A New Element on the Supplement Scene
Meanwhile, neuroscientists keep trying to unravel the mysteries of the brain, bit by bit, while clinicians keep looking for newer and better ways to treat mental disorders—whether the neuroscientists can explain the rationales for them or not. Often the time lapse between discovering that something works and understanding why it works is very long indeed. One example is the use of lithium for treating bipolar disorder, also called manic-depressive illness or just manic depression. This is the disease in which, for no apparent reason, the patient’s mood and behavior alternate between the extremes of mania (a kind of exaggerated and unfounded elation) and depression, usually in cycles of months or years.
Lithium Works—But How?
We’ve known for half a century that lithium can control the mood extremes of bipolar disorder, and lithium-based drugs have been successfully used as therapy during that time. Lithium’s mechanism of action on the brain is still unknown, however. It has been speculated—and there is some evidence for this—that it may affect the levels of the neurotransmitters serotonin and norepinephrine in the brain. There is also evidence that lithium inhibits the action of inositol monophosphatase and several other enzymes that play key roles in mood-related neuromodulation (a complex type of signaling process related to neurotransmission).
And now there is growing evidence that lithium may provide some degree of protection against the brain damage that is characteristic of neurodegenerative diseases, such as Alzheimer’s. Before we discuss this exciting new avenue in dementia research, however, let’s talk a bit more about the use of lithium in treating bipolar disorder.
Lithium Is Still the Treatment of Choice
Long before anyone knew about lithium, let alone neurotransmitters or enzymes, it had been noticed that the waters of certain mineral springs seemed to have curative powers for people suffering from mania or depression. In the second century A.D., the Greek physician Seranus Ephesios recommended “natural waters such as alkaline springs” as a treatment for mania. Over the ensuing two millennia, countless people have “taken the waters” for a variety of ailments, real and imagined, at fashionable (and not so fashionable) spas throughout the world, particularly in Europe.
We now have an idea why these waters often seemed to helped manic individuals calm down, or depressed individuals perk up: it may have been not just the soothing spa ambience, but perhaps also the lithium in the water, which the spa clients were encouraged to drink as well as to soak in.
Lithium is so effective in controlling the mood extremes of bipolar disorder that to this day it is still the treatment of choice, even though a variety of effective, but sometimes dangerous, synthetic drugs have also come on the scene. The fact that lithium controls both mania and depression (the former more effectively than the latter) is both wonderful and puzzling, as it suggests that both of these conditions are, somehow, symptoms of the same underlying neurochemical disturbance.
It’s sobering to realize, though, that bipolar disorder goes beyond mere molecular imbalances: it also entails measurable losses of brain matter owing to neuronal death in a number of regions of the brain, including the hippocampus, a region that is also particularly hard hit by neuronal loss in Alzheimer’s disease.Lithium Therapy Requires Careful Management
A typical maintenance dosage at which lithium (usually in the form of lithium carbonate) is prescribed for controlling bipolar disorder is 900 milligrams of the carbonate per day, which is equivalent to 170 mg of elemental lithium.* This is about 50 times greater than the amount of lithium (3.5 mg) contained in 1 liter of water from the famous Vichy mineral springs in France, and it’s hundreds of times greater than the trace amounts that we normally ingest with our food (about 200–600 micrograms per day). Thus, by either spa-water standards or nutritional standards, the therapeutic dosages of lithium are very high. That would be all right but for one thing: these therapeutic dosages are perilously close to being toxic dosages—not a good situation for any kind of medicine. For every patient, therefore, the physician must individualize and carefully monitor the treatment to avoid toxic overdosage.
*The lithium is in the form of lithium ions, of course. The maintenance dosage produces plasma lithium-ion concentrations of about 0.6 millimoles per liter, which represents the low end of the desired “therapeutic range” of about 0.6–1.5 millimoles per liter (4–10 milligrams per liter). For laboratory studies with cell cultures, researchers generally use lithium solutions within this range of concentrations so as to mimic real-life clinical conditions, and for animal studies they use dosages that will produce plasma lithium-ion concentrations in this same range.
At these high levels, there are also many potential side effects of lithium, ranging from minor to severe. Among the most common (and benign) are dizziness, drowsiness, diarrhea, nausea, vomiting, excessive urination and thirst, a metallic taste, shakiness, tremors, and weight gain.
Lithium Inhibits Plaques and Tangles
Lithium solutions (usually lithium chloride or lithium carbonate) in the therapeutic range or beyond have been used in several recent laboratory and animal studies, and one human study, that have intriguing implications for preventing or inhibiting the progression of Alzheimer’s disease.
One such study dealt with the relationship between two of the three most characteristic neuroanatomical features of Alzheimer’s: the formation in the brain of harmful proteinaceous deposits called amyloid-beta plaques and neurofibrillary tangles.1 Both of these contribute to the death of brain neurons—which is the third characteristic feature. It turns out that the plaques are partly responsible for the formation of the tangles, and the researchers discovered that lithium (at about 10 times the therapeutic dosage) blocked this process in cultured rat cortical neurons, resulting in a strong protective action against neuronal death. In effect, the lithium protected against the neurotoxicity of amyloid-beta (which is also called beta-amyloid).
In a related study, researchers used mouse cortical neurons and live mice that were bred to be highly susceptible to Alzheimer’s disease.2 They found that treatment with lithium in therapeutic doses (for 3 weeks in the case of the live mice) sharply reduced the production of amyloid-beta in the first place, apparently by inhibiting the action of an enzyme, glycogen synthase kinase-3-alpha (GSK-3-alpha), that is required for this process to occur, as well as for the production of neurofibrillary tangles. The reductions observed were in the range of 40–78%. [Certain nonsteroidal anti-inflammatory drugs (NSAIDs) also reduce amyloid-beta levels, by the way, and the authors speculated that combination therapy with lithium and an NSAID might have an enhanced effect.*]
*It’s tempting to speculate that another agent, the Indian spice turmeric, may also be beneficial against the neuropathology of Alzheimer’s, as has been suggested in the scientific literature.3 Turmeric’s most active component is curcumin, an antioxidant, anti-inflammatory compound known to have a variety of important health benefits, including strong antitumor activity.
Lithium Protects Against Neuronal Death
In a third study, researchers examined the effects of lithium on glutamate-induced excitotoxicity, which is neuronal death caused by excessive amounts of glutamate, the brain’s most prevalent neurotransmitter.4 This phenomenon has been strongly implicated in the origin of a variety of neurodegenerative diseases, including dementia. The researchers found that lithium in the therapeutic range largely prevented glutamate-induced excitotoxicity in rodent cortical neurons. It apparently did so by stimulating the production of a protective protein called brain-derived neurotrophic factor, or BDNF, which is vital for the development and maintenance of healthy neurons (neurotrophic means pertaining to neural nutrition). Evidence for this mechanism came from the observation that when an antibody that neutralizes BDNF was added to the culture, lithium’s neuroprotective effect was blocked.
Lithium Stimulates New Neuronal Growth
Protecting neurons from destruction is one thing; it’s quite another to stimulate the growth of new neurons—a process called neurogenesis.* Numerous factors can affect neurogenesis, and lithium is apparently one of them. Researchers treated mice with lithium in dosages that produced plasma concentrations equivalent to those in the human therapeutic range; then they killed the mice and examined their brains.5 They found a 25% increase in the number of dividing cells in a structure of the hippocampus called the dentate gyrus—a clear indication of neurogenesis. This fit with the fact that lithium is known to stimulate production of a brain protein called B-cell lymphoma protein-2 (bcl-2) in certain areas of rodent brains; bcl-2 not only actively protects neurons from a variety of threats, including apoptosis (programmed cell suicide), but also promotes new cell growth. (Hippocampal neurogenesis has also been observed with a variety of antidepressants, so lithium’s action in this regard is not unique.)
*Until the late 1990s, it was widely believed that neurogenesis could not occur in adult human brains. We now know, however, that it can occur, and does.
A Lithium Primer
Not surprisingly, lithium (from the Greek lithos, meaning stone) is never found in nature as the free metal, but only in the form of stable chemical compounds (from which the free metal can be produced). These compounds are found in small amounts in nearly all igneous rocks (rocks formed by volcanic action), but the primary sources of lithium are the alkaline waters of many mineral springs and certain salt lakes, such as Searles Lake in California.Lithium is an odd element that most people don’t know much about. Like the more familiar elements sodium and potassium, lithium is an alkali metal, and its chemical properties derive from that fact. It’s the lightest of all metals, with a density only half that of water. Thus it floats in water, with which it reacts chemically, producing hydrogen gas. It also reacts rapidly with oxygen, and it’s the only element that reacts with nitrogen at room temperature. With such extreme chemical reactivity, it obviously can’t be stored in air or water, so it’s usually stored in kerosene, with which it does not react. Lithium is so soft that it can be cut with a knife.
The main uses of lithium are in batteries, medicines, alloys (it increases corrosion resistance and tensile strength), lubricants, ceramic glazes, nuclear reactors, and hydrogen bombs.
Lithium compounds are found in trace amounts in fish, processed meat, dairy products, eggs, potatoes, and vegetables; we ingest only about 200–600 micrograms of lithium daily. Although lithium is not one of the nine trace elements that are vital for human nutrition (because without them, life itself would not be possible), it is one of the 14 (and perhaps more) auxiliary trace elements that are believed—with widely varying degrees of evidence—to be essential for our health. (For more on minerals as nutrients, see “The Trace Minerals in BioEnhance with DNAble” in Life Enhancement, July 2000.)
Lithium Increases Gray Matter
MRI of human brain: actual (left) and artificially colored (right) to illustrate different neuroanatomical features.
Lithium Might Be Helpful in Alzheimer’s
In all five of the studies outlined above, the researchers concluded their reports with statements to the effect that their results, along with those of various other recent studies, point to the possibility that long-term treatment with lithium might prove useful for reducing brain damage and stimulating new neural growth in neurodegenerative diseases such as Alzheimer’s.
That’s encouraging, and it illustrates the value of looking constantly for new (or old) and better ways to attack the problem of Alzheimer’s disease and other age-related diseases, so that we can all look forward to longer, healthier, happier lives.
For 4 years, researchers followed 980 elderly Manhattanites who were free of any dementia at the outset of the study. During that period, 260 of the subjects developed dementia: there were 199 cases of Alzheimer’s disease and 61 cases of vascular dementia.
Sure enough, the results showed that drinking wine—up to three glasses a day—substantially reduced the risk for Alzheimer’s disease. Compared with the nondrinkers, the wine drinkers’ risk was 45% lower. No such benefit was seen with other alcoholic beverages—probably because they don’t contain resveratrol, the chemical compound believed to be primarily responsible for wine’s remarkable health-giving properties. (Resveratrol may also play an important role in extending human lifespan; see “Resveratrol May Be a Longevity Molecule” in Life Enhancement, November 2003.)
Two caveats: (1) no benefit from wine drinking was seen in this study in people with the APOE epsilon-4 gene, which predisposes one to Alzheimer’s; and (2) most medical authorities caution against drinking more than one or two glasses of wine a day (three glasses tops), because beyond that amount, the health benefits quickly disappear and become health liabilities.
Researchers at the University of Washington studied 521 newly diagnosed Alzheimer’s patients over the age of 60 and found that the median survival time was 4.2 years for men and 5.7 years for women—about half the time that people of the same age would be expected to live if they did not have Alzheimer’s.1
This study is even more sobering than one published in 2001 indicating that life expectancy in people suffering from dementia is much shorter than had previously been believed.2 Canadian researchers found that the median survival rate for 821 elderly dementia patients with an average age of 84 was 3.3 years after the onset of the disease. This figure is much lower than those suggested by previous, less carefully controlled studies: from 5 to 9.3 years. (A fundamental difficulty in such studies lies in trying to ascertain the starting point of a disease that develops gradually and subtly.)
The American authors of an editorial that accompanied the Canadian paper painted a grim picture of dementia, projecting that in the next half-century, the prevalence of Alzheimer’s disease in the United States will nearly quadruple, meaning that one in every 45 Americans will be afflicted (the rate among the elderly will, of course, be much higher than that, because so few young people are afflicted).3 They went on to say, “In the new study, the prognosis for patients with dementia was similar to that for patients with some of the most malignant diseases, including many forms of cancer and heart disease.”
Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.
For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.
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