Lithium Packs a Stunning Punch
Lithium Promotes the
Formation of New Brain Cells
It can help protect against neurodegenerative
diseases, including manic depression, as well as brain injury
By Will Block
eethoven is known to have been moody—which may be an understatement. By most accounts, he was a difficult man to be around, and the few friends he had were often sorely tested by his rude and abusive behavior. One could argue, of course, that the tragedy of his deafness—surely one of the cruelest twists of fate in human history—justified his moodiness, if that’s the correct word for it. We’ll probably never know, but perhaps it was more than that. Beethoven might have been afflicted by a mood disorder, a problem that goes far beyond the garden-variety bad moods to which all of us fall prey from time to time.
Psychiatrists define mood disorders as a group of mental disorders in which disturbance of mood is accompanied by either a full or partial manic or depressive syndrome that is not due to any other mental disorder. There are many varieties of mood disorders, but what they have in common is a pathological state of mania (a kind of exaggerated and unfounded elation) or depression. By themselves, mania and depression are called unipolar disorders. If, however, the patient alternates between these two extremes of mood—usually in cycles of months or years, and for no apparent reason—the condition is called bipolar disorder, which is also known as manic-depressive illness or just manic depression.
Lithium—It Is “Something in the Water”
According to the Japanese authors of a recent literature review (from which most of the information in this article is taken), bipolar disorder is one of the most common (3–5% worldwide), chronic, recurrent (90%), life-threatening psychiatric diseases (the threat comes from the tendency to suicide). The traditional treatment for both elements of this disorder (mania and depression) has been with lithium, a metallic element found primarily in the alkaline waters of many mineral springs and in certain dry lakes, such as California’s Searles Lake in the Mojave Desert.
For thousands of years before anyone knew about lithium, people throughout the world had been “taking the waters” at mineral springs, such as those in Baden-Baden, Germany. Bathing in these hot springs made people feel better, but drinking the water probably helped even more, by providing lithium in much greater amounts than are normally found in food.
Three Surprising Discoveries
Now that we know what it is in these waters that helps alleviate mood disorders, the question is: how does lithium work? To gain some insight on this, we need to be aware of three surprising discoveries made during the past decade.
Mood disorders entail brain damage
Mood disorders are not just neurochemical in nature, i.e., they are not just attributable to simple imbalances in brain chemistry. Instead, they are now considered to be systemic diseases that entail multiple abnormalities in such areas as cognitive, motor, nervous, and endocrine functions and in the sleep/wake cycle. These dysfunctions are the result of impairments of complex biochemical signaling pathways having to do with both cell survival and cell death, and such impairments can culminate in both functional and structural abnormalities in the neurons themselves. In other words, the mood disorders entail actual brain damage, which is typically manifested as a loss of gray matter and as reductions in the number and size of neurons and glia (nonneuronal brain cells) in certain regions of the brain.
Lithium’s ability to stimulate neuro-
genesis is important because impaired
neurogenesis is the common, unifying
factor in the origin of various
Lithium protects against multiple types of brain damage
Antidepressants, including lithium, can protect against, and may even reverse, the functional and structural abnormalities in the brain’s neurons. It has become increasingly evident that lithium, in particular, has neuroprotective effects against cell injuries caused by a strikingly wide variety of factors, including ischemia (inadequate blood supply), amyloid-beta (the protein constituting senile plaques in Alzheimer’s disease), irradiation, heat shock, and a number of different kinds of neurotoxins. The protective effects occur not just in laboratory cell cultures, but also in animals with a variety of neurodegenerative diseases and in human patients with bipolar disorder (which has come to be regarded as a neurodegenerative disease itself).
The brain produces new neurons throughout life
Contrary to the long-standing belief that no new neurons are ever formed in the brain after it has fully matured (at around the age of 20), this does occur throughout our entire adult lifetime. The process, called neurogenesis, occurs primarily in the hippocampus, the region of the brain most closely associated with learning and memory. Apparently, however, neurogenesis does not occur at a rate sufficient to offset certain pathological processes that cause a loss of neurons (as occurs most strikingly in Alzheimer’s disease). This suggests that either increased cell death or decreased neurogenesis (or both) is associated with mood disorders. And mood disorders, as we have seen, can be prevented or treated with antidepressants.
Mood Disorders Are Neurodegenerative Diseases
Taken together, these discoveries suggest that mood disorders are a novel class of neurodegenerative diseases, i.e., they may be the manifestations of chronic brain damage, in the same sense in which such diseases as Alzheimer’s and Parkinson’s are. There is, however, an important difference between these diseases and mood disorders: the former cannot be cured, whereas the latter often can be. Thus there must be something fundamentally different about the types of brain damage involved. (The progress of Alzheimer’s disease can be slowed down and sometimes temporarily reversed, notably by galantamine, but the final outcome remains inevitable; there is, as yet, no cure in sight.)
Lithium Promotes Neurogenesis
It turns out that lithium increases or decreases the production of a wide variety of substances in our cells, and it interacts with a multitude of cell-survival and cell-death signaling pathways, with the overall result of enhancing the survival of existing cells and promoting the formation of new ones (neurogenesis). A recent study by a research team at Wayne State University School of Medicine in Detroit showed that administration of lithium to manic-depressive patients increased the volume of their gray matter by 3%, on average.* The same team also showed that lithium increased the levels of N-acetyl aspartate, an indicator of neuronal viability and function. Referring to these studies, the authors of the above-cited review stated,
These exciting results unveil that in human patient brains, brain atrophy is reversible, and neurogenesis may be promoted by pharmacological strategies. In addition to its current use in manic-depressive illness, it has been proposed that lithium could be used to treat acute brain injuries (e.g., ischemia) and chronic progressive inexorable neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, tauopathies, and Huntington’s disease).
Tauopathies are a diverse category of neurodegenerative diseases, of which Alzheimer’s is the most important (Parkinson’s and Huntington’s are not tauopathies). To learn more about these diseases, see the sidebar “When Bad Things Happen to Good Proteins.”
When Bad Things Happen to Good Proteins
Tau (rhymes with wow) is the 19th letter of the Greek alphabet. It’s also the name of an elementary particle, and it’s the name of a protein that serves a vital function in our neurons. Tau (τ) is associated with other proteins called tubulins in the formation and stabilization of important cellular components called microtubules. As the name implies, these are tiny, cylindrical, hollow structures (their diameter is 22 nanometers, or 22 billionths of a meter). They act not only as structural elements of the cell’s architecture but also as conduits for various materials, such as neurotransmitters and bits of cellular debris, that must be shuttled from one part of the cell to another.* Some microtubules are also involved in cellular locomotion, such as the “swimming” action of sperm cells.
The trouble with tau is that it’s vulnerable to a biochemical process called hyperphosphorylation, which means the attachment of an excessive number of phosphate groups (–OPO3) to its molecular structure. When this occurs, the hyperphosphorylated tau molecules become disengaged from the tubulin molecules, causing destabilization and collapse of the microtubules. This compromises the neuron’s ability to function properly, and it may die as a result.
But that’s only part of the story. Once free of the tubulins, the hyperphosphorylated taus self-aggregate in the form of paired helical filaments, which tend to get tangled up with other such pairs. The resulting superaggregates, which can be seen under the microscope, are called neurofibrillary tangles; they’re one-half of the dreaded team of “plaques and tangles” that degrade, and ultimately destroy, significant portions of the brains of Alzheimer’s victims.† (The plaques are extracellular, whereas the tangles are intracellular.)
Alzheimer’s is the most important example of a tauopathy (pronounced tau-AW-pathy), a neurodegenerative disease characterized at least in part by a pathology involving tau. Various factors are implicated in the formation of neurofibrillary tangles, but one is particularly noteworthy: it’s amyloid-beta, the deleterious protein that forms the core of the senile plaques in Alzheimer’s. Thus, the plaques help spawn the tangles, which explains why the latter usually appear later in the course of the disease than the former.
The distribution of neurofibrillary tangles within the brain also changes with time. It starts mainly in the entorhinal cortex, a region from which bundles of cholinergic neurons project to the hippocampus, the most critical region for learning and memory. Over time, tangles then make their appearance in the hippocampus itself and in nearby regions of the cerebral cortex, and they eventually spread throughout the cortex.
Aside from Alzheimer’s disease, the other 20-plus tauopathies are not well known to laymen—with one exception. Physicians call it dementia pugilistica, but we know it better as being punch drunk. Boxers who take too many blows to the head suffer from a tau-related dementia that closely resembles Alzheimer’s disease, including the presence of abundant plaque deposits. It appears that both diseases share common pathogenic mechanisms leading to the formation of plaques and tangles. This idea jibes with the fact that head trauma is a known risk factor for Alzheimer’s.
- Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG. Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol (Berlin) 1991;82:280-5.
Impairment of Neurogenesis Underlies Neurodegenerative Disease
Lithium’s ability to stimulate neurogenesis is exceptionally important because, according to some scholars, the impairment of neurogenesis is the common, unifying factor in the origin of various neurodegenerative diseases, including both tauopathies and non-tauopathies. Although the clinical symptoms and neuropathological abnormalities exhibited by these diseases are distinct in each case, they overlap one another to form a continuous spectrum, suggesting that common threads may run through them all.
Factors that tend to promote neurogenesis include: task-learning; an enriched environment (i.e., one that contains abundant sensory stimuli and mental challenges); physical exercise; various growth factors (substances that promote the growth and development of tissues); various neurotransmitters (e.g., serotonin, dopamine, and noradrenaline); various hormones (e.g., estrogen and DHEA); and antidepressants, such as lithium. A study published in 2003 provided the first direct evidence that the behavioral improvements seen with antidepressants are caused in part by the neurogenesis they induce.
Lithium Combats Both Plaques and Tangles
Meanwhile, much experimental evidence has accumulated showing that lithium inhibits the production of amyloid-beta and the hyperphosphorylation of tau, apparently by inhibiting the actions of two enzymes, GSK-3α and GSK-3β (GSK stands for glycogen synthase kinase), that are involved in these processes. Lithium thus shows promise for combating both plaques and tangles, the two most destructive agents in the brains of Alzheimer’s victims. Experiments have also shown that lithium has potential benefits (as mentioned in the quotation given above) for the treatment of other tauopathies and for Parkinson’s and Huntington’s diseases, as well as for brain injury caused by ischemia.
Taking the Lead Is Good, Unless . . .
Although we don’t know whether Beethoven suffered from a true mood disorder of neurological origin, we do know that he died, at age 57, from severe, chronic lead poisoning. This was proved in 2005 by scientists at the Argonne National Laboratory, near Chicago, who analyzed authenticated skull and hair samples from the great composer. (They also debunked the long-standing belief that Beethoven had syphilis. The antisyphilitic drugs of his time contained mercury, traces of which would have been detectable in his remains—but none were found.)
Scientific evidence reveals that Beethoven’s poisoning began no later than his early twenties. It probably accounted for the many illnesses and the chronic pain he suffered throughout his adult life, all of which surely contributed to his bad moods. How the poisoning came about is unknown, but Vienna in his time did have a large lead-manufacturing industry. It has also been speculated that his first serious exposure to lead may have occurred accidentally when, at the age of 16, he visited the famed spa at Baden-Baden, whose mood-healing waters owed their efficacy to … lithium.
- Wada A, Yokoo H, Yanagita T, Kobayashi H. Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. J Pharmacol Sci 2005;99:307-21.
- Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithium-induced increase in human brain grey matter. Lancet 2000;356(9237):1241-2.
Erratum: Lancet 2000;356(9247):2104.
- Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Jolkovsky L, Manji HK. Lithium increases
N-acetyl-aspartate in the human brain: in vivo evidence in support of
bcl-2’s neurotrophic effects? Biol Psychiatry 2000;48:1-8.
- Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al.
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003;301:805-9.
- Alvarez G, Muñoz-Montano JR, Satrústegui J, Avila J, Bogónez E, Díaz-Nido J. Regulation of tau phosphorylation and protection against β-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer’s disease. Bipolar Disord 2002;4:153-65.
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.
It’s also a good idea to take the following:
- Green tea polyphenols, a class of antioxidants, operating together as a system, that can also fight amyloid-beta toxicity
- Vitamin C and Vitamin E, which have been shown to work together to help protect your brain's hotbeds of free radical activity
- Turmeric curcuminoids, a system of antioxidants that helps protect your neurons from damage or death caused by amyloid-beta
- Folic acid, vitamin B6, and vitamin B12, important vitamins that help prevent damage to mitochondria (where they help repair DNA damage), cofactor the production of nitric oxide, and reduce levels of homocysteine (a neurotoxin)
- Lithium, an important brain food that is found in the bottled waters of American and European health spas ... that also lowers the toxicity of amyloid-beta while causing an increase in neurotrophic factors that help induce neurons to repair themselves when under stress ... that helps cause an increase in gray matter and helps enhance neurogenesis of hippocampal neurons
Will Block is the publisher and editorial director of Life Enhancement magazine.