Can Lithium Benefit Brain Health?

A New Element on the Supplement Scene

New research shows this element to have a variety of neuroprotective properties
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Remember when people thought that mental illnesses, such as schizophrenia or chronic depression, were “all in the mind”? You do? Then you may be “youth-challenged,” because it’s been many years since that quaint old idea bit the dust. We’ve known for a long time that mental disorders are the result of physical and chemical disturbances in the brain—but deducing the molecular mechanisms involved is a tremendous challenge for neuroscientists. Some diseases are at least partially understood at that level, but many others remain mysterious.

The human brain is the most complex object in the known universe, so it’s perhaps forgivable that we haven’t figured it all out yet. Not to mention the ultimate paradox: the only thing we have with which to understand the workings of our brains is . . . our brains. (That one gives some philosophers nightmares.)

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.
Finally, researchers at the Wayne State University School of Medicine in Detroit studied ten human patients (average age 33) with bipolar disorder.6 For 4 weeks they gave the patients a daily therapeutic dosage of lithium (they didn’t specify the actual dosage, but rather the plasma lithium-ion concentration that resulted from it—about 0.8 millimoles per liter, which would have required roughly 1000 mg per day of lithium carbonate). They then did magnetic resonance imaging (MRI) of the patients’ brain and compared the scans with those taken at the outset of the study. In eight of the ten patients’ brains, the lithium treatment significantly increased the total volume of gray matter: the average increase was 3%, corresponding to a volume of about 24 cm3 (1.5 in.3). The authors attributed the effect to lithium’s neurotrophic properties and its ability to stimulate the growth of such non-neuronal objects as glial cells, but they did not describe it as neurogenesis.

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.

References

  1. Alvarez G, Muñoz-Montaño JR, Satrústegui J, Avila J, Bogónez E, Díaz-Nido J. Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration. FEBS Lett 1999 Jun 25;453(3):260-4.
  2. Phiel CJ, Wilson CA, Lee VM-Y, Klein PS. GSK-3-alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 2003 May 22; 423(6938):435-9.
  3. Calabrese V, Scapagnini G, Colombrita C, Ravagna A, Pennisi G, Giuffrida Stella AM, Galli F, Butterfield DA. Redox regulation of heat shock protein expression in aging and neurodegenerative disorders associated with oxidative stress: a nutritional approach. Amino Acids 2003 Dec;25(3-4): 437-44.
  4. Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang D-M. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 2002 Dec;43(7):1173-9.
  5. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochem 2000 Oct; 75(4):1729-34.
  6. Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithium-induced increase in human brain grey matter. Lancet 2000 Oct 7;356(9237): 1241-2. Erratum: Lancet 2000 Dec 16;356(9247):2104.

 

Wine May Cut Alzheimer’s Risk

Just in case you needed another justification for drinking wine (but only in moderation, of course), here comes a study from Columbia University in New York that seeks to determine whether elderly American wine drinkers enjoy a degree of protection from Alzheimer’s disease similar to that of their European counterparts.1 (We already know about the cardiovascular benefits of moderate wine consumption, which also seems to confer protection against cancer.)

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.

  1. Anon. Wine seems to reduce Alzheimer’s disease risk. Reuters Health report, New York, April 5, 2004.

 

 

 

Alzheimer’s Cuts Life Expectancy in Half

Alzheimer’s disease has no cure and is invariably fatal. The question then is, how long will that take? It’s impossible to give an answer in any individual case, but there are some rules of thumb that can be invoked in order to get a general idea. One that has just been proposed is that Alzheimer’s will cut a newly diagnosed person’s remaining life expectancy in half.

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.”

  1. Anon. Alzheimer’s cuts life expectancy in half—study. Reuters Health report, Washington, DC, April 6, 2004.
  2. Wolfson C, Wolfson DB, Asgharian M, M’Lan CE, Østbye T, Rockwood K, Hogan DB. A reevaluation of the duration of survival after the onset of dementia. New Engl J Med 2001 Apr 12;344(15): 1111-6.
  3. Kawas CH, Brookmeyer R. Aging and the public health effects of dementia. New Engl J Med 2001 Apr 12;344(15):1160-1.

 

 

 

Dual-Action Galantamine

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.