Herbal Medicine in
the Treatment of Alzheimer's Disease

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Am J Alzheimers Dis Other Demen. 2006 (Mar); 21 (2): 113–118 ~ FULL TEXT

Akhondzadeh S, Abbasi SH.

Psychiatric Research Center,
Roozbeh Hospital,
Tehran University of Medical Sciences,
Tehran, Iran.

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Alzheimer's disease (AD) is characterized by profound memory loss sufficient to interfere with social and occupational functioning. It is the most common form of dementia, affecting more than 20 million people worldwide. AD is characterized by an insidious loss of memory, associated functional decline, and behavioral disturbances. Patients may live for more than a decade after they are diagnosed with AD, making it the leading cause of disability in the elderly. The incidence of AD ranges from 1 to 4 percent of the population per year, rising from its lowest level at ages 65 to 70 years to rates that may approach 6 percent for those over the age of 85 years. The first neurotransmitter defect discovered in AD involved acetylcholine (ACh). As cholinergic function is required for short-term memory, the cholinergic deficit in AD was also believed to be responsible for much of the short-term memory deficit. Clinical drug trials in patients with AD have focused on drugs that augment levels of ACh in the brain to compensate for the loss of cholinergic function. These drugs have included ACh precursors, muscarinic agonists, nicotinic agonists, and acetylcholinesterase inhibitors. The most highly developed and successful approaches to date have employed acetylcholinestrase inhibition. Although some Food and Drug Administration-approved drugs are available for the treatment of Alzheimer's disease, the outcomes are often unsatisfactory, and there is a place for alternative medicine, in particular, herbal medicine. This paper reviews the clinical effects of a number of commonly used types of herbal medicines for the treatment of AD.

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From the FULL TEXT Article

Pharmacologic treatment

While no drug has been shown to completely protect neurons, agents that inhibit the degradation ofACh within the synapse are the mainstay of treatment for AD. Acetylcholinesterase/cholinesterase inhibitors and memantine are the only agents approved by the Food and Drug Administration for the treatment of AD. Other drugs, such as selegiline, vitamin E, estrogen, and antiinflammatory drugs have been studied, but their use remains controversial. [20, 21] Various other agents have been used in an attempt to modify the course or improve the symptoms ofAD, including Ginkgo biloba. [22-24] The cholinesterase inhibitor tacrine is used rarely because of potential liver toxicity and the need for frequent laboratory monitoring. Nevertheless, donepezil, rivastigmine, and galantamine have low incidences of serious reactions, but they commonly have cholinergic side effects such as nausea, anorexia, vomiting, and diarrhea. [20-24]

Many of today's synthetic drugs originated from the plant kingdom, and only about two centuries ago the major pharmacopoeias were dominated by herbal drugs. Herbal medicine went into rapid decline when basic and clinical pharmacology established themselves as leading branches of medicine. Nevertheless, herbal medicine is still of interest in many diseases, in particular, psychiatric and neurological disorders. There are some reasons for this issue: 1) patients are dissatisfied with conventional treatment, 2) patients want to have control over their healthcare decision, and 3) patients see that herbal medicine is congruent with their philosophical values and beliefs. [20] There are several studies and documents that indicate a unique role of herbal medicines in the treatment ofAD.

Galantamine

An alkaloid cholinesterase inhibitor originally derived from European daffodils or common snowdrops, this drug is a competitive and selective acetylcholinesterase inhibitor. Galantamine also allosterically modifies nicotinic ACh receptors, potentiating the presynaptic response to ACh. Like donepezil and rivastigmine, galantamine is brain selective. Galantamine has a half-life of five to six hours and is metabolized by the same CYP-450 enzymes as donepezil. Galantamine has not been associated with hepatotoxicity in clinical trials. [20, 25] Pooled data from four randomized trials of patients with mild AD indicate that patients who received galantamine 24 mg/d for six months had improved cognition more often than those who received placebo, and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment. [20, 25]

Ginkgo biloba

Ginkgo biloba is an herbal medicine that has been used to treat a variety of ailments for thousands of years in China. An extract of Ginkgo biloba has been found in several studies to improve the symptoms and slow the progression of AD. A study of 309 patients with mild dementia was performed. The patients were given either 120 mg of Ginkgo biloba extract (GBE) or placebo every day for up to a year. [26] At the six-month point, 27 percent of those using Ginkgo biloba had moderate improvement on a variety of cognitive tests. Only 14 percent of those using placebo had an improvement on these tests. In a separate trial, 112 patients with chronic cerebral insufficiency received 120 mg/d of GBE. [27] The researchers found that the use of this extract led to significant improvements in blood and oxygen flow. Restricted blood and oxygen flow to the brain may be an important factor in the development of AD.

GBE appears to be most effective in the early stages of AD. This could potentially mean that patients with early AD may be able to maintain a reasonably normal life. GBE has been shown to have the ability to normalize the ACh receptors in the hippocampus area of the brain (the area most affected by the disease) in aged animals. [28] GBE has also demonstrated the ability to increase cholinergic activity and to provide improvements in other aspects of the disease. [29] A double-blind study of 216 patients with AD or dementia caused by small strokes found that 240 mg of GBE daily led to significant improvements in a variety of clinical parameters when compared to placebo. [30] The most effective form of GBE is one that is standardized to a concentration of 24 percent Ginkgo flavoglycosides.

A study compared the effectiveness of the most common AD drugs, such as donepezil and rivastigmine, to that of a Ginkgo biloba extract called EGb761. [31] The researchers determined that EGb761 was as effective as any of these commonly prescribed drugs in treating the symptoms ofAD patients. In general, various forms of Ginkgo biloba have been found to be safe, but in individuals who take aspirin or other anticoagulant drugs, Ginkgo biloba should be taken with great caution and with the advice of a physician. Ginkgo biloba is sold as a drug and regulated in Germany, and it is used in many other parts of the world to slow the progression of various forms of dementia. The most commonly sold form of Ginkgo biloba in Europe is EGb761 (80 to 120 mg/d).

A different study found that EGb76 1 prevents f-amyloid toxicity to brain cells, a key part ofthe development of the disease. [32] All forms of Ginkgo biloba need to be taken consistently for at least 12 weeks, a potentially difficult task for AD patients, to determine whether the supplement is working. A recent double-blind placebo-controlled randomized study of patients with AD found that EGb761 produced significant improvements in cognitive function compared to a placebo group. [33] Other recent comprehensive surveys of multiple clinical trials found similar results with EGb761 in these patients. [33] An additional study found that EGb76 1 produced cognitive improvement compared to placebo over a 26-week period using a variety of research measures. This study also demonstrated that EGb76 1 was as safe as placebo during the study period. [33] Nevertheless, the clinical trial data for cholinesterase inhibitors, reported in reviews by the Cochrane Collaboration, appear to be more consistent and robust than those for Ginkgo biloba, and also show greater effects on cognition. Considering the evidence, it is suggested that cholinesterase inhibitors should be used in preference to Ginkgo biloba in patients with mild to moderate AD. [34]

Huperzine A

Huperzine A is a chemical derived from a particular type of club moss (Huperzia serrata). Like caffeine and cocaine, huperzine A is a medicinally active plantderived chemical that belongs to the class known as alkaloids. This substance is really more a drug than an herb, but it is sold over the counter as a dietary supplement for memory loss and mental impairment.

According to three Chinese double-blind trials enrolling a total ofmore than 450 people, use of huperzine A can significantly improve symptoms ofAD and other forms of dementia. [35-37] One double-blind trial failed to find evidence of benefit, but it was relatively small. [38]

Vinpocetine

Vinpocetine is a chemical derived from vincamine, a constituent found in the leaves of common periwinkle (Vinca minor) as well as the seeds of various African plants. It is used as a treatment for memory loss and mental impairment.

Developed in Hungary more than 20 years ago, vinpocetine is sold in Europe as a drug under the namc Cavinton. In the United States, it is available as , "dietary supplement," although the substance probably does not fit that category by any rational definition. Vinpocetine does not exist to any significant extent in nature. Producing it requires significant chemical work performed in the laboratory.

Several double-blind studies have evaluated vinpocetine for the treatment of AD and related conditions. [39-45] Unfortunately, most of these studies suffered from significant flaws in design and reporting. A review of the literature found three studies of acceptable quality, enrolling a total of 728 individuals. [39] Perhaps the best of these was a 16-week double-blind placebo-controlled trial of 203 people with mild to moderate dementia that found significant benefit in the treated group. [39] However, even this trial had several technical limitations, and the authors of the review concluded that vinpocetine cannot yet be regarded as a proven treatment. Currently, several better-quality trials are underway. [39]

Melissa officinalis and Salvia officinalis

It has been reported that Melissa officinalis (lemon balm) improves cognitive function and reduces agitation in patients with mild to moderate AD. M. officinalis is known to have ACh receptor activity in the central nervous system with both nicotinic and muscarinic binding properties. [46, 47] A recent study has shown that this plant modulates mood and cognitive performance when administered to young, healthy volunteers. [48] In addition, a parallel, randomized, placebo-controlled study assessed the efficacy and safety of M. officinalis in 42 patients with mild to moderate AD. [49] Subjects were treated for four months. The main efficacy measures were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinical Dementia Rating-Sum of the Boxes (CDR-SB) scores. The CDR-SB provides a consensus-based global clinical measure by summing the ratings from six domains: memory, orientation, judgment, problem solving, community affairs, home and hobbies, and personal care. The results revealed that patients receiving M. officinalis extract experienced significant improvements in cognition after 16 weeks of treatment. Improvements were seen on both the ADAS-cog and CDR-SB scores. The changes at the end-point compared to baseline (mean [SD]) were -1.92 (1.48) and 1.03 (0.54) for Melissa extract and placebo, respectively, on the CDR-SB scores. The researchers observed no significant difference in the frequency of side effects between the placebo group and those receiving the herb extract. However, the frequency of agitation was higher in the placebo group compared to those receiving active treatment. [49] Moreover, another study showed that patients with mild to moderate AD receiving Salvia officinalis (sage) extract experienced statistically significant benefits in cognition after 1 6 weeks of treatment. [50] The clinical relevance of these findings was emphasized by the improvements seen in both the ADAS-cog and CDR-SB measures in the S. officinalis extract group on both observed case and intention-to-treat analyses. The changes at the endpoint compared to baseline (mean [SD]) were -1.60 (1.35) and 0.73 (0.41) for Salvia extract and placebo, respectively, on the CDR-SB scores. The side effects associated with Salvia in this study were generally those expected from cholinergic stimulation and were similar to those reported with cholinesterase inhibitors. [51] Frequency of agitation appeared higher in the placebo group, and this may indicate an additional advantage for M. officinalis in the management of patients with AD.

In conclusion, treatment strategies will have to include a variety of interventions directed at multiple targets. So far, the outcomes with available Food and Drug Administration-approved medications for AD are often unsatisfactory, and there is a place for alternative medicine, in particular herbal medicine. [52] As described for many ofthese herbs, there is, in fact, a putative pharmacological target such as a receptor or neurotransmitter; none ofthe herbs can be said to treat the "whole disorder."

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