Lithium In The Drinking Water

 

Lithium In The Drinking Water

 

The title is an inside joke for any physicians trained in my generation. It was a standard line to indicate how common it is to prescribe a certain medication.  The first time I heard it I was an intern in the emergency department (ED) at St. Paul-Ramsey Medical Center.  It was (and is) a very busy ED and one of 3 Level I trauma centers in the Minneapolis St. Paul area with a population of about 3.6M people.  In those days there were no urgent care centers so the ED was informally split into a trauma and high acuity side and a low acuity side.  The interns would rotate from one side to the other every other day.  I had just assessed a couple of sisters on the low acuity side and diagnosed otitis media (ear infection) and was writing scripts for amoxicillin while I waiting for my attending to confirm the diagnosis.  He came out, agreed with the diagnosis and treatment plan and said: “We should put amoxicillin in the drinking water.”

And so it went.  Since that day I have heard the same thing about H-2 blockers, proton pump inhibitors, and statins.  All medications that are commonly prescribed for common problems.  Nobody has ever said that about lithium. In the conversations I have had about lithium over the past 30 years – people generally slow down, look concerned, and say something like: “That is a heavy-duty med isn’t it doc?” 

Lithium apparently got that reputation after it when it started to be widely used by psychiatrists for the treatment of bipolar disorder.  It was approved by the FDA in 1970 but was used as early as 1894 that for both bipolar disorder and melancholic depression (1).  It was also used in popular beverages and sought in the form of mineral water.  From 1929 to 1948 it was in 7-UP Lithiated Soda – a brand that eventually became 7-UP.  Lithium citrate was the active form and there is no reliable information on the concentration it originally contained.  One source suggests 5 mg/L (8) but it is not clear if this is as Li or a compound.  In psychiatry, that would be a trivial dose as either lithium carbonate or lithium citrate.  If it was really 5 milliequivalents (mEq) of lithium that would be roughly equivalent to 300 mg of lithium carbonate (Li₂CO₃) or 550 mg of lithium citrate (Li₃C₆H₅O₇).  Practically all the lithium prescribed by psychiatrists in the US is lithium carbonate in a range of 600-1800 mg/day.      

Lithium is considered a disease modifying drug in psychiatry for long term stabilization of bipolar disorder.  It is probably underutilized in the United States for both antidepressant augmentation and treatment of depression.  It may be underprescribed in general because it requires monitoring, has a narrow therapeutic index, can cause renal and thyroid complications, and has the potential for significant drug-drug interactions with a variety of medications that are commonly prescribed.  Investigations of its mechanism of action has led to some speculation that it may prevent neurodegeneration and be effective against psychiatric disorders even in very low doses.  These studies look at lithium exposure in the water supply and in animal models of neurodegeneration.  A recent paper suggests that lithium deficiency may cause Alzheimer’s dementia.

Before I get to a discussion of that paper, I thought I would review the ecology of lithium in the environment that is primarily focused on water chemistry.  I am referencing two major studies of lithium in the drinking water in the United States.  The first (3) looks at groundwater measurements at 18,027 states and uses that data to model lithium in the groundwater across the US.  They map that data and the maps are shown along with the original sampling sites at the maps at the top of this post.  As noted in the table, about 15% of these sites have a concentration of lithium that is greater than >30 μg/L.  That is significant because the Health Based Screening Level (HBSL) is 10 μg/L.  HBSLs are non-enforceable good faith benchmarks based on the latest drinking water and toxicity data.  Some of the sites measured in this study were exceeded by 1500 fold.

The second study was more specific for drinking water because it looked at samples directly from drinking water treatment plants (DWTP) (4).  Even though DWTPs have no specific processes for removal of lithium, the levels are significantly lower in range than the groundwater survey.  The surface water had a median level below the HBSL and groundwater level was higher.   The authors noted that 56% of the groundwater and 13% of the surface water sources of DWTPs exceeded the HBSL. 

In terms of pharmaceutical doses of lithium – the lowest dose I have ever prescribed was 150 mg as lithium carbonate.  Lithium carbonate is 18.79% lithium; therefore, each tablet or capsule contains about 28.185 mg of Li or 28,185 μg.  Looking at the range of concentration in the Lombard study (3) it would take ingesting 1.88 to 28M liters of those waters to be equivalent to a single 150 mg capsule per day.  In the case of the median groundwater and surface water from the Sharma (4) study it would take 176 to 216 liters to take in the equivalent amount. That study also suggests that drinking water sourced for treatment for human use is less likely to have extraordinary levels but does have levels that are currently flagged as a potential health risk.  Most people on lithium maintenance for bipolar disorder have much higher exposure to lithium than is likely from any drinking water source.  There are some commercially available lithium mineral waters that advertise a lithium level of 490 μg as Lithium Bicarbonate (LiHCO₃). That is equivalent to 50.3 μg Li (per liter) putting it in the range of both studies.

What does all of this say about the ecology and water chemistry of lithium?  Cleary there is a lot of variability.  Most water sources are not problematic but some with very high levels may be.  Drinking water surveillance appears to be a good approach to reducing exposure to high levels and many municipalities test for uncommon elements and organic compounds. Any attempts to correlate lithium in the water with medical or psychiatric outcomes needs to account for this variability and it is significant.  In the study that used machine learning to predict lithium levels with meteorological and geological variables – the results were modest.  I agree with the opinion that since the long-term effects of Li as a micronutrient are unknown and there is some toxicological concern as evidenced by the HBSL it should be studied (4).

That brings me to the recent study that has been heavily covered in the news (9).  I have received several questions about it and the most common questions are: “Does lithium prevent Alzheimer’s Disease?” and “If it does should I take it.”  I will preface my comments by saying this is a very well-done study.  It is also an intense study that is typical of what is published in both Nature and Science.  There are a mix of experiments using state of the art technology and they are all presented as crowded and very small graphics in the paper.  There is also a supplemental document (in this case 13 pages) of additional graphs and figures). 

The experimental sections of the paper can be broken down into a naturalistic look at a panel of metals concentrations in the brain and blood of subjects with normal cognition versus Alzheimer’s Disease (AD) or mild cognitive impairment, the effect of lithium deficiency in normal and mouse models of AD (3xTg and J20Ag), the effect of lithium on glycogen synthase kinase 3β  (GSK3β), the effect of lithium replacement, the impact of lithium on brain ageing in wild type mice, and determining an optimal form of lithium for replacement. 

The human brain samples depending on the experiment were from groups with no cognitive impairment (NCI)(n=22-133), Alzheimer’s Disease (AD)(n=5-105), and mild cognitive impairment (MCI)(n=7-66).  Brain samples were fractionated to check for metallic ion gradients and 27 ions were investigated.  Only Li showed lower levels in the cortex in both MCI and AD and it was also concentrated in the Aβ plaques.  The authors conclude that this shows a significant problem with Li homeostasis in both MCI and AD.  Some of the sampled ions like lead and arsenic are known neurotoxins.

Results of the experiments in mice are depicted in the diagram below.  3xTg mice are transgenic mice with three mutations (APPswe, PS1M146V, and TauP301L) associated with AD.  As noted, they accumulate Aβ and tau protein.  The J20Ag mice are transgenic mice that results in overexpression of amyloid precursor protein (APP).  Both mouse lines are considered models of AD.  In all cases lithium deficiency leads to accumulation of amyloid-β protein and other processes (where measured) consistent with AD like neurodegeneration at the behavioral, ultrastructural, and biochemical level. 

The authors demonstrate that lithium supplementation in mice prevents these changes in wild type mice.  They illustrate how blocking GSK3β prevents AD like changes.  They also demonstrate how a lithium compound (lithium orotate) with low solubility prevents lithium form being sequestered in Aβ plaques.  All experiments considered they provide a compelling backdrop for considering lithium as a therapy for MCI and AD.  Are there any other considerations?

First, there have been clinical trials of lithium in a number of neurodegenerative diseases including AD.  There have been several.  After some initial isolated enthusiasm for Li in the 1970s and 1980s for Parkinson's, some syndromes associated with Parkinson's (on-off, anergia), and Huntington’s – most of the reported research started in 2009.   Since then, there has been research on AD (10-13), ALS (14-19), MSA (20), MCI (21-23), Niemann Pick Disease (24), Machado Joseph Disease (26-27), and Spinocerebellar Ataxia, Type 2 (28).  In most of these papers the authors cite putative mechanisms of action of lithium based on preclinical trials and some positive pilot studies – but the overwhelming results were negative.  In all cases, the trials were approached from the perspective of using lithium in pharmaceutical ranges except for the trial that states it used microdosing on the range of 300 μg.  Tolerability varied widely among research subjects due to varying diagnoses, but even from study to study using modest doses.

My experience treating people with lithium in all age ranges leads me to a few conclusions that may apply here.  First, I have treated patient with lithium who have been on it for decades and developed AD. I recall one patient in particular who had marked cortical atrophy on brain imaging despite all of those years on lithium and no episodes of toxicity.  That obviously does not rule out lithium as a neuron sparing therapy but it does suggest that it will not work for everybody.  Second, part of the population will not be able to tolerate it or will not want to take it. I am fairly certain that any psychiatrist experienced in prescribing it will have no problems minimizing or preventing side effects.  In most 50-70 year olds that would be lithium carbonate in the range of 150-600 daily.  In the experiments cited above, microdoses of lithium orotate (4.3 μEq/L) for 12-14 months was the dose that prevented brain aging in mice (microgliosis and astrogliosis) and reduced pro-inflammatory cytokines.  That oral dose is roughly 1/1,000 the lowest prescribed pharmaceutical dose.  Third, I am not aware of any cases of lithium toxicity from people drinking groundwater or surface water with high Li concentrations.   

The question on many minds is “Should I start taking lithium to prevent Alzheimer’s Disease?”  The answer lies in the way the authors frame the discussion section of their paper.  Despite a lot of positive findings they state that “Disruption of Li homeostasis may contribute to the long prodromal period of neuropathological changes that occur prior to the onset of clinical AD.”    And – “Li deficiency is therefore a potential common mechanism for the multisystem degeneration of the brain that leads to the onset of AD”.  It is going to take replication and more work before these findings are widely accepted.  There are still a lot of unknowns about GSK3β signaling.  There have been mistakes made extrapolating from the preclinical studies in mice in the past.  Some of those mistakes were attributed to differences in mouse and human genetics and less heterogeneity in mice.   

That said, I know that will not prevent people from attempts at biohacking and taking supplemental lithium. If you are in that category, you should keep a few things in mind.  First, you have to know about drug dosing and the difference between pharmacological doses and supplemental doses. Lithium at pharmacological doses has a low therapeutic index (toxic dose range to therapeutic dose range) and it can cause kidney, thyroid, and parathyroid problems.  Second, there are many lithium orotate supplements currently available in a wide range of doses (5, 10, 20, 130 mg). They are advertised for "memory, state of mind, and behavioral health". None of these are clinical or FDA approved indications.  Any use of these products has to be considered experimental at this time and I recommend waiting for further data.

In summary, this is an excellent study that synthesizes clinical and preclinical data across a wide array of parameters that I have just touched on here.  If I was a young researcher just starting out, this would be the kind of research team I would be interested in joining.  It was an exciting paper to read.  At the same time it is a good test of how research may or may not be reproducible.  A common misconception is that it means the researchers did something wrong.  It seems obvious that it can happen just based on the sheer complexity. 

 

George Dawson, MD, DFAPA

 

Supplementary 1:

I am really interested in the mechanism of action of Li and all the links to GSK3β signaling.  I ran out of space in the above post and hope to elaborate on the mechanism soon.

Graphics Credit:

The lead graphic for this post is from reference 3 per the open access CC-BY-NC-ND 4.0 license. The remaining graphic and table were made by me from data in the given references.

 

References:

1:  Shorter E. The history of lithium therapy. Bipolar Disord. 2009 Jun;11 Suppl 2(Suppl 2):4-9. doi: 10.1111/j.1399-5618.2009.00706.x. PMID: 19538681; PMCID: PMC3712976.

2:  Coppen A. 50 years of lithium treatment of mood disorders. Bipolar Disord. 1999 Sep;1(1):3-4. doi: 10.1034/j.1399-5618.1999.10102.x. PMID: 11256652.

3:  Lombard MA, Brown EE, Saftner DM, Arienzo MM, Fuller-Thomson E, Brown CJ, Ayotte JD. Estimating Lithium Concentrations in Groundwater Used as Drinking Water for the Conterminous United States. Environ Sci Technol. 2024 Jan 16;58(2):1255-1264. doi: 10.1021/acs.est.3c03315. Epub 2024 Jan 2. PMID: 38164924; PMCID: PMC10795177.

4:  Sharma N, Westerhoff P, Zeng C. Lithium occurrence in drinking water sources of the United States. Chemosphere. 2022 Oct;305:135458. doi: 10.1016/j.chemosphere.2022.135458. Epub 2022 Jun 23. PMID: 35752313; PMCID: PMC9724211.

5:  Norman JE, Toccalino PL, Morman SA, 2018. Health-Based Screening Levels for evaluating water-quality data (2d ed.). U.S. Geological Survey web page, accessible at https://water.usgs.gov/water-resources/hbsl/, doi:10.5066/F71C1TWP

6:  Seidel U, Jans K, Hommen N, Ipharraguerre IR, Lüersen K, Birringer M, Rimbach G. Lithium Content of 160 Beverages and Its Impact on Lithium Status in Drosophila melanogaster. Foods. 2020 Jun 17;9(6):795. doi: 10.3390/foods9060795. PMID: 32560287; PMCID: PMC7353479.

7:  El-Mallakh RS, Roberts RJ. Lithiated lemon-lime sodas. Am J Psychiatry. 2007 Nov;164(11):1662. doi: 10.1176/appi.ajp.2007.07081255. PMID: 17974929.

8:  Neves MO, Marques J, Eggenkamp HGM. Lithium in Portuguese Bottled Natural Mineral Waters-Potential for Health Benefits? Int J Environ Res Public Health. 2020 Nov 12;17(22):8369. doi: 10.3390/ijerph17228369. PMID: 33198207; PMCID: PMC7696288.

One of the most popular soft drinks in the world was launched in 1929; the “Lithiated Lemon Soda” that was supplemented with 5 mg Li (as Li citrate/L) until 1948 [16], when it was banned by the government. It was believed to cure alcohol-induced hangover symptoms, make people more energetic and give lust for life and on the top of that shinier hair and brighter eyes [17]. In fact, it is still on the market but since 1936 its name changed to 7UP. In 1949, John Cade discovered that higher Li concentrations were toxic. Nowadays, according Seidel et al. [16] 7UP only contains 1.4 µg Li/L.

9:  Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner BA. Lithium deficiency and the onset of Alzheimer's disease. Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09335-x. Open Access.

The paper suggests that Li may be a critical micronutrient in terms of brain function.

AD: 

10:  Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res. 2013 Jan;10(1):104-7. doi: 10.2174/1567205011310010014. PMID: 22746245.

As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 μg, administered once daily on AD patients for 15 months

11:  Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009 Jun;70(6):922-31. PMID: 19573486.

“The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.”

12:  Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. A feasibility and tolerability study of lithium in Alzheimer's disease. Int J Geriatr Psychiatry. 2008 Jul;23(7):704-11. doi: 10.1002/gps.1964. PMID: 18181229.

“Lithium treatment in elderly people with AD has relatively few side effects and those that were apparently due to treatment were mild and reversible. Nonetheless discontinuation rates are high. The use of lithium as a potential disease modification therapy in AD should be explored further but is not without problems.”

13:  Leyhe T, Eschweiler GW, Stransky E, Gasser T, Annas P, Basun H, Laske C. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. J Alzheimers Dis. 2009;16(3):649-56. doi: 10.3233/JAD-2009-1004. PMID: 19276559.

“We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found.”

ALS:

14:  Boll MC, Alcaraz-Zubeldia M, Rios C, González-Esquivel D, Montes S. A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients. Neurologia (Engl Ed). 2025 Jan-Feb;40(1):32-40. doi: 10.1016/j.nrleng.2022.07.003. Epub 2022 Aug 29. PMID: 36049647.

15:  UKMND-LiCALS Study Group; Morrison KE, Dhariwal S, Hornabrook R, et al. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013 Apr;12(4):339-45. doi: 10.1016/S1474-4422(13)70037-1. Epub 2013 Feb 27. Erratum in: Lancet Neurol. 2013 Sep;12(9):846. PMID: 23453347; PMCID: PMC3610091.

16:  Verstraete E, Veldink JH, Huisman MH, Draak T, Uijtendaal EV, van der Kooi AJ, Schelhaas HJ, de Visser M, van der Tweel I, van den Berg LH. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. J Neurol Neurosurg Psychiatry. 2012 May;83(5):557-64. doi: 10.1136/jnnp-2011-302021. Epub 2012 Feb 29. PMID: 22378918.

17:  Miller RG, Moore DH, Forshew DA, Katz JS, Barohn RJ, Valan M, Bromberg MB, Goslin KL, Graves MC, McCluskey LF, McVey AL, Mozaffar T, Florence JM, Pestronk A, Ross M, Simpson EP, Appel SH; WALS Study Group. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology. 2011 Sep 6;77(10):973-9. doi: 10.1212/WNL.0b013e31822dc7a5. Epub 2011 Aug 3. PMID: 21813790; PMCID: PMC3171956.

18:  Chiò A, Borghero G, Calvo A, Capasso M, Caponnetto C, Corbo M, Giannini F, Logroscino G, Mandrioli J, Marcello N, Mazzini L, Moglia C, Monsurrò MR, Mora G, Patti F, Perini M, Pietrini V, Pisano F, Pupillo E, Sabatelli M, Salvi F, Silani V, Simone IL, Sorarù G, Tola MR, Volanti P, Beghi E; LITALS Study Group. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology. 2010 Aug 17;75(7):619-25. doi: 10.1212/WNL.0b013e3181ed9e7c. Epub 2010 Aug 11. PMID: 20702794.

“Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS.”

19:  Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M; Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 May;9(5):481-8. doi: 10.1016/S1474-4422(10)70068-5. Epub 2010 Apr 1. PMID: 20363190; PMCID: PMC3071495.

Multiple System Atrophy (MSA)

20:  Saccà F, Marsili A, Quarantelli M, Brescia Morra V, Brunetti A, Carbone R, Pane C, Puorro G, Russo CV, Salvatore E, Tucci T, De Michele G, Filla A. A randomized clinical trial of lithium in multiple system atrophy. J Neurol. 2013 Feb;260(2):458-61. doi: 10.1007/s00415-012-6655-7. Epub 2012 Aug 30. PMID: 22932748.

MCI: 

21:  Damiano RF, Loureiro JC, Pais MV, Pereira RF, Corradi MM, Di Santi T, Bezerra GAM, Radanovic M, Talib LL, Forlenza OV. Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment. Braz J Psychiatry. 2023 Mar 11;45(1):46-49. doi: 10.47626/1516-4446-2022-2767. PMID: 36049127; PMCID: PMC9976922.

22:  Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668-674. doi: 10.1192/bjp.2019.76. PMID: 30947755.

23:  Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. doi: 10.1192/bjp.bp.110.080044. PMID: 21525519.

Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better performance on the cognitive subscale of the Alzheimer's Disease Assessment.

Niemann Pick Disease:

24:  Han S, Zhang H, Yi M, Liu X, Maegawa GHB, Zou Y, Wang Q, Wu D, Ye Z. Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1. Front Pharmacol. 2021 Jun 9;12:667361. doi: 10.3389/fphar.2021.667361. PMID: 34177581; PMCID: PMC8220070.

MS:

25:  Rinker JR 2nd, Meador WR, King P. Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis. Heliyon. 2020 Jul 28;6(7):e04528. doi: 10.1016/j.heliyon.2020.e04528. PMID: 32760832; PMCID: PMC7393418.

Machado Joseph Disease:

26:  Saute JA, Rieder CR, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D'Ávila R, Souza GN, Russo AD, Furtado GV, Gheno TC, Souza DO, Saraiva-Pereira ML, Portela LV, Camey S, Torman VB, Jardim LB. Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial. J Neurol Sci. 2015 Nov 15;358(1-2):72-6. doi: 10.1016/j.jns.2015.08.019. Epub 2015 Aug 14. PMID: 26297649.

27:  Saute JA, de Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D'Ávila R, Souza GN, Russo AD, Furtado GV, Gheno TC, de Souza DO, Portela LV, Saraiva-Pereira ML, Camey SA, Torman VB, de Mello Rieder CR, Jardim LB. A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord. 2014 Apr;29(4):568-73. doi: 10.1002/mds.25803. Epub 2014 Jan 7. PMID: 24399647.

Spinocerebellar Ataxia Type 2:

28:  Saccà F, Puorro G, Brunetti A, Capasso G, Cervo A, Cocozza S, de Leva M, Marsili A, Pane C, Quarantelli M, Russo CV, Trepiccione F, De Michele G, Filla A, Morra VB. A randomized controlled pilot trial of lithium in spinocerebellar ataxia type 2. J Neurol. 2015 Jan;262(1):149-53. doi: 10.1007/s00415-014-7551-0. Epub 2014 Oct 28. PMID: 25346067.

Huntington’s Disease:

29:  Aminoff MJ, Marshall J. Treatment of Huntington's chorea with lithium carbonate. A double-blind trial. Lancet. 1974 Jan 26;1(7848):107-9. doi: 10.1016/s0140-6736(74)92339-3. PMID: 4130308.