370 (flavonoid) extract at 240mg has been found to not significantly influence REM sleep despite improving subjective sleep and sleep efficiency in otherwise healthy participants.^[156]

In persons with depression, six weeks supplementation of EGb-761 (240mg daily) alongside standard antidepressant therapy (trimipramine) has noted an improvement in sleep efficiency associated with increased stage II sleep and overall increases in non-REM sleep.^[157]

Limited evidence supports the usage of ginkgo biloba to improve sleep efficiency (reducing waking during the night and prolonging non-REM sleep) although both studies have failed to find an influence on REM sleep

40-60% of persons with multiple sclerosis (MS) experience cognitive decline associated with decrements in processing speed, memory, and executive skills.^[158][159] Due to this, ginkgo has been investigated for therapeutic benefits to MS.

Supplementation of 120mg EGb-761 twice daily (240mg daily for a period of 12 weeks) has failed to improve cognition and memory in persons suffering from multiple sclerosis.^[160]

Alterations in antioxidant/oxidant balance have been noted in persons with schizophrenia, as endogenous antioxidant molecules such as uric acid tend to be reduced^[161] alongside an increase in general oxidation^{[162][163][164]} that may underlie relative increases in antioxidant enzymes including SOD (25.9%), glutathione (39.2%), and catalase (14.4%).^[165][164]

The increase in antioxidant enzymes seen in schizophrenia is normalized with 300mg ginkgo biloba supplementation over eight weeks, and this improvement correlates with the reduction of positive symptoms of schizophrenia.^[165]

The state of schizophrenia is associated with alterations in antioxidant status of the body (seems to be a reduction in antioxidant capacity which then begets an increase in antioxidant enzyme activity), and supplementation of ginkgo is able to normalize these changes

Ginkgo biloba appears to be supported for use as an adjuvant treatment (alongside main treatment) in schizophrenic individuals^[123] and has been tested alongside haloperidol (360mg EGb-761 daily),^[166] clozapine (120mg twice daily),^[167] and olanzapine (150mg of an unspecified extract twice daily).^[165] The net symptom reduction appears to be statistically significant for positive symptoms of schizophrenia, while the improvement seen in negative symptoms trends to be relevant^{[123][166][167][165]} and only infrequently reaches significance.^[167]

Supplementation of ginkgo biloba appears to be useful as an adjuvant therapy for schizophrenic individuals, and appears to reduce positive symptoms of schizophrenia more than negative symptoms

Tardive Dyskinesia is an involuntary, hyperkinetic movement disorder^[168] with a relatively poorly understood pathophysiology, but has links to oxidative damage in the basal ganglia^[169] as well as being associated with lower circulating BDNF concentrations.^[92][170] BDNF is of particular interest as the degeneration of neurons in the dopaminergic nigrostriatal system^[171] and glutaminergic cell death^[172] are both attenuated by BDNF.^[173][174]

The state of tardive dyskinesia is associated with reduced circulating levels of BDNF, which are thought to contribute to the pathology observed

In schizophrenic patients with tardive dyskinesia, supplementation of 240mg EGb-761 daily for twelve weeks is able to increase circulating concentrations of BDNF and the increase in BDNF positively correlated with symptom relief.^[92] This study is replicated in Medline.^[175]

Supplementation of EGb-761 appears to enhance BDNF while reducing symptoms of tardive dyskinesia

It has been claimed^[176] that due to similar pharmacodynamic profiles between ginkgo biloba and piracetam^[177] and the efficacy of piracetam in aiding autism as an add-on therapy,^[178] that ginkgo biloba may have a potential role in its treatment.

A series of three case studies using 100mg EGb-761 twice daily over four weeks noted improved symptoms as assessed by the Aberrant Behavior and Symptom Checklist (ABSC) and in particular the subsets of hyperactivity, irritability, inappropriate speech and inadequate eye contact.^[176] However, clinician ratings of symptoms were not affected^[176] and thus it was suggested that ginkgo biloba can potentially be an adjuvant but is not potent enough for monotherapy

This has been followed up with a double-blind trial where ginkgo at 80-120mg daily (EGb-761) was added to risperidone, and ginkgo has failed to outperform placebo.^[179]

Preliminary research into ginkgo biloba for the treatment of autism has failed to find remarkable benefits, and the slight benefit that has been noted suggests that it may have a role as an adjuvant therapy. The first trial investigating this failed to find a benefit

At least one study has noted that effects were seen acutely, but not at the end of the trial, and suggested adaptation.^[129]

Ginkgo biloba (EGb-761) appears to possess competitive PDE4 inhibiting potential with an IC₅₀ value of 25.1µg/mL (PDE5 to a lesser extent of 47.3µg/mL).^[180]

While EGb-761 does not appear to influence basal calcium concentrations, the influx of calcium induced by some molecules (histamine, thrombin, ATP) is attenuated at 20-100µg/mL^[180] which was thought to be due to PDE4 inhibition as it was mimicked by rolipram and this mechanism is known to attenuate calcium influx.^[181]

Some components of ginkgo biloba appear to interact with phosphodiesterase enzymes, and in particular there may be relevant inhibitory effects on PDE4 and PDE5 (albeit somewhat weak, due to needing high concentrations)

The potency of ginkgolides on inhibiting the platelet activating factor receptor are (following numbers are IC₅₀ values) Ginkgolide A (3.33+/-0.92µM^[11]), Ginkgolide B (0.57+/-0.15µM^[11]), Ginkgolide P (15.65+/-2.94µM^[11]), Ginkgolide Q (11.01+/-2.73µM^[11])

The ginkgolide skeleton appears to be involved in inhibiting platelet aggregation, and ginkgolide B is potent enough (in the nanomolar range) to be biologically active following oral ingestion of ginkgo extracts

In isolated endothelial cells, EGb-761 at 12.5-100μg/mL has been noted to reduce endothelial dysfunction induced by oxidized LDL cholesterol (oxLDL; known to play a role in initiating artherosclerosis^[182]) in a concentration dependent manner associated with antioxidant effects;^[183] the reduction in reactive oxygen species (ROS) being known to attenuate the dysfunction associated with oxLDL.^[184] This was later found to be due to reducing the actions of NADPH oxidase secondary to preventing oxLDL from suppressing AMPK, and abolishing AMPK blocked the effects of ginkgo.^[185]

Beyond preventing LDL oxidation from occurring, ginkgo biloba (EGb-761 at 12.5-100μg/mL) may reduce the pro-artherosclerotic effects of oxidized LDL (oxLDL) on endothelial cells^[186][183] as it seems oxLDL uses reactive oxygen species as a signalling molecule and ginkgo directly sequesters this free radical with near absolute potency (95.6%) at 100μg/mL EGb-761.^[183]

Ginkgo appears to preserve AMPK function in the presence of oxidized LDL cholesterol, which is known to reduce the activity of AMPK. Ginkgo may additionally circumvent the ability of oxidized LDL to induce damages to blood vessel cells, although this is an activity that is common to many antioxidants

Macrophages are immune cells that can at times bioaccumulate too much cholesterol (either due to increased uptake from modified LDL or reduced efflux) and convert into cells known as foam cells, which then get deposited on the endothelium as artherosclerotic buildup.^[187][188]

Transporters mediate the internalization of modified LDL (via SR-A^[189] and CD36^[190]) and efflux cholesterol via 'reverse cholesterol transporters' or RCTs (SR-BI and ABCA1/G1^[191][192]). Antioxidant compounds have been noted to increase RCT activity while reducing SR-A activity (seen with resveratrol^[193] and anthocyanins^[194]) ultimately causing less foam cell formation, and this appears to extend to ginkgo biloba EGb-761 at 100mg/kg oral intake in mice.^[195] This was thought to be related to an induction of heme oxygenase-1 (HO-1) as preventing the increase in HO-1 prevented the observed effects.^[195]

Macrophages can convert into foam cells and contribute to artherosclerotic buildup, and it appears that the antioxidant properties of ginkgo biloba are sufficient to reduce foam cell formation

The upregulation of connexin 43 in rabbits fed a high fat diet is attenuated witH EGb-761,^[196] which is thought to be relevant as connexin 43 is involved in artherosclerotic progression^[197] and reducing it inhibits artherosclerosis.^[198][199]

A suppression of connexin 43 upregulation has been noted with ginkgo biloba, which is thought to contribute to the anti-artherosclerotic effects. The relevance of this mechanisms in the grand picture is not clear

When looking at circulating biomarkers of artherosclerosis, supplementation of EGb-761 is associated with reductions in C-reactive protein (39.3%^[200]), Myeloperoxidase (^[200]), and MMP-9 (32.9%^[200]), the latter two being biomarkers of LDL modification^[201] and of plaque stability, respectively.^[202]

Supplementation of 240mg EGb-761 in persons with metabolic syndrome has been noted to reduce the ratio of oxidized LDL cholesterol relative to unaltered LDL by 17.0+/-5.5% alongside an upregulation of superoxide dismutase by 15.7+/-7.0%;^[200] due to these changes, two months of supplementation was associated with less plaque formation (11.9+/-2.5%) and size (24.4+/-8.1%) relative to placebo.^[200]

The anti-arthersclerotic potential of ginkgo biloba appears to be relevant following oral administration of EGb-761

When looking at blood vessel reactivity, supplementation of EGb-761 at 80-160mg/kg to rats is able to attenuate noradrenaline induced vessel contractions and increase acetylcholine and SNP induced vasorelaxation,^[203] which has been noted elsewhere in hypertensive rats^[204][205] and has been reported to be without effect in rats that do not have hypertension.^[205]

Possible secondary to the antioxidant effects, ginkgo biloba appears to improve the reactivity of the blood vessels to relaxing signalling molecules. This does not occur in blood vessels from otherwise healthy animals, suggesting only a rehabilitative effect

A reduction in ACE activity in renal tissue by 60-84% has been noted with EGb-761 in hypertensive rats at 60-180mg/kg for 4 weeks, although serum ACE values were unchanged.^[203]

In some pathological cases of high blood pressure that are associated with excessive angiotension II and its superoxide production^[206][207] that inherently causes reduced nitric oxide bioavailability,^[208] supplementation of any antioxidant compound is thought to have a therapeutic benefit for blood pressure as well as blood flow via this mechanism.^[209] Due to the potent antioxidant properties of ginkgo biloba, it has been investigated for this role.

In a rat model of hypertension (2K1C), supplementation of 60-180mg/kg EGb-761 for 4 weeks is able to reduce systolic (but not diastolic) blood pressure in a dose and time dependent manner^[203] and this protective effect is also observed in corticosterone^[210] and salt^[204] induced hypertensive rats as well as spontaneously hypertensive rats.^[205] Rats without hypertension do not experience changes in blood pressure.^[205]

Ginkgo is reported to havs a vasodilatory actions (claims from reviews and traditional medicine)^[27][211]

These effects are seen both by enhancing the neuronal release of endogenous relaxing factors, and via inhibiting the COMT enzyme.^[212]

Mechanistically, ginkgo may be able to release endogenous relaxing factors

Nitric oxide is produced by the NOS enzymes (the most relevant one to blood pressure is the endothelial form, or eNOS^[213]) and via a cGMP-mediate pathway it regulates blood pressure and may improve blood flow/reduce blood pressure. Incubation of endothelial cells with 100-500µg/mL of the EGb-761 extract can improve blood flow by around 1.5-fold (the entire range being equally potent) and has been found to be active on eNOS (via phosphorylating eNOS at Ser-1177 via PI3K/Akt) at concentrations as low as 6.4-10µg/mL.^[214]

EGb-761 as a 5mg injection to rats (90-110µg/kg) is able to acutely reduce blood pressure in a manner that is abolished by L-NAME, showing that it is able to reduce nitric oxide in vivo.^[214]

Ginkgo biloba appears to be able to promote nitric oxide formation, and although the magnitude of this effect is not overly remarkable it does appear at low enough concentrations that it is probably biologically relevant with oral supplementation

Acute supplementation of EGb-761 in otherwise healthy young men at 360mg has failed to significantly influence blood flow, heart rate, and blood pressure between 2-6 hours after supplement ingestion.^[215]

Microcirculation has been noted to be increased with 180mg of a ginkgo extract (a 3-5:1 extract conferring 2.1% flavones and bilobalide (988mcg), ginkgolide A (440mcg), and ginkgolide B at 262mcg) in a time-dependent manner over the course of 30 days.^[216]

A supplement known as Gibidyl Forte (7.2mg terpenoids and 28.8mg ginkgoflavonglucoside in three divided doses) over six weeks appears to enhance forearm blood flow in otherwise healthy persons by 33-35% relative to baseline (placebo in the 9-19% range)^[217] and 240mg of the EGb-761 extract appears to also improve blood flow in healthy persons,^[218] although the degree of improvement appears to be inversely related to how poor one's blood flow was relative to other participants at the start of the study.^[218][218]

Injections of ginkgo (87.5mg daily) in persons with coronary artery disease have been confirmed to increase peak blood flow and circulating nitric oxide concentrations (12.42%) alongside a reduction in endothelin-1 (5.82%);^[219] this study being duplicated in Medline^[220] and replicated in healthy elderly adults where injections of ginkgo were similarly effective in improving the measured parameters of blood flow (MDPV, MSPV, and DTVI).^[221]

Ginkgo appears to increase blood flow following oral ingestion in otherwise healthy persons, and improvements in microcirculation have also been noted. These benefits may require daily dosing for a few weeks to manifest, rather than benefitting from a single dose

Ginkgo biloba supplementation, in an analysis of a large trial on dementia, has failed to show promise in reducing the occurrence of cardiovascular diseases (myocardial infarction, angina, or stroke) relative to placebo^[113] and another analysis of the same study failing to find any influence on hypertension risk or blood pressure between groups.^[222]

May have limited use in reducing the development of diseases associated with blood flow, although those related to the cardiac tissue itself seem unaffected

Peripheral Artery Disease (PAD) is a circulatory conditions in which arteries to peripheral tissues (arms and legs) are reduced in size, restricting blood flow.^[223][224] Persons with PAD are at higher risk for experiencing intermittent claudication, which is a painful cramping of muscularity (usually in the calf) during walking due to restricted blood flow.^[225] Due to this pathophysiology, ginkgo is thought to be therapeutic due to its vasodilatory and pro-circulatory benefits as well as potential anti-platelet effects.

The overall risk of developing PAD appears to be reduced with daily supplementation of EGb-761 at 240mg in older individuals (1.5% occurrence reduced to 0.8%).^[113] The reason for this reduced risk of developing PAD is not clear.

When looking at prevenative supplementation, EGb-761 may be able to reduce the risk of developing peripheral artery disease in older adults

A meta-analysis has noted 'modest' improvements in walking distance in intermittent claudication^[226] and the three trials that can be located online (others not located online) have noted improvements in walking distance in persons with intermittent claudication usually between two-fold and three-fold (pain free walking distance and total walking distance, respectively) over 24 weeks of 40mg EGb-761 thrice daily^{[227][228][229]} while the meta-analysis itself conducted a more modest improvement in walking distance of 26-47m whereas placebo increases 4-33m.^[226]

A study not included in the aforementioned meta-anlaysis used 300mg EGb-761 that was able to improve walking time on a treadmill test, but due to a large variability (placebo improved by 20+/-80s and ginkgo 91+/-242s) the difference was not significant.^[230]

The influence of ginkgo biloba on walking distance and symptoms of PAD and intermittent claudication appear to be present, although they are very unreliable (some good responders, many not) and due to this unreliability the overall 'effect' for the whole group is either insignificant or barely significant and low in magnitude

160mg EGb-761 twice daily for four weeks in persons with peripheral arterial occlusive disease has been noted to reduce cerebral ischemia (38% as assessed by TcPO₂) despite no inhernet influence on walking distance.^[231]

Possible anti-ischemic effects in this cohort that may exist even if walking distance does not improve

Acute mountain sickness (AMS) is a sickness that occurs when one ascends from a low altitude or sea level upwards, most commonly seen in mountain climbers and thought to be related to low blood oxygen concentrations; ginkgo is thought to help with this sickness as it can increase oxygen carrying capacity in persons at high altitudes.^[232]

Studies that note benefit to acute mountain sickness note a reduction from 68% occurrence of sickness in placebo to 33% with ginkgo at 120mg twice daily,^[233] 80mg EGb-761 twice daily abolishing the 40.9% occurrence of headache and attenuating the 81.9% respiratory sickness in placebo to 13.6%,^[234] 60mg EGb-761 thrice daily reduced severe AMD from 64% to 17% of the sample while reducing overall sickness,^[235] and 80mg EGb-761 twice daily abolished the increase in AMS relative to placebo.^[232]

Other studies have failed to find a significant protective effect with a basic leaf extract,^[233] EGb-761 at an unspecified dose,^[236] and 120mg EGb-761 twice daily.^[237] Additionally, one of the previous studies using a single day pretreatment (120mg EGb-761) that noted reductions in the severity of AMS failed to find an overall reduction in occurrence rates which may be related to the low sample size.^[235]

Ginkgo biloba has both positive and null evidence to support its role in preventing acute mountain sickness. When it does show benefit, the magnitude of this benefit is quite large whereas it unexpectedly fails outright in other instances

One study that conducted two trials which noted a success followed by a failure to treat AMS claimed that the source of ginkgo was the reason, and despite both trials getting 120mg twice daily only the supplement with a higher ginkgolide content (and some other ginkgolides including J and M) was effective.^[233] The ineffective supplement was also not standardized to flavonoid glycosides,^[233] although other trials that note inefficacy have used EGb-761^[236][237] which does not fit with this hypothesis.

Although one study suggested that the lack of ginkgolides and flavonoids may be a reason for inefficacy in some trials, it does not appear likely

Ginkgo biloba paired with rhodiola crenulata (similar composition as rhodiola rosea) in a 1:9 ratio totalling 1,080mg in otherwise healthy active men over the course of seven weeks appears to be able to improve absolute and relative VO2 max.^[238]

EGb-761 at 100µg/mL has been noted to induce heme oxygenase-1 (HO-1)^[195][239] which is known to be dependent on Nrf2^[239] that accumulates in the nucleus with EGb-761 incubation^[195][240] due to inhibiting Keap1 (a negative regulator of Nrf2) and allowing its accumulation.^[240]

The antioxidant enzyme HO-1 (secondary to activation of the antioxidant response element and Nrf2) appears to be increased in response to EGb-761, which may underlie some of the antioxidant effects of ginkgo biloba supplementation

Chinese medicinal herbs have traditionally been used for treating symptoms of PMS^[241][242] and ginkgo biloba appears to be one of the herbs used for this purpose.

Ginkgo has been shown to be effective (thrice daily dosing of 40mg EGb-761) in alleviating congestive and neuorpsychological symptoms of PMS^[243]|published=1993 Jul-Sep|authors=Tamborini A, Taurelle R|journal=Rev Fr Gynecol Obstet] and supplementation of 40mg EGb-761 thrice daily for the course of approxiately a month was elsewhere associated with a greater reduction in overall PMS symptoms (23.68%) than was placebo (8.74%) with efficacy against both physical and neuropsychological symptoms.^[244]

The active dose of ginkgo biloba may be beneficial in reducing symptoms of PMS, although larger trials are needed to confirm. No direct comparisons have been conducted, but it seems less potent than Vitex Agnus Castus

Ginkgo is being investigated as a herbal supplement to attenuate the effects of SSRI-induced sexyal dysfunction (similar to Maca).^[245]A preliminary trial has used an average dose of 209mg daily (ranging from 60mg four times daily to 120mg twice daily) and found 84% efficacy in improving SSRI related libido (91% efficacy in females and 76% in males, the difference being statistically significant)^[245] although subsequent studies have noted that ginkgo (240mg for twelve weeks) noted improvements in individuals that were too sporadic to reach statistical significance^[246] and this dose for eight weeks also failing relative to placebo.^[247]

Although the first pilot study was highly promising, subsequent double blind studies have failed to find a significant and reliable benefit of ginkgo supplementation. There appear to be a few hyperresponders to treatment that experience a large amount of benefit, but they are too infrequent to influence statistical significance

In women with sexual arousal disorder and a subsequent impairment of libido, 300mg of ginkgo (EGb-761) for eight weeks with or without weekly sex therapy failed to significantly improve symptoms.^[23]

Acute supplementation of ginkgo (300mg EGb-761) 90 minutes prior to an erotic film in women with sexual arousal disorder noted an improvement in sexual reactivity to the filsm as assessed by an increase in vaginal pulse amplitude (via vaginal photoplethysmography^[248]) although the degree was deemed to be clinically insignificant and did not differ between women on antidepressants and those without.^[23]

The sexual dysfunction associated with antidepressants seems to be similar to organic sexual arousal disorder, where ginkgo does not appear to have significant libido enhancing properties

Ginkgo is thought to enhance erections secondary to its ability to enhance blood flow via nitric oxide metabolism,^[249] although a rat study noted that supplementation of 50mg/kg EGb-761 for 15 days was able to enhance noncontact erection (thought to be an animal model of human psychogenic erections in response to sexual arousal^[250][251]) suggested that increased dopaminergic neuron populations in the PVN and the mesolimbic system were associated with the observed effects,^[62] as dopaminergic drugs are known to enhance noncontact erections^[252] and these two brain regions are implicated in erections and sexual arousal from dopaminergic drugs;^[253][254] ginkgo also appeared to increase dopamine concentrations in these brain regions.^[62]

Possible pro-erectile effects, which are currently thought to be related to dopamine metabolism and a central influence on penile tissue (although nitric oxide's contribution cannot be ruled out)

Although not erections, the clitoris as well as penis express nitric oxide synthetic enzymes^[255] and is associated with engorgement and muscle relaxation; due to this, ginkgo is thought to also benefit the sexuality of women secondary to enhancing blood flow.^[23]

The same mechanisms that enhance erectile properties in men can potentially also positively modulate female sexuality

A 70% ethanolic extract of the leaves is able to promote hair regrowth when fed orally to mice.^[256]

Ginkgo is sometimes used in facial creams^[257] due to its flavonoid content and antioxidant capacity.^[258]

The flavonoids from ginkgo biloba at 0.3% of a facial cream was noted to improve skin quality after, particularly on the parameters of moisture content (27.88% increase), smoothness (4.32% increase), roughness (0.4% reduction) and wrinkles (4.63% reduction).^[258]

Tinnitus is the name used to refer to a chronic and pathological ringing of the ears, and ginkgo appears to be used for this condition at times.^[259]

Supplementation of 40mg ginkgo has failed to provide therapeutic benefit to persons suffering from tinnitus in one open label comparative study (where clonazepam was found effective)^[260] and a thrice daily dose of 50mg LI1370 extract over twelve weeks has similarly been found to be no more effective than placebo^[4] although this latter study has been criticized for being conducted over the phone and mail,^[261] and due to usage of LI1370 it could not assess the influence of terpenoid structures (present in EGb-761).

A meta-analysis on this topic^[262] has concluded that there is insufficient evidence to support the usage of Ginkgo biloba for the treatment of tinnitus where tinnitus is the primary complaint although one study in persons who had tinnitus from cerebral insufficient (where tinnitus is a symptom fo the disorder) noted benefit;^[154] the benefit seen in this state is not overly reliable, as other studies measuring tinnitus symptoms in persons with cognitive decline fail to note a significant effect.^[145]

Ginkgo biloba likely does not have a therapeutic benefit for primary tinnitus (when you have tinnitus and nothing else), but in instances of secondary tinnitus due to dementia or cognitive decline there is some limited evidence that in treating dementia the symptoms of tinnitus also decline

Normal tension glaucoma (NTG; sometimes also called low tension glaucoma) is a form of primary open-angle glaucoma is a form of eye damage to the optic nerve and visual field, but is not associated with an elevation in intraocular pressure.^[263]

Oral supplementation of 80mg EGb-761 twice daily (over the course of four weeks) in persons with NTG appears to promote ocular blood flow^[264] and in persons with NTG who also have visual field damage thrice daily dosing of 40mg EGb-761 found improvements in visiual acuity^[265] (which is sometimes impaired despite medical treatment of NTG^[266]).

In persons with normal tension glaucoma, ginkgo biloba supplementation at standard dosages is able to improve ocular blood flow without influencing intraocular pressure. This results in a restoration of the impaired vision in this disease state

This has been replicated in otherwise healthy adults where two days of ginkgo biloba at 40mg (thrice daily EGb-761) was able to improve ocular blood flow without affecting intraocular pressure.^[267] Other studies in healthy persons have noted that a single oral dose (240mg EGb-761) was able to increase blood flow but not to a degree that could outperform placebo over the next three hours,^[268] suggesting that repeated dosing is required.

The increase in ocular blood flow without increase in intraocular pressure applies to healthy controls as well, although the visual ramifications of this are not clear (ie. it is not ascertained as to whether ginkgo can improve vision in somebody without apparent visual impairments)

Supplementation of ginkgo biloba extract as eyedrops alongside a hyaluronic acid solution (also used in control) to persons suffering from seasonal allergic conjunctivitis (pink eye from allergies) is able to reduce symptoms more than placebo treatment.^[269]

Ginkgo can be used in eye drops, and appears to be effective in reducing symtoms of pinkeye when used in this manner

In diabetic patients with early diabetic nephropathy, three capsules of a ginkgo extract (19.2mg flavonoid glycosides and 4.8mg terpenes) daily for eight weeks is able to reduce urinary albumin (55% of baseline) and serum creatinine (87.5% of baseline) without affecting blood glucose.^[270] These changes were associated with higher nitric oxide and improved blood flow.^[270]

In persons who had a brain tumor irradiated within the last six months on stable preventative therapy and no intervention to treat the brain tumor who were then divided into placebo or 120mg ginkgo biloba for 24 weeks, there was an improvement in cognition (executive function and verbal memory) and mood relative to placebo.^[271]

In a secondary analysis of a 6.1 year intervention with 240mg EGb-761 assessing dementia risk in persons 75 or above,^[142] it was noted that during this analysis that supplementation of ginkgo biloba appears to be associated with an increased risk of breast cancer as assessed by hazard ratio (2.50; 95% CI of 1.03–6.07) with 18 reported hospitalizations relative to 9 in placebo.^[272] The authors cautioned that false positives may arise due to the low sample size^[273] and that the age demographic investigated is the one at highest risk of developing cancers.

Secondary analysis of large trials has found a statistically significant increase in the risk of developing breast cancer in eldelry persons

Ginkgo appears to have been used in persons with intermittent claudication (research dating back to 1966 and a meta-analysis both published in German, but mentioned via the following citation^[217]).

Raynaud's phenomena is a condition in some persons where skin color in extremities such as their hands experience color changes in response to cold or emotional stress, which can be either secondary (due to another condition) or primary (not due to another condition).^[274][275] It is primarily thought to be a disorder of blood circulation, and thus ginkgo has been investigated for its treatment (although the main treatments are calcium channel blockers^[276]).

120mg of EGb-761 twice daily for a period of ten weeks failed to outperform placebo in reducing symptoms of Raynaud's phenomena^[277] and elsewhere the 30.1% improvement seen with ginkgo from baseline (no placebo comparison) was outperformed by the pharmaceutical calcium channel blocker nifedipine.^[278]

The evidence is currently not strong enough to support the usage of ginkgo biloba for the treatment of Raynaud's phenomena, with the higher quality evidence coming back null

Vitilgo vulgaris is a skin depigmentation disorder with a 1-3% prevalance globally^[279] that may lead to distressing effects in those suffering from it, as some persons confuse vitilgo (a benign syndrome) with leprosy.^[280][281] The pathology is currently not well understood, but thought to be related to cellular death of melanocytes and possible interactions with the immune system.^[282]

Supplementation of 60mg EGb-761 twice daily for twelve weeks in a small pilot study was associated with improvements in the symptoms of vitilgo vulgaris with an average 15% repigmentation and 0.4% reduction in lesion area^[283] and a small double-blind study (n=47) using 40mg EGb-761 thrice daily was similarly effective in improving skin repigmentation (with 40% of the experimental group yet only 9% of the placebo reporting repigemtnation).^[284] The efficacy of ginkgo seems to be similar depending on whether the vitilgo is deemed to be vulgaris, acrofacial, or focal.^[284]

Although it is not currently known why, low doses of orally supplemented EGb-761 appear to be beneficial in promoting skin repigemtnation in persons with vitilgo vulgaris

Ginkgo biloba is known to be complexed with phosphatidylserine (120mg EGb-761 and 360mg phosphatidylserine; known as Virtiva^TM) which has failed to increase blood levels of terpenoids any more than regulato ginkgo biloba or that which is complexed with phosphatidylcholine, yet acute usage of this supplementation pair appears to slightly exceed the efficacy of ginkgo biloba by itself on attention and memory tasks with no alterations in calmness or mood state (relative to ginkgo, both increased calmness);^[285] it should be noted that this study was funded by the supplier of the supplement in question. ^[285]

The pairing of phosphatidylserine and ginkgo biloba appears to be either comlementary or synergistic in regards to nootropic usage based on preliminary evidence; this does not appear to be due to enhanced absorption

The combination of ginkgo biloba and Panax Ginseng is commonly used under the name of 'Gincosan'^[286] which is a combination of these two herbs in a 3:5 ratio (usually one capsule containing 60mg EGb-761 and 100mg panax ginseng G115).^[287] This combination is used since they are both cognitive enhancing herbs from traditional chinese medicine, and they seem to benefit all ages when they work.^[288]

240-960mg of the combination in otherwise healthy youth was associated with improved performance on a serial threes and serial sevens task relative to placebo as assessed by the reduction in errors and increase in substractions (overall, an increase in processing speed and accuracy on an arithmetic test). No comparison was made to either agent in isolation, both of which also showed improvements.^[287] This population has been studied elsewhere on a variety of outcomes^[289] but no consistent changes in attention, reaction time, nor recognition tasks were noted; a slight increase in spatial memory and delayed word recall relative to both herbs in isolation and placebo was noted.^[289] Quality of memory has been noted to be increased elsewhere in youth given a single dose of these herbs.^[290]

In middle-aged adults given either 160mg (100mg panax ginseng) of the combination twice daily or 320mg once daily for 12 weeks, there was an improvement in quality of memory despite no changes in speed of memory formation, mood, or attention.^[288] Elsewhere in a similar group of adults albeit with neurasthenic complaints, 80-320mg twice daily for 90 days was associated with an improvement on a Cognitive Drug Research assessment and Symptom Checklist-90-revised rating scale^[291] yet otherwise healthy post-menopausal women given the combination (120mg ginkgo and 200mg panax) for 6-12 weeks failed to have significant changes to their mood or vigilence during testing and the outcome of the testing (attention processing and episodic memory) was also unaffected.^[286]

Although synergism between these two herbs has not yet been outright demonstrated, they appear to interact with each other on memory. The combination works more often than it doesn't (there is some evidence showing no effect, and it is not certain why) and the combination seems to mostly benefit 'quality of memory' and recall times without any apparent influence on attention, mood, or reaction time

Ginkgo Biloba has been investigated in being paired with aspirin for heart health.

The combination of Ginkgo Biloba and Aspirin does not seem to further increase bleeding time or coagulation, suggesting they are a safe combination.^[292][293]

Bacopa Monnieri is a herb from Ayurveda that is seen as a reliable cognitive enhancer.

A bacopa supplement (55-60% bacosides) and a 24% flavone extract of ginkgo (GINKOCER) given at 30mg/kg for the length of one week were comparable in improving memory formation in a passive avoidance task in rats,^[28] but although the improvement seen with GINKOCER was associated with acetylcholinesterase inhibition bacopa seemed to be mediated by other mechanisms.^[28]

One study has used a combination of bacopa (300mg at 20% bacosides) and ginkgo (120mg at 7.5% flavones and 3% terpenes) in otherwise healthy adults has failed to find a cognitive enhancing effect over four weeks, although this may be due to the low doses used.^[294]

Both herbs are cognitive enhancers from traditional medicine, although currently the investigation into whether they are additive/synergistic has not yielded positive results

Possibly due to the compound Ginkgolide B, which is an inhibitor of platlet activating factors, Ginkgo Bilboa has been associated with case studies of subdural hematomas.^[295][296] This compound may also be responsibly for a case of hyphema (blood in the anterior chamber of the eye) associated with the combination therapy of Ginkgo Biloba and Aspirin^[297] at 80mg (50:1 concentrated extract) of ginkgo biloba with 325mg aspirin.