Ginkgo Biloba for Treating Anxiety

Ginkgo Special Extract EGb 761® Demonstrates Efficacy in Treatment of Anxiety and Mild to Moderate Dementia with Neuropsychiatric Symptoms — American Botanical Council

Ginkgo Biloba for Treating Anxiety

Reviewed: Napryeyenko O, Borzenko I [GINDEM-NP Study Group]. Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57(1):4-11.

Two recently published clinical trials demonstrate that a ginkgo (Ginkgo biloba, Ginkgoaceae) special extract is effective in treating various cognitive disorders. This ginkgo special extract is called EGb 761® (Willmar Schwabe Pharmaceutical Co.

, Karlsruhe, Germany; imported into the United States and distributed as Ginkgold® by Nature’s Way of Springville, UT). EGb 761 is a phytomedicine used in patients with dementia disorders and is licensed in 70 countries worldwide.

The results of 2 large trials have shown that this extract improves cognitive performance, activities of daily living, and social functioning.1,2 EGb 761 is standardized to contain 22–27% flavonol glycosides and 5–7% terpene trilactones (ginkgolides and bilobalides).

In the 2 clinical trials featured in this summary, the extract was tested for its efficacy in treating generalized anxiety disorder and dementia, respectively.

The Woelk et al Trial

Generalized anxiety disorder (GAD) and adjustment disorder with anxious mood (ADWAM) are frequent reasons for seeking medical help.

Patients with GAD have been shown to respond favorably to psychotherapy and pharmacotherapy, including benzodiazepines, buspirone, and antidepressants (especially the serotonin and norepinephrine uptake inhibitors).

However, these drugs are all associated with various unfavorable side effects. Evidence of the effectiveness of treatments for ADWAM is lacking.

The aim of the first randomized, double-blind, placebo-controlled trial was to determine whether the anxiety-alleviating effects of EGb 761 observed in other patient populations would translate into clinically meaningful effects in patients with specified non-psychotic and non-phobic types of anxiety.

The trial contained 107 patients aged 18–70 years with GAD or ADWAM—established in accordance with the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition revised.

The patients were enrolled by 15 private practices of medical specialists and by the outpatient clinic of a psychiatric hospital associated with the University of Erlangen-Nuremberg in Bavaria.

Patients were compliant during a 7-day qualification period and their Hamilton Rating Scale for Anxiety (HAMA) did not change more than 7 points in either direction during the qualification period. The patients were randomly assigned by the investigators to 1 of 3 treatments: high-dose EGb 761, low-dose EGb 761, or placebo.

Over a 4-week study period, the patients took 2 EGb 761 tablets containing either 40 mg (240 mg/day) or 80 mg (480 mg/day) or a placebo 3 times per day. It is unclear how the investigators chose the doses since the “low dose” referred to in this trial is the same as the normally-recommended high dose (240 mg/day) for ginkgo extract while the “high dose” in this trial was double the normally-recommended high dose.

The primary outcome measure was the HAMA score, which was determined at baseline and on days 4, 8, 15, and 29. Secondary outcomes included the safety and tolerability of the treatment as well as clinician- and patient-determined improvements in condition.

The decrease in HAMA score was significantly greater in both ginkgo groups (P = 0.0003 for the high-dose group and P = 0.01 for the low-dose group) than in the placebo group. Scores decreased (mean ± standard deviation) by 14.3 ± 8.1, 12.1 ± 9.0, and 7.8 ±

9.2 in the high-dose, low-dose, and placebo groups, respectively. A greater than 50% reduction in the HAMA score was observed in 44% of the high-dose group, in 39% of the low-dose group, and in 22% of the placebo group.

Total remission of the patients’ disorder, defined as a total HAMA score less than/equal to 7 on day 29 of the study, was achieved by 9%, 8%, and 5% of the high-dose, low-dose, and placebo groups, respectively.

Using global judgment scales, the clinicians determined that 81%, 67%, and 38% of the patients in the high-dose, low-dose, and placebo groups, respectively, were “much improved” or “very much improved”; 78%, 61%, and 30% of these same groups, respectively, rated their condition as at least “markedly improved.” Nine adverse events were reported during randomized treatment (3 in each group); none of these events were deemed to be serious.

The results suggest that “EGb 761® has a specific anxiolytic effect that is dose-dependent and significantly exceeds the placebo effect commonly seen in trials of psychoactive drugs.” The improvement seen with EGb 761 was similar to that observed for the class of anti-anxiety drugs known as benzodiazepines in previous studies.

Although the mechanism of the observed effect of EGb 761 is not clear, suppression of corticotrophin-releasing hormone is one possibility.

Because of the excellent tolerability, lack of serious adverse effects, and absence of risk of dependence associated with this extract, the authors believe it to be suitable for treating both young and elderly patients with GAD and ADWAM.

The Napryeyenko and Borzenko Trial

The purpose of the second study was to assess the efficacy of ginkgo in patients with dementia and neuropsychiatric symptoms (also known as BPSD: Behavioral and Psychological Symptoms of Dementia). Studies show that neuropsychiatric symptoms are very common in people with dementia.

One study reported that 36% of patients with dementia have apathy, 32% have depression, and 30% have agitation/aggression.3 Moreover, neuropsychiatric symptoms start early in the course of the disease.

The clinical efficacy of ginkgo in dementia has been demonstrated in previous clinical trials.

This large randomized, double-blind, multicenter study with parallel treatment groups was conducted in Kiev, Ukraine, and elsewhere.

Patients (n=400) with clinically evaluated mild to moderate dementia and moderate neuropsychiatric symptoms participated in the trial. Patients were medication free for up to 4 weeks prior to randomization.

Patients received either placebo or EGb 761 at 240 mg/day for 22 weeks. At weeks 12 and 22, patients underwent a battery of cognitive and neuropsychiatric tests.

Patients treated with EGb 761 improved with respect to the neuropsychiatric symptoms and activities of daily living. In contrast, those who received placebo deteriorated slightly or remained unchanged. EGb 761 was significantly superior to placebo with respect to all efficacy variables (P < 0.001). Of those treated with EGb 761, 65.

7% had a clinically meaningful improvement in cognitive functioning compared to 6.1% of those in the placebo group. There was a 35% decrease in caregiver distress (related to patients’ behavioral and psychiatric symptoms) in caregivers of patients treated with EGb 761 compared with a 4% increase in such distress in caregivers of patients receiving placebo.

Fewer people in the EGb 761 group reported adverse events compared to the placebo group.

These results corroborate other studies of EGb 761 in dementia. EGb 761 was well tolerated. There was a marked reduction in caregiver burden as a consequence of EGb 761 treatment.

One strength of this trial is that patients were recruited the mainstream daily practice and thus the eligibility criteria were less restrictive than those employed in other studies. The authors conclude that patients suffering from both cognitive and neuropsychiatric symptoms of dementia can benefit from EGb 761.

The study was well designed and reported, which gives additional support for their findings. The study was sponsored and funded by Schwabe.


  1. Kanowski S, Herrmann WM, Stephan K, Wierich W, Horr R. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry. 1996;29:47-56.
  2. Le Bars PR, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF.

    A placebo-controlled, double-blind randomized trial of an extract of Ginkgo biloba for dementia. JAMA. 1997;278:1327-1332.

  3. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky

S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment. Results from the Cardiovascular Health Study. JAMA. 2002;288:1475-1483.


A Systematic Review and Meta-Analysis of Ginkgo biloba in Neuropsychiatric Disorders: From Ancient Tradition to Modern-Day Medicine

Ginkgo Biloba for Treating Anxiety

Ginkgo biloba (Gb) has demonstrated antioxidant and vasoactive properties as well as clinical benefits in several conditions such as ischemia, epilepsy, and peripheral nerve damage. Additionally, Gb is supposed to act as potential cognitive enhancer in dementia.

So far, several trials have been conducted to investigate the potential effectiveness of Gb in neuropsychiatric conditions. However, the results of these studies remain controversial.

We conducted a systematic review and a meta-analysis of three randomised controlled trials in patients with schizophrenia and eight randomised controlled trials in patients with dementia.

Gb treatment reduced positive symptoms in patients with schizophrenia and improved cognitive function and activities of daily living in patients with dementia. No effect of Gb on negative symptoms in schizophrenic patients was found.

The general lack of evidence prevents drawing conclusions regarding Gb effectiveness in other neuropsychiatric conditions (i.e., autism, depression, anxiety, attention-deficit hyperactivity disorder, and addiction). Our data support the use of Gb in patients with dementia and as an adjunctive therapy in schizophrenic patients.

1. Introduction

Ginkgo biloba (Gb) is one of the most ancient seed plant, often referred to as a “living fossil.” This large tree may live over 1000 years and reach 40 m of height. Originally native to China, Gb is now cultivated worldwide.

Extract from Gb leaves has been used in traditional Chinese medicine for centuries to treat circulatory disorders, asthma, tinnitus, vertigo, and cognitive problems [1]. Today, Gb extracts are one of the most commonly taken phytomedicines globally [2] and are often prescribed in Europe as a nootropic agent in old age and dementia [3].

Of note, since 2000, Gb extract is included in ATC-classification as an anti-dementia drug together with cholinesterase inhibitors and memantine [4]. Gb extract contains mainly terpenoids, flavonol glycosides, and proanthocyanidins. The most prevalent of these three groups are the flavonol glycosides (quercetin, catechin).

The terpenoids include ginkgolides and bilobalides, which represent unique components of Gb. Terpenoids, flavonoids and proanthocyanidins are thought to be responsible for the pharmacological properties of Gb [1].

On the basis of animal studies, several mechanisms have been proposed to explain the pharmacological properties of this plant: extract from Gb leaves inhibits platelet-activating factor [5] and enhances NO production in vessels, with subsequent effect on peripheral and cerebral blood flow [6].

Gb extract is thought to module different neurotransmitter systems: it is a strong inhibitor of monoamine oxidase A and synaptosomal uptake of DA, 5-HT, and norepinephrine [7–9].

Additionally, Gb displays a free radical scavenger activity and has neuroprotective and antiapoptotic properties, such as inhibition of amyloid-β neurotoxicity and protection against hypoxic challenges and increased oxidative stress [10–12]. Several previous reviews have been mainly focused on the potential efficacy of Gb in dementia. However, inconsistent and controversial results have been reported [13–16]. On the other hand, to date no systematic review has been conducted on the effect of Gb on neuropsychiatric disorders other than dementia. Therefore, we aimed to perform a systematic review on the effects of Gb in different psychiatric conditions.

2. Methods

In April 2012, we searched the following databases: MEDLINE, EMBASE, PsycINFO, and the Cochrane Database of Systematic Reviews.

The search terms were as follows: ginkgo biloba (gingko biloba; ginkgo; ginko; gingko; bilobalid*; egb 761) and dementia (dementia OR cognitive impairment OR Alzheimer), autism (autism OR autistic spectrum disorder), schizophrenia (schizophrenia OR psychosis OR psychotic disorder OR delusion), depression (depression OR major depression OR depressive symptom), anxiety (anxiety OR generalized anxiety disorder OR anxious), attention-deficit/hyperactivity (ADHD) (attention deficit disorder OR ADHD or attention deficit OR hyperactivity), and addiction. All search terms were searched individually in each database and combined together. The search strategy had no time restriction but was limited to articles in English, Italian, French, Spanish, and German. Additionally, all recovered papers were reviewed for further relevant references. Researchers in the field were reached to obtain additional or unpublished data, if available.

We selected controlled randomized clinical trials, yielding primary results on the effects of the administration of Gb extracts in neuropsychiatric patients.

Every neuropsychiatric disorder was defined according to internationally valid diagnostic criteria such as the International Classification of Diseases (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM).

Other inclusion criteria were a minimum number of participants of ten per group, a treatment period of at least 6 weeks, and the availability of a full-text publication. Of note, all the included studies in the meta-analysis were conducted using the standardized Gb extract Egb 761, which is the most commonly used form of Gb [17].

Two researchers (NB and SR) independently reviewed all information about the articles provided by the databases. Any discrepancies were solved by consensus. We assessed the quality of the study design, duration of the study, comparability of study groups, and clinical outcomes on different widely used rating scales.

The following rating scales were accepted for clinical outcomes: (1) dementia: cognition: Syndrom-Kurz test (SKT) [18], Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-cog) [19]; activities of daily living (ADL): Alzheimer’s Disease Activities-of-Daily-Living International Scale (ADL-IS) [20], Geriatric Evaluation by Relatives Rating Instrument (GERRI) [21], Gottries-Bråne-Steen-Activities of Daily Living (GBS-ADL) scale [22], Nürnberger Alters-Alltagsaktivitäten-Skala (NAA), and Nürnberger Alters-Beobachtungsskala (NAB) [23]; (2) schizophrenia: Scale for the Assessment of Positive (SAPS) [24] and Negative (SANS) Symptoms [25], Brief Psychiatric Rating Scale (BPRS) [26], (3) autism: Aberrant Behavior Checklist-Community (ABC-C) [27]; (4) Attention-Deficit/Hyperactivity Disorder (ADHD): Parent and Teacher ADHD Rating Scale-IV [28], Conners’ Parent Rating Scale-Revised [29]; (5) anxiety: Hamilton Rating Scale for Anxiety (HAMA) [30], State-Trait Anxiety Inventory (STAI) [31]; and (6) tardive dyskinesia: Abnormal Involuntary Movement Scale (AIMS) [32].

When it was possible, data were pooled by means of meta-analysis. Effect measures on rating scales were expressed as standardized mean differences (SMDs) with the 95% CIs. A random-effects model (DerSimonian-Laird) was used to calculate a pooled effect estimate, because of heterogeneity. A value


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