How saving Ginkgo biloba could save humankind: Paleobotanical Future

By V. Anne Burg, MPH

History of Ginkgo biloba

Ginkgo biloba (ginkgo) dates back 270 million years, to the early Jurassic era (Roston, 2009; Isah, 2015). During its long history, it has seen quite a few changes around the world, including nuclear war. Despite how well this tree can survive, it has found its way onto the endangered species list. The history of gingko trees is particularly difficult to study as there is a limited number of fossils that exist of the species (Roston, 2009). Gingko trees were brought to Europe in 1730 and were introduced to the United States less than 60 years later in 1784 (Tyler, 1993; Foster, 1996). It was likely brought to America because of its tolerance for coal soot, which a horticulturalist observed in the 19^th century (Roston, 2009). As of 2015, it is estimated that all the ginkgo trees in the world combined are worth over $500 million USD (Isah, 2015).

Paleobotanical Tree

Being such an old tree – dating to the Jurassic period (Roston, 2009) – it is not surprising that we do have some fossils of this plant. The Ginkgoales order left behind fossils from six families, 19 genera, and many species. However, Ginkgo biloba is the only currently surviving species of the Ginkgoaceae family (Tyler, 1993). Fossils remain from four Ginkgo species, ranging in date from 58.3 million to 53.4 million years ago (Roston, 2009). Scientists have even been able to extrapolate carbon dioxide levels from these fossils leading to the discovery that one of the Earth’s five great extinctions was likely caused by methane bursts from the oceans. These methane bursts could have triggered a hot, greenhouse type of environment for the Earth, causing what is referred to as the Paleocene-Ecocene thermal maximum (Roston, 2009). It would be about another 100 million years before the ginkgo would have to worry about climate change again.

During that Jurassic period, the genus Ginkgo was widely distributed in the Northern Hemisphere. Having survived the Pliocene and Pleistocene epochs, fossils of this magnificent tree have been found in the Dalou Mountains, in southwest Japan (Tang, et al., 2012). Unfortunately, there is a gap in the fossil record of 100 million years coinciding with a crucial time period during which ovulate organs evolved from the Jurassic type. Since this period, not much has changed for the ginkgo! There are a lot of similarities seen in the shape and size of the leaves and stomata between historic ginkgo species; additionally, “newer” fossils from the Lower Cretaceous period in China fill some of that gap, showing that the reproductive structures haven’t changed significantly. Ginkgo biloba is considered a missing link in Paleobotany (Roston, 2009; Zhou & Zheng, 2003).

Tenacity

Ginkgo is very tenacious, having survived not only the Paleocene-Ecocene thermal maximum and the current climate crisis, but also having survived the bombing of Hiroshima, Japan. It was one of the first plants to re-grow, free of any signs of genetic mutation, within the months following the nuclear attack. Other trees such as bamboo were completely decimated. One particular ginkgo tree at the front of the Hosenbou temple, about 700 meters from the epicenter of the explosion, had a ginkgo tree sprout from the roots in the Spring of 1946, less than one year after the bombing. This led to the tree becoming a symbol of renewal and survival in Japan (Jacobs, B. P., & Browner, W. S., 2000; Roston, E., 2009).

During periods of heavy warming, which are often associated with high atmospheric carbon dioxide levels, the ginkgo’s growing season expands to adapt to these changes. This phenomenon is reflected in the fossil record of oxygen isotopes ratios in marine fossils and even in modern-day Japan between 1953 to 2000 when growth began four days earlier in spring and ended eight days later in autumn. By studying the relationship between the number of stomata and the amount of carbon in the fossil and wet records, scientists have shown that ginkgo requires little carbon dioxide while producing large amounts of oxygen. This suggests that the ginkgo tree could help urban areas survive climate change (Roston, 2009). The gingko tree can also benefit metropolis life because of its high resistance to environmental stresses, microbial diseases of all kinds, pests, and gas pollutants. It is the ideal tree to model and study disease resistance and stress in other plants (Isah, 2015)!

Chemistry

The ginkgo tree has many beneficial components; which come from the seed, the leaf, and even the root. The leaf alone contains flavonol, flavone glycosides, diterpene lactones, ginkgolides, sesquiterpenes, iron-based superoxide dismutase, p-hydroxybenzoic acid, ascorbic acid, and catechin (Jacobs & Browner, 2000). For example, there are ginkgolides, which suppress cyclo-oxygenate-2 (COX-2) and 5-lipo-oxygenate (5-LOX), limiting enzymes. This reduces the endoplasmic stress that is responsible for inflammation in humans, like when you have an asthma attack. One terpene, called Ginkgolide B, inhibits the platelet-activating factor (PAF) in humans, which reduces the release of cytokines, a response the body has when there is an infection. Although there is still more research to be done on this process, this could be a potential area of research for infectious disease control, such as the current Coronavirus pandemic. Additionally, when in the body, Ginkgo biloba extract (GBE) can capture free radicals, indirectly inhibit the formation of free radicals, and positively regulate the expression of mRNA of antioxidant enzymes. This means that circulation is improved, and cortical neurons are protected – so your cardiovascular system and brain get a boost (Achete de Souza, et al., 2020). Flavonoids may protect hypoxic tissues and seem to have antioxidant activity, reducing endothelial cell damage from oxidation due to free radical injury and progression of atherosclerosis (Jacobs & Browner, 2000). Human immortalized keratinocytes (HaCaTs) have been evaluated for skin toxicity of GBE using a lactase dehydrogenase (LDH) cytotoxicity assay by Chassagne, et al., (2019). Four strains showed antibacterial activity, specifically a protein in the leaves called Ginkbilobin, which works against Staphylococcus aureus, Enterococcus spp. and Pseudomonas aeruginosa. Chassagne et al. (2019) believe there may be more diseases this protein protects against and that more research is needed. This knowledge has already been applied to modern Western medicine; a synthesized Ginkgolide B compound was created and became a commercial option, and as of 1992, was being researched to check its use in organ transplant rejection prevention. Some additional hopeful experiments for this pharmaceutical are with asthma and toxic shock syndrome (Kupiec & Raj, 2005).

The crude form of ginkgo as a drug is obtained from the dried green leaves. GBE is made from these dried green leaves in a few different ways, one of the more popular ones being with an acetone-water mixture. The concentrate activates constituents and removes toxic compounds like ginkgolic acids. Manufacturers have standardized GBE products to contain 24% flavonoid glycosides. The Germans government has approved 22-27%, with 5-7% of terpene lactones and less than 5 parts per million of ginkgolic acids. GBE can also contain bilobalide, depending on how the manufacturer makes it. Unfortunately for the United States, the 1994 Dietary Supplements Health and Education Act means that any herbal supplements are not required to undergo any screenings by the Food and Drug Administration (FDA) for safety, effectiveness, or quality, which means that any GBE supplements bought in America could contain various, unregulated levels of ginkgolic acids (Jacobs & Browner, 2000).

Toxicity

Dosage and consumption must be done carefully. If too much is taken orally, it can cause gastrointestinal distress such as diarrhea, along with headaches, irritability, and restlessness (Tyler, 1993; Adderly, 1998). High levels of ingested Ginkgo could also cause liver damage and contact with the leaves or bark could cash a rash and/or inflammation (Adderly, 1998). The plant does contain toxic ginkgolic acids in the leaves, which are normally removed during the extraction process, however, due to its status as an herbal supplement in the United States, there is no regulation on the amount of those acids are in each pill (Jacobs & Browner, 2000). When combined with other pharmaceutical medications, ginkgo can also be unsafe or toxic. Some studies show that when taken with aspirin, St. John’s Wort, Warfarin, Ticlopidine, Clopidogrel, and Dipyridamole, GBE is unsafe. When taken with antidepressants, is also unsafe due to serotonin reuptake, causing an overload of serotonin in the brain. When taken with anticonvulsants, case studies show that there may be a possible correlation that led to death (Kreijkamp-Kaspers, et al., 2015; Kupiec, & Raj, 2005).

Discussion

The earliest recorded evidence of Ginkgo biloba usage is 4,820 years ago, in Shen Nong Ben Cao Jing, a Chinese book on agriculture and plants from 2,800 BCE (Tyler, 1993; van Beek & Montoro, 2009). The fruits or seeds have been valued for their medicinal properties in the Eastern cultures of the world for centuries before, long before the plant was taken back to Europe by explorers and colonizers in the 18^th century (Tyler, 1993). Modern research on the benefits of G. biloba only began 60 years ago in Germany, to determine what, if anything can be extracted from the green leaves of the tree (Isah, 2015; van Beek & Montoro, 2009). This extract is now used extensively in Western medicine, however, in America, its categorization as a supplement means the extract is not subject to any regulations (Jacobs & Browner, 2000). This is concerning as too much of the seed has the potential to be deadly, and even contact with the bark or leaves can give an allergic reaction (Adderly, 1998; Jacobs & Browner, 2000). Additionally, this tree holds importance for urban developers, horticulturalists, and hobby gardeners (Isah, 2015).

In Eastern medicine, ginkgo is said to have many effects such as prolonging youth, promoting longevity, increasing blood flow and oxygen to the brain, being an antioxidant, and alleviating memory loss, cough, bedwetting, alcoholism, as well as treating asthma and respiratory disease, skin infections, anxiety, schizophrenia, diabetes, erectile dysfunction, and gastrointestinal ‘wurm’ infections (Adderly, 1998; Chassagne, et al., 2019; Kreijkamp-Kaspers, S., et al. (2015); Achete de Souza, et al. 2020; van Beek, & Montoro 2009). Multiple ancient texts from China tout these benefits – Pen Ts’ao Kang Mu by Li Shih-chen and Ben Cao Gang Mu from the 16^th century, and Shen Nong Ben Cao Jing from 2,800 BCE (Chassagne, et al., 2019; van Beek & Montoro, 2009). This plant has been consistently used on its own, along with other natural supplements such as ginger and ginseng, to promote general well-being. Gingko is also believed to have antioxidant qualities, to have heart-strengthening properties, and to help reduce fluid retention (Adderly, 1998; Mindell, 1992).

Despite its long history, experiments on how or if Ginkgo was beneficial to humans did not begin in the Western world, until the 1960s in Germany. Research initially focused on whether the leaf extract could be used to help benefit blood circulation (van Beek & Montoro, 2009). Since then, it has slowly gained more attention until suddenly a flurry of research appeared in the 1990s to the present day. In 2020 alone, new research from Achebe de Souza, et al. (2020) shows that Ginkgo biloba extract (GBE) helps reduce oxidative stress (the loss of body tissue) and slows the dysfunction of organs and aging at a cellular and molecular level. Previous research indicates that as a topical antimicrobial, the seeds can be used to treat skin infections such as Streptococcus pyogenes, which causes Necrotizing Fasciitis, and Cutibacterium acnes, which causes plenty of teenage acne – and heartbreak (Chassagne, et al., 2019). Additionally, it has been found through this research that G. biloba can also treat: claudication, pain, dementia, peripheral arterial disease, post-thrombotic syndrome, anxiety, depression, headaches, Alzheimer’s disease, and stabilize blood sugar (Jacobs & Browner, 2000; Kreijkamp-Kaspers, et al., 2015; Keheyan, Dunn, & Hall, 2011; Mindell & Hopkins, 2003; Kupiec & Raj, 2005; Tyler, 1993). It is now one of the most popular phytotherapeutic products in the world (Achete de Souza, et al., 2020).

Speculated Use

It is hopeful that some new uses can be initiated, such as help with kidney dysfunction or with other mental health issues such as Attention Deficient with Hyperactivity Disorder [ADHD] (Adderly, 1998). It has also been suggested to complete further research into ginkgo as a solution for multi-drug resistant bacterias, through the plants’ secondary metabolites, and into the neuroprotective effects (Chassagne, et al., 2019). It is also listed as the “logical choice” for treated carpal tunnel syndrome by Mindell & Hopkins, (2003), in a book full of homeopathic and natural remedies for every type of ailment imaginable.

Conclusion

Despite its long history and ability to survive quite literally anything, this incredible plant is listed as a threatened species. This is likely due to its very specific and long germination and growth cycles. This plant has a low seed germination rate and a long juvenile phase. It can live in temperate and subtropical climates, but if the soil is too wet or too dry then it will not grow well. Conservation strategies have selected for high-yielding individuals, but the low yield of compounds in undifferentiated tissue are impediments to the supply of ginkgo and therefore, GBE. Thankfully, large-scale initiatives for plantations to conserve the populations are occurring in China, France, and Germany (Isah, 2015). It is hoped that the many health benefits of ginkgo, alongside its use as a food for humans and animals, with its ability to produce large amounts of oxygen, will result in increased research efforts and conservation. This could help to reverse some of the human damage done to the ozone, causing climate change. In addition, it could be a unique way to combat infectious diseases for other plants and humans, which is all the more important as we live through the second year of the Coronavirus (SARS-CoV-2) pandemic. If we take the lessons of the trees’ history and we listen to one another, as we should in science (and as humans), then we can take the steps to not only save this Paleobotanical wonder but also to potentially save humankind.

References

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Author: V. Anne Burg, MPH, LinkedIn