Limitations of Conventional Treatments Invite Research on Herbs

Dementia is a neurodegenerative disease that causes progressive impairments in memory and learning, executive functioning and activities of daily living. There are more than 47.5 million people with dementia worldwide and 7.7 million new cases are added to the dementia pool each year. Increased risk of vascular dementia (VaD) is associated with obesity, hypertension, cardiovascular disease and cerebrovascular accidents (i.e. ‘stroke’). VaD accounts for 10 to 15% of all cases of dementia in industrialized countries and 30% of dementia cases in less developed world regions and is the second most prevalent form of dementia after Alzheimer’s disease (AD). Over 40% of vascular dementia cases also have AD neurodegenerative pathology, representing the most common type of mixed dementia.

Available pharmacologic agents such as cholinesterase inhibitors and glutamate receptor antagonists are helpful in some cases of AD but have limited efficacy against VaD. The result has been that many people with VaD are using herbs and other complementary and alternative (CAM) approaches such as acupuncture, nutraceuticals, yoga, tai chi, and music therapy. 

Many herbs used in Chinese medicine have been investigated alone and in different combinations for their potential beneficial effects on symptoms of AD and VaD, including Ginkgo biloba, Huperzia serrata, Curcuma longa, Panax ginseng, Panax notoginseng, Bacopa monnieri, Salvia miltiorrhiza, Crocus sativus, and Camellia sinensis. Below is a concise review of studies on single Chinese herbs and complex Chinese herbal formulas being investigated for their potential cognitive enhancing benefits in healthy adults and individuals with dementia.  

Single Herbs are Beneficial but Limited

Recent findings suggest that Ginkgo biloba extracts improve learning and memory in animal models of VaD. Large placebo-controlled studies and meta-analyses of studies that meet strict inclusion criteria for rigor support that G. biloba extract slows the rate of decline in cognition, executive functioning and behavior in individuals diagnosed with AD and VaD. Proposed mechanisms by which G. biloba enhances brain function resulting in improved memory and cognitive functioning include decreased activity of pro-inflammatory macrophages, improved blood flow, reduced activity of platelet-activating factor (which reduces stroke risk), reduced corticosteroid production and increased glucose uptake, enhancing neural stem cell proliferation, accelerating synaptic plasticity following brain injury, reducing circulating free cholesterol, and reducing brain β-amyloid precursor protein production.

Curcuma longa (turmeric) has been used for centuries in Chinese, Hindu, and Ayurvedic medicine for centuries for numerous medical disorders including pancreatitis, arthritis, cancer, and inflammatory, neurodegenerative, and digestive disorders. Animal and in vitro studies suggest that cognitive enhancing benefits of curcumin are based on multiple mechanisms of action including inhibition of lipid peroxidation, scavenging reactive oxygen species (ROS), and reactive nitrogen species, inhibition of NF-kB activation, and its anti-inflammatory actions. Curcumin may also directly bind small beta-amyloid species to block aggregation and the formation fibrillary tangles. In a 24 month randomized clinical trial 36 patients with mild to moderate AD randomized to curcumin (2 and 4gm/day) vs placebo experienced equivalent non-significant changes in cognition and memory. These findings may be due in part to the low bioavailability of the curcumin preparation used in the study. 

Findings of animal studies suggest that bioactive constituents of Panax ginseng may improve cognition and memory in patients with dementia. Ginsenoside Rg5 reduces amyloid-β and cholinesterase activity, and ginsenoside Rg3 promotes β-amyloid peptide degradation via enhancing gene expression. Panax ginseng may also decrease blood pressure and improves blood circulation by enhancing vasodilation. Two open 12-week trials suggest that ginseng may improve cognition in individuals diagnosed with AD. In two recent small open trials individuals diagnosed with AD who received P. ginseng in doses of 4.5 and 9gm/day, experienced significant improvement in cognition and memory. Findings of two small placebo-controlled trials suggest that Panax notoginseng improves cerebral blood flow and enhances memory in individuals diagnosed with VaD.  

Bacopa monnieri (Brahmi) has neuroprotective and antioxidant effects, works as a free radical scavenger and may increase cerebral blood flow. The herbal is widely used in Ayurvedic medicine for memory problems. Studies on cognitive enhancing benefits of the herbal in healthy adults and individuals diagnosed with AD are currently ongoing. 

Saffron (Crocus sativus) is used in Chinese medicine as antidepressant, antispasmodic, and anticatarrhal. Extracts containing crocin have antioxidant and antiplatelet properties and have been shown to improve learning and memory in animal models of dementia. In a 22-week double-blind randomized clinical trial AD patients randomized to saffron 30mg/day and the cholinesterase inhibitor donepezil 10mg/day showed comparable improvements in cognition while saffron was better tolerated. In a16-week double-blind trial AD patients who received saffron responded significantly better than the placebo group.

Tea (Camellia sinensis) is widely consumed for health, contains epigallocatechin-3-gallate (EGCG), which has neuroprotective benefits mediated by anti-inflammatory effects, its role as a free-radical scavenger, and others. Individuals who frequently drink tea may have a reduced risk of developing AD. Two prospective studies found that regular consumption of green tea in the elderly is associated with a relatively lower risk of cognitive impairment and dementia. 

Findings of studies on single herbs in dementia are limited by small sample sizes of individual clinical trials, poor methodological quality, and short study duration. Further, plasma concentrations of bioactive constituents of many single herbs may be too low to have beneficial effects suggesting that observed improvements in cognition may be related to synergistic interactions between two or more bioactive constituents. Chinese medicine and other Asian systems of medicine often employ combinations of herbs, possibly resulting in synergistic interactions between discrete bioactive constituents that may more effectively target diseases with complex etiologies such as AD and VaD. A novel research method called system-to-system analysis has recently been applied to the study of complex synergistic interactions in herbal formulas. 

The Promise of Complex Herb Formulas

Only a few studies have been done on complex herbal formulas in VaD. While some have reported positive findings, the significance of findings is limited by small study size and methodological flaws. A 2012 systematic review of studies on complex herbal formulas in VaD reported that the majority of formulas examined resulted in significantly greater improvements in cognitive functioning compared to conventionally used medicines or placebo. 4 studies in which herbal medicines were combined with conventional medicines reported better cognitive functioning compared to conventional medicines alone, however, the significance of these findings is limited by serious methodological flaws. A more recent meta-analysis included 24 randomized clinical trials (all conducted in China) on individuals diagnosed with VaD. In a subgroup analyses complex Chinese herbal interventions significantly enhanced cognitive function when compared to piracetam (in 10 studies) or placebos (in 3 studies). Individuals receiving herbal medicine experienced greater improvements in activities of daily living compared to those treated with piracetam. However, as in the above studies, the significance of findings was limited by methodological flaws.  

Ongoing Efforts to Develop a Complex Herb Formula for Vascular Dementia

In response to the above challenges for over a decade, a collaborative effort has been ongoing between the Academy of Chinese Medical Sciences and Western Sydney University to develop a standardized complex herbal formulation for the treatment of VaD. The formula, called SLT, contains standardized preparations of Ginkgo biloba (ginkgo), Panax ginseng (ginseng), and Crocus sativus (saffron) extracts. 

The optimal ratio of bioactive constituents and the optimal dosage of SLT were determined through a series of animal studies. Preclinical trials demonstrated significant improvement in learning and memory, markers of neuropathology and antioxidant activity in animal models of dementia. At the time of writing large phase III studies are underway to establish efficacy in individuals diagnosed with VaD. Cumulative findings from preclinical trials have demonstrated numerous cerebrovascular benefits of SLT including decreased areas of focal cerebral ischemia/reperfusion injury, decreased platelet aggregation, and increased free radical scavenging activity. 

Individuals treated with SLT or placebo have the same risk of adverse effects. In a small 1-week RCT, 16 healthy adults randomized to SLT experienced improvements in working memory. In a small phase II study individuals diagnosed with probable VaD randomized to SLT showed significantly greater improvement in cognitive functioning, and a subset showed increased blood flow in brain regions associated with memory, auditory and speech processing. A second 12-month phase II study on 325 individuals with probable VsD found similar cognitive improvements either phase II study reported SLT-related serious adverse events. At the time of writing two multicenter phase III trials are ongoing. Pending confirmation by phase III findings, SLT may emerge as an evidence-based herbal treatment of VsD, a neurodegenerative disorder for which there is presently no effective treatment. 

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