REALLY Low Dose Lithium Stabilizes Alzheimer’s Disease Patient Cognition Over 15 Months

A group of scientists, concerned about increased toxicity of lithium in the aged at the usual dosages used therapeutically (for bipolar disorder, for example), ranging from 150 to 600 mg daily, as a result of reduced glomerular filtration in the kidney, among other things, decided to do a study on Alzheimer’s patients at a truly tiny dose, 300 micrograms once a day.¹ Well water in areas with higher than usual amounts of lithium may contain that much lithium and commercially-available premium priced mineral waters from some springs and artesian wells often contain water with prized increased amounts of lithium, highly sought after by many looking for the healthful benefits of the mineral at low doses. See next section below for more on lithium in natural sources of water.

The 113 patients included in the study had their mental states evaluated every three months using MMSE (mini-mental state examination) applied in a double-blinded manner at the hospital (the physicians, patients, family, and caregivers did not know which patients received lithium and which received placebo). The MMSE is designed to measure the ability of a person to function doing normal everyday tasks.

During the study, those receiving microdose lithium showed no decrease in performance on the MMSE, whereas the control group (receiving no lithium) had decreasing scores, indicating cognitive decline. The authors note that relying just on the MMSE was a limitation of the study, as it does not give a complete picture for the determination of the assumption of homogeneity between the groups, though they did administer two other statistical tests to verify the homogeneity between groups, the Friedman non-parametric test followed by the Bonferroni test.

The results of this study, using a dose so small and registering a stabilization of the AD patients over such a long period, 15 months, is remarkable and is a worthy subject for determination of the mechanisms involved.

We note that this amount of lithium per day is so small that even our own low dose lithium contains 6 mg in a daily capsule. We based this dose on the amount of lithium you could get from drinking a reasonable amount of famous European health spa mineral water naturally high in lithium sold legally in the United States. The 6 mg dose is 6000 micrograms, 20 times as much as in the 300 microgram microdose used in this Alzheimer disease study.¹

Reference

1. Nunes, Viel, Buck. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 10:104 – 7 (2013).

Lower Dose Lithium Protects Against Amnestic Mild Cognitive Impairment in Human Study Possible Mechanism Identified

A small-randomized controlled study of 45 individuals with mild memory impairment received lithium (150 mg a day titrated to serum levels of 0.25 – 0.5 mmol/l, a range lower than the usual dosage used to treat bipolar disorder) or placebo over 12 months. Lithium treatment was associated with a significant decrease in cerebrospinal fluid concentrations of p-TAU (p=0.03) and better performance on the cognitive subscale of the Alzheimer’s disease Assessment Scale and in attention tasks.^1A

The most interesting datum mentioned in the paper was that preliminary data from the lab that performed the study1A described above (data said to be available upon request) showed that lithium treatment in the dose range used in the above study for two weeks in healthy volunteers caused a 50% reduction in GSK3B activity in leukocytes. Although this enzyme is known to be inhibited by lithium at therapeutic doses (those used to treat bipolar disorder) and is thought to be a major mechanism of its action at those doses, this is the first time we’ve seen a measurement at lower doses of lithium. This might suggest that even lower doses of lithium may have an inhibiting effect on the enzyme, though it might be inhibited less than at the higher doses depending on the shape of the dose-response curve.

References

1A. Forlenza, Diniz, Radanovic, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 198:351 – 356 (2011).

LITHIUM AS AN ESSENTIAL NUTRIENT

A 2012 paper² provided detailed information on the presence of lithium in drinking water and vegetation and on its essentiality in a large number of animal and human studies.

The review reported that there is a wide variation in the amount of lithium found in drinking water, spring water, spa water and bottled water. One study of 132 brands of bottled water from 28 countries found lithium concentrations ranging over 5 orders of magnitude (from 0.057 to 5,460 μ/l. “Li concentrations of 8.7 mg/l and of >9 mg/l have been reported for the Friedrich-Quelle, a famous spring in Baden-Baden/Germany, and for the spa water in Pompeya/Argentina, respectively.”²

“The long-term consumption of low-Li drinking water is regarded as a risk factor for higher incidences of suicides, homicides, and crimes as shown in several studies. For example, in 24 counties in Texas/USA with a total population of 6 million (>60% of the state population), during a 2-year study (1967 – 1969), a significantly inverse relationship between (1) Li concentration of local drinking water, (2) Li concentrations of the urine among the respective residents, and (3) mean annual rainfall amounts in the respective county sites and (1) state mental hospital admission rates, (2) admitting rates for four major mental disorders (psychosis, neurosis, schizophrenia, personality problems), (3) homicide rates, and (4) road distance from resident county to nearest state mental hospital was found (p≤0.05 to <–0.001). The Li levels in drinking water were classified into 4 groups: <11.0; 11.0 – 29.9, 30.0 – 69.9; >70.0 μg/l.”¹

A second study reported in the review² included 27 counties and lasted for 10 years (1978 – 1987) and found that that the incidence rates of suicide, homicide, and rape were significantly higher in counties whose drinking water contained low (0–12 μg/l) and medium (13–60 μg/l) lithium concentrations than in counties whose drinking water had high Li concentrations (79 – 160 μg/l)(p<0.01). They also found associations with the rates of robbery, burglary, and theft significant at p<0.05. These are really remarkable differences that suggest improved mental function with low dose lithium.

On the basis of these and many other studies, the basic requirement of lithium in humans has been assessed at 1 μg/kg body weight/d in humans derived from intake data in Germany, thus, the lithium requirement for an adult of 70 kg body weight would be 70 μg/d. In another assessment study, Schrauzer suggested a provisional recommended dietary allowance (RDA) of 1 mg lithium/day for an adult of 70 kg body weight.³

References

2. Evaluation of beneficial and adverse effects on plants and animals following lithium deficiency and supplementation, and on humans following lithium treatment of mood disorders. Trace Elem Electrolytes. 29(2):91-112 (2012). 
3. Schrauzer. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 21:14-21 (2002).

Lithium at Therapeutic Doses Protects Neurons Robustly Against NMDA-induced Excitotoxicity

In another study,⁴ lithium at therapeutic doses in cultured cerebellar granule cells from 8 day old Sprague Dawley rats pretreated with lithium chloride for 6 – 7 days and then exposed to 100 μM of glutamate for 24 hours. Preincubation of the cultures with 2mM lithium chloride for 7 days markedly protected the neurons against glutamate-induced excitotoxicity. Although significant protection was detected at 0.5 μM lithium, the maximal effect detected in this study occurred at 3 μM.

Of course, the therapeutic dose of lithium is far higher than that in commercially available high lithium containing mineral water or tap water with naturally high levels of lithium. We are stunned by the findings reported in the study above of protection against cognitive decline in AD patients over 15 months from only 300 μg per day.

Also, see Will Block’s review of other papers on lithium in brain health ( “Can Lithium Benefit Brain Health?” in the June 2004 issue of Life Enhancement.)

References

1. Nunes, Viel, and Buck. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 10:104 – 7 (2013). 
4. Nonaka, Hough, Chuang. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci U S A. 95:2642 – 47 (March 1998).

Lithium, an Essential Nutrient, Has Neuroprotective Effects at Low Dosage

Lithium salts act as a drug at high doses, but act as a neurologically beneficial essential nutrient at much much smaller amounts.

First, a brief description of the very high dose medical use of lithium — it can be effective as a drug treatment for manic-depressive (or bipolar) illness. It provides nearly complete protection against attacks in about 1⁄3 of bipolar patients, improved symptoms in another 1⁄3, and is ineffective in the remaining 1⁄3.^A However, the treatment of bipolar illness requires high doses of lithium, close to the toxic dose. The clinically effective dose range is 0.6 – 1.0 μM serum level, while the toxic level begins at about 1.2 μM or greater. Symptoms in the dose range of 1.2  –  2.0 μM are said to be usually mild and to seldom cause death or permanent neurological damage.¹ Lithium is excreted via the kidneys or in sweat. Because the toxic dose is not much higher than the therapeutic dose and because prolonged exposure to serum levels of 2μM or greater may cause liver and kidney damage,¹ though, it is necessary for those receiving pharmacological doses for bipolar disorder to receive periodic blood tests to ensure the lithium blood levels remain in the therapeutic range and that liver and kidney functions remain normal.

What is more interesting to us than its use at the highest level that is tolerable before toxic effects ensue is what lithium does at low doses, a dose so low that it would NOT be an effective treatment for bipolar disorder and, hence, the mechanisms of its actions may differ from those that take place at a high dose. It is particularly interesting in light of the fact that, as mentioned above, lithium at small amounts has been found to be an essential mineral with a suggested RDA of 1 mg/day for a 70 kg adult human.

Lithium in Spring Water Reported to Be Positively and Significantly Associated with Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is an important growth factor involved in many cognitive processes including learning and memory, emotional processes, and sometimes psychopathological conditions such as addiction. The effect depends on the specific tissue in which the BDNF is released, the conditions under which it is released, and the dosage released.

In a study of 43 Japanese subjects who did not have psychiatric dysfunction, the participants drank 3.64 liters of spring water from two springs, one of which contained 6.1 mg/liter of lithium and the other contained 15.7 mg/liter, much lower than lithium in clinical use (900 to 1800 mg/day of lithium carbonate, containing 170 – 340 mg lithium/day) but at much higher levels than generally contained in lithium-containing tap water (generally much less than 1 mg/liter). Their serum lithium levels increased from 0.026 to 0.073 mEq/L, a much lower level than if they had been treated with bipolar treatment levels of lithium. The results of a Profile of Mood States indicated that most ratings were significantly improved (though whether this was caused by lithium is unclear  —  the authors suggested it could possibly be a placebo effect). More interestingly, however, serum lithium levels were significantly and positively associated with BDNF levels. BDNF was also negatively and significantly associated with changes in the State-Trait of Anxiety Inventory scores. The researchers cited an earlier study in which lithium had been reported to increase BDNF levels. As this^B was a small open (no blinding, no placebo control) study, the authors rightly noted that further studies are needed to confirm these findings.

German studies have reported the effects of lithium-deficient diets in animals such as goats, pigs, cattle, broiler chickens, and rats.^C For example, one such study of a 13 year investigation with lithium-deficient goats reported that 41% of the lithium-deficient goats but only 7% of the controls (lithium adequate) died during the first experimental year indicating a highly significant difference (p<0.001) between the groups. Moreover, by the end of the third experimental year, all lithium-deficient goats had died, but 18% of the controls were still alive.^C

The same paper^C also described the analyses of various types of bottled water that included spring water, mineral waters, etc. from 28 countries finding that natural lithium concentration varied over 5 orders of magnitude, from 0.057 to 5,460 mg/l. The waters of the Friedrich-Quelle, a famous curative spring in Baden-Baden, Germany, were reported to be 8.7 mg/l. The upper crust of European society visits there for restorative effects. While there, visitors are encouraged to drink only the spring water.

Few data are available on what mechanisms are operative at the very low doses of lithium (except possibly for an increase in BDNF, as discussed above) as compared to mechanisms that help explain the therapeutic effects of high dose lithium in the treatment of bipolar disorder. Lithium has been reported to inhibit phosphatases in both plant and animal cells but we didn’t find any specific data on how this might be involved in (for example) suicide or homicide rates.

Lithium is reported to have a small ionic radius that results in lithium having the highest electronegativity and strongest polarization power among all alkali metal ions and is said to have a relatively large stable radius of the hydrated ion.^C The implications of all this obviously bears upon its biological effects. We await with great interest an elaboration of the effects of lithium that provide mechanistic data explaining its biological properties. In the meantime, lithium is an essential nutrient, appears safe to use at low doses, is very inexpensive, and is available without a prescription!

References

A. Young. Review of lithium effects on brain and blood. Cell Transplant. 18:951 – 75 (2009). 
B. Shiotsuki et al. Drinking spring water and lithium absorption: a preliminary study. German J Psychiatry. 11:103 – 6 (2008). 
C. Schafer. Evaluation of beneficial and adverse effects on plants and animals following lithium deficiency and supplementation, and on humans following lithium treatment of mood disorders. Trace Elem Electrolytes. 29(2):91 – 112 (2012).

Possible Life Extending Effects of Low Dose Lithium

A large epidemiological study^D has reported that there was an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total population of 1,206,174 people. The researchers also found that, lithium chloride at a similar dose to that ingested by the humans in their drinking water, extended lifespan in C. elegans.^D

The authors^D adjusted the mortality data for suicide rates (as higher levels that would still be considered low dose lithium has already been found to be associated with reduced suicide rate) and found that overall mortality rate was still inversely associated with tap water lithium levels. In the roundworm Caenorhabditis elegans, mortality in populations exposed to 10 μM of lithium chloride was reduced, while roundworms exposed to 1 μM of lithium chloride showed no effect on mortality rate. These results are consistent with a possible life extending effect of low dose lithium. A dose of 6 mg/day of lithium for an adult human is higher than the lithium level found to be effective in the roundworms.

Chronic Supplementation with Low Dose Lithium May Protect Against Ischemic Damage as Occurs in Stroke

A further study of low dose lithium^E reports neuroprotective effects in a rat model of ischemia (inducing ischemia by middle cerebral artery occlusion for 90 minutes followed by reperfusion). The experimental animals received lithium at 1 mmol/kg (given subcutaneously) for 14 days prior to middle cerebral artery occlusion and then 2 days following. Lithium chloride significantly reduced the infarct volume (number of cells killed by the procedure) by 32.7% compared to the animals receiving vehicle containing no lithium. The chronic treatment with low-dose lithium increased the expression of the antiapoptotic protein Bcl-2 and reduced the expression of the apoptotic-inducing proteins p53 and Bax. The low dosage administered to the experimental animals here was about six times higher than would be ingested from a single serving of our lithium capsules (6 mg per cap).

References

D. Zarse et al. Low-dose lithium uptake promotes longevity in humans and metazoans,” Eur J Nutr. 50:387 – 389 (2011). 
E. Xu et al. Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death,” Stroke. 34:1287 – 1292 (2003).

Neuroprotective Effects of Chronic Low Dose Lithium in Traumatic Brain Injury in Mice

Considering the high number of automobile accidents and falls resulting in injury or death in the U.S. every year, it would be expected that many incidents of traumatic brain injury occur. The sequelae of such injuries may take place over a period of time and may not receive timely or adequate treatment to prevent temporary (or even permanent) cognitive dysfunction. It is of considerable interest, therefore, to find that, as reported in a recent paper,^F chronic low dose lithium can provide substantial protective effects against a negative outcome in traumatic brain injuries, at least as demonstrated in a mouse model. Since the mechanisms responsible for the damaging effects of such injuries are very similar for mice and men, we consider low dose lithium to be plausibly protective against brain damage, as could occur in a car accident or a fall.

SIDEBAR: In fact, falls are becoming much more common as the population ages and can result in considerable disability or even death as a result of brain damage. Sandy’s mother and father both died as a result of falls, so even at 85 (her mother) and 91 (her father) they might have lived on for years had they not fallen. Her mother died of a neck fracture after falling, while her father died of a stroke resulting from brain damage induced by a fall. We reported earlier (in Vol. 6 No. 3 of the June 2003 issue of this newsletter) the results of a human clinical trial of 122 elderly women in a geriatric long-stay care facility, that receiving 1200 mg calcium plus 800 IU of cholecalciferol (vitamin D) per day over 12 weeks resulted in 49% reduction in falls as compared to calcium alone!*

As the authors of the paper explain, the initial mechanical damage in traumatic brain injury results in blood-brain barrier disruption, cerebral edema, and subsequent increase in intracranial pressure. Later, the secondary effects emerge as a result of an inflammatory response with the release of pro-inflammatory cytokines and the subsequent death of neurons. Cognitive deficits may linger.

The mice were treated daily for 2 weeks with 1 mmol/kg of lithium chloride by intraperitoneal injection and then, under deep anesthesia, were subject to a “controlled cortical impact” to simulate the result of an accidental traumatic brain injury. The researchers found that the animals receiving low dose lithium had significant reduction of loss of hemispheric brain tissue and lesion volume as compared to saline treated controls also subject to traumatic brain injury but receiving no lithium. Low dose lithium also attenuated the learning and memory deficits resulting from the experimental brain injury (as assessed by how long it took the animals to find the hidden platform in the Morris Water Maze).

The authors^F conclude that “[t]aken as a whole, these observations suggest lithium may be a beneficial ‘preventive’ therapeutic approach for reducing the neuronal degeneration and related behavioral dysfunction associated with neurodegenerative illnesses.”

We are personally aware of the extent of cognitive deficits that can ensue following a vehicular accident as a result of what happened to a longtime dear friend of ours. She had been involved in a serious accident while riding a bus and has never been the same since then, a few years later. Since we knew her well before the accident, the changes were very clear to us, that she has problems now with learning and memory that she didn’t have before and overall a substantial decline in her quality of life. She constantly needs reminding of things, even while keeping extensive lists to try to remember. We don’t know how much of this could have been prevented by regular low dose lithium taken before the accident, but we certainly wish she’d had the chance to find out.

Reference

F. Zhu et al. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull. 83:272 – 7 (2010). 
* Bischoff et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 18(2):343 – 51 (2003).

Daily Injections of Low Dose Lithium for 14 or 28 Days in Wistar Mice Resulted in Increased Size of Neurons and a Denser Dendrite Network

Finally, a paper partly in French and partly in English reported interesting effects of low dose lithium (80 ng/kg lithium carbonate) in the brain cortex of mice: larger neurons and a denser dendrite network.^G These changes remind us of those observed (via fMRI) in the brains of humans receiving lithium at therapeutic levels for bipolar disorder, where brain grey matter volume is increased after 4 weeks of treatment. The increased volume (about 3%) was observed in 8 out of the 10 patients studied.^H

G. Neiri et al. Effects of low doses of Li carbonate injected into mice. Functional changes in kidney seem to be related to the oxidative status. C R Biol. 331:23 – 31 (2008). 
H. Moore et al. Lithium-induced increase in human brain grey matter. The Lancet. 356:1241 – 2 (2000).