Ginko Biloba Leaves Extract for the Treatment of Anxiety, Stress, and Depression

Anxiety, stress and depression are exceedingly comorbid psychological illnesses that the predominance will expand to the second most important risk of morbidity and sociodemographic burden. Due to several side-effects of chemical drugs, numerous specialists and patients prefer complementary herbal therapies like Ginkgo Biloba Extracts (GBE) to medicate the illnesses. In this review, we summarized the antidepressant, anxiolytic and antistress properties of GBE. We perceived that GBE could be beneficial for treatment of these disorders. Although experience of repeated studies on models and humans have proved reliability of antidepressant properties of GBE, further clinical trials are still required to validate the anti-stress and anti-anxiety effects of GBE on humans. ASEAN Journal of Psychiatry, Vol. 23(4): April 2022:1-7.


Introduction
Anxiety and depression are universal brain disorders approximately 7.3% and 7% prevalence. These disorders are characterized by stress-linked mood problems and may cause early death [1,2]. Surprisingly, the prevalence of depression is 3 times higher in young people and women are 1.5 times to 2 times more susceptible to anxiety and depression [3,4]. Sleep disorder, weight loss or gain, retardation, fatigue, concentration and decision-making challenges, and even tenderness of suicide are the most reported depression symptoms [5]. Furthermore, these complications caused a significant number of years of life lost to disability in multiple countries [6]. Therefore, controlling mental health challenges became an important aim for many researchers [7]. Scientists have long been aware of the close relationship between anxiety and depression [8]; moreover, notable comorbidities of these patients cause several difficulties in treatment [9]. For several years, diazepam, defined as Ben Zo Diazepine (BZD), has long been a routine treatment for depression. Over time, specialists replaced diazepam with alprazolam due to its lesser sedation [10]. Despite the proper efficiency of these treatments, all these therapies have considerable adverse effects as well [11].
Herbal therapies have been used for a long time to treat depression. For many years, scientists carried out many trials to target monoamine transmission systems of the brain, such as Norepin Ephrine (NE), 5-Hydroxytryptamine (5-HT), and dopamine. 20(S)-protopanaxadiol, extracted from ginseng, developing NE and 5-HT in the mice brain and decrease depression pathogenesis. Moreover, paeonia lactiflora pall is another traditional Chinese treatment that restricts depression symptoms. The root extract of this blessed species diminishes monoamine oxidase activity. Albizia julibrissin, Perilla frutescens and several components of Rhodiola rosea are the other ancient candidates for depression treatment. To date, the herbal treatments for anxiety have been emphasized on repairing dysregulated brain mechanisms, such as noradrenergic, glutamatergic, and serotonergic pathways. For example, Bacopa monnieri restricts anxiety by enhancing 5-HT2C receptors. Studies on other species, like valeriana officinalis, centalla asiatica, humulus lupulus, and matricaria recutita showed detectable anti-anxiety properties, based on inhibiting glutamate receptors. Ginkgo Biloba Extract (GBE) is another promising herbal treatment for several mental disorders such as dementia and anxiety. Besides, GBE downregulates 5-HT, domapin and NE uptake through an unclear mechanism. Herein, we review the different aspects of GBE effects on depression, anxiety, and stress.

Methods
This study reviews the data about Ginko biloba leaves extract for the treatment of anxiety, stress, and depression. English articles were searched up to December 2020 through various databases including ISI Web of Science, SID, Google Scholar, PubMed, Scopus, and Science Direct. The searched keywords included Ginko biloba, Antidepressant, Anxiolytic, and Antistress. The references of the relevant studies were also searched manually.

Anti-stress effects of GBE
In 1994 to evaluate the anti-stress properties of Ginkgo biloba (G. biloba) leaves among young and old rodent models. The extract of these leaves showed a detectable development of plasma hormones such as norepinephrine, corticosterone, and epinephrine; moreover, despite noxious environmental influences, GBE ameliorates cognitive impairment, especially in old rats. Although the next study on Ginkgo showed relatively encouraging treatments for memory and aging-related cognitive disorders but started a new quarrel about anti-stress uses of GBE. Further, Rai et al. carried out another experimental trial on herbal treatments against Chronic Stress (CS) and Acute Stress (AS) to measure anti-stress effects of GBE and Panax ginseng. This study demonstrated that GBE has better success in treating acute stress and Panax ginseng for the latter.
In the following, scientists tried lipophilic extracts of Ginkgo leaves (LEG). This study introduced intact carboxylic acid, one of the LEG bioactive components, as a promising anti-depressant and anti-stress agent. Supporting previous results, another trial on mice treated with GBE showed significant anti-stress effects; furthermore, analyzing cortex and hippocampus samples demonstrated no detectable immunoreactivity effect on Cyclic-AMP response element-binding protein. Recently, introduced GBE as a protecting treatment. GBE successfully preserved rodent models against chronic unpredictable mild stress. Therefore, future trials on humans are required to prove the clinical function of this blessed species in controlling stress (Table 1).

Author/year
In-vivo studies Outcomes

Rapin et al./ 1994
In first stage, Mice were allowed to adapt environment for 15 days. Models were divided to different groups based on age 4 months and 20 months and administration placebo, 50 or 100mg/kg GBE). Daily inoculation occurred half an hour before exams continued for 3 weeks.
GBE repaired stress symptoms in both ages. These results proved G. biloba leaves as a promising therapy for stress.

Rojas et al./ 2011
The study contains 2 control groups (1.Saline without FST/2.Saline with FST) and 2 intervention groups (A.15mg/kg imipramine with FST and B.40mg/kg, 20mg/kg, 10mg/kg or 5mg/kg GBE with FST). After 17 days of implementing FST following injection, analysis of brain tissue and hormone levels performed.
GBE resulted in 39% decrease in immobility of models in FST.

Chen et al./ 2019
The experimental models divided into 2 groups: 1) 300mg/kg GPS 2) 30mg/kg paroxetine. Treatment continued for 4 weeks and 3 days experimentation in the following. Hence, we require designing novel extended trials among human subjects to light more aspects of GBE and its combinations with other therapies in controlling depression.

Anxiolytic effects of GBE
From the first studies, GBE showed unique antianxiety effects. In an experimental trial, flumazenil significantly neutralized traditional therapies diazepam but showed no obstruction on GBE activities. Surprisingly, low and high doses of GBE showed reliable efficiency and safety in controlling anxiety. Furthermore, combining GBE regimen with traditional therapies improved anxiety, fatigue and tiredness through enhancing cerebrovascular perfusion and strong antioxidant activities. Despite GBE provides reliable treatments with and without other drugs for anxiety, further studies are still required to discover all aspects of this merciful herbal treatment.

Conclusion
Extract of G. biloba leaves showed promising efficiency and safety in several studies. The different components of G. biloba control mental disorders through regulating neurobiological mechanisms such as dopamine, serotonin and inflammatory glial-derived proteins. Despite the long history of repeated studies on rats and humans, that proved GBE as a reliable antidepressant treatment, we require further clinical trials to evaluate the anxiolytic and anti-stress effects of GBE on humans.