Endogenous Lithium & the claimed effect on dementia, suicide etc: A critique
Endogenous Lithium & the claimed effect on dementia, suicide etc: A critique
Papers by various research groups have suggested relationships between (inter alia) suicide, dementia, and aggressive behaviour, with the (ultra-low) levels of lithium (Li) in reticulated drinking-water supplies (‘tap-water’). The notion of adding Li to drinking water supplies has even been mooted and covered in the mass media. However, Li in tap-water is only a small proportion of the total dietary Li intake. There are no data in these population studies confirming the crucial question of whether there are actually different blood levels of Li, and 24 hr Li excretion, in subjects from the different areas that have different Li tap-water levels, who are included in such associative epidemiological analysis. This commentary clarifies these fundamental errors with relevant data from the scientific literature which has not been cited previously in this context. Such data clarify certain key points about Li intake, and the regulation of usual, but very low, endogenous Li levels. These data indicate clearly and unequivocally that such ‘associative epidemiology’ is conceptually flawed, methodologically unsound, incorrect, as well as being naïvely over-interpreted. It constitutes yet another example of science that would never have been published if editorial and refereeing standards of journals were adequate, or up to proper scientific standards.
There are an increasing number of publications that can be described as ‘associative epidemiology’ trying to link lithium (Li) in reticulated tap-water with various aspects of nervous system functioning, such as dementia, mood states and suicide, aggressive behaviour, and onychocryptosis.
I refer to these studies as ‘associative epidemiology’ because the scientific and logical observations and requirements that might indicate even a slight chance of an actual causal link are absent. The old trope of ‘association is not causation’ endures because each new generation of researchers repeat the same mistakes, with dispiriting and tedious regularity. This expanding area of investigation is an example of ignorance of basic science, of methodology, and misunderstanding of statistics and P-values (1). A Bayesian would want to think about the ‘prior probability’ and require rather better evidence. See:
I have previously discussed concepts related to establishing cause-and-effect relationships (the Bradford Hill ‘criteria’), which are not well-observed in psychiatry (2). The above link contains a summary about this — my previous discussion (3, 4) was related to criticism of the weak cause-and-effect nexus between neuroleptic drugs and neuroleptic malignant syndrome (NMS).
The principles enumerated by Sir Austin Bradford Hill, that are often referred to as the Bradford Hill criteria, have sometimes been used a little simplistically and have been further refined more recently (5-7).
There are major misunderstandings in the published studies concerning regulation of the usual trace-amounts of dietary Li intake in humans, and the sources of the ingested Li. This review discusses how these errors and misconceptions demonstrate that the studies thus far are invalid.
Endogenous Lithium: trace levels and their regulation
The best replicated and most recent data indicate that typical human ‘endogenous’ serum Li levels (i.e. background levels arising from obligate-ingestion from food and water) are around 0.0003 mmol/L and show low variation (~ 0.0001 -0.0005) in relation to dietary ingestion amounts. Current best estimates of dietary daily intake are 0.1-3 mg/day, of which ~30% is from ‘water’ (see below).
We were taught that naturally (i.e. in people not taking any form of Li treatment) there was no Li the body, and many doctors may still think that. It is, of course, a question of limits of detection/quantification (LODs/LOQs): usual laboratory methods are insufficiently sensitive to measure such low Li levels, and they are therefore not detected by medical laboratory tests.
The measurement of microgram levels of endogenous Li (and other trace metals) in biological tissues and fluids involves technical challenges and difficulties (8-10) and some older (<1996) reported measurements are probably best discounted.
The use of the measurement of fractional Li excretion in hypertension research, which involves measuring endogenous Se Li and 24 hr. Li excretion, has produced large samples of endogenous serum Li levels in humans (well in excess of 1,000 subjects). As a result, the group at the Studies Coordination Centre, Laboratory of Hypertension, Leuven, Belgium (11, 12), have concluded ‘These observations suggest that serum lithium is tightly regulated (at ~0.0003 mmol/l), despite large variations in dietary intake’. All subjects had 24 hr urine Li estimated, which had, in the Belgium sample an average of 5 µmol of Li, equating to a daily intake of ~0.3 mg of Li, and in a South African sample 1 µmol, equating to a daily intake of ~0.06 mg: yet the mean Se Li levels in these two groups were almost identical, and within a narrow range.
Cwynar et al. found almost identical results in 130 subjects in Poland (13).
Since Li intake can be inferred from the 24-hour urine samples, these data also represent the largest body of values approximating typical dietary intake, and they suggest an intake of ~0.2 mg/day: the French TDS estimate was 0.05 mg.
Incidentally, out of 1278 subjects 36 were excluded because of a ‘very high Li concentration in serum (>0.001 mmol/L)’ which they considered indicated ‘external contamination’ (i.e. ingestion of ‘supplements’, e.g. Li-rich mineral water, see below).
In view of the size of the above sample, discussion of other results (especially those using older assay methods), is superfluous. However, Miller found serum Li levels around 0.00016 mmol/L for normal subjects dwelling in the Denver metropolitan area. The mean 24-hr excretion rate was 0.005 mmol/day (14), identical to the value found by the Leuven group. Folkerd (15) found a mean 0.00027 +/- 0.02 mmol/l (n = 25, range 0.00013-0.00055 mmol/l).
In summary: at usual levels of dietary intake (~0.1-3 mg/day), which are now rather more reliably established, Se Li is tightly regulated between about 0.0001-0.0003 mmol/L. Se Li is not proportional to daily intake in this range.
These data are informative concerning how unscientific some research has been: Nunes et al. gave 0.3 mg/day to try to help dementia. Since this is in the normal dietary intake range, it is a misconceived trial, since it is unlikely to have significantly altered pre-existing levels (16).
Shiotsuku’s study (17) of subjects drinking large amounts of Li-rich mineral-water at a spa, although methodologically weak and lacking key data, seems to be the only study with Se Li estimations in subjects (n=43) ingesting Li in doses of around 20-50 mg/day — despite the poor description and methodology (one can hardly believe this fellow is really a ‘professor’) the Se Li averaged 0.07 mmol/L, which is 100 times higher than usual endogenous levels.
NB. An insight into the lax methodology in this study “After drinking lithium mineral water, body weight was increased but not significantly (57.6±10.0 to 59.3±9.1 kg, p<0.08).
If you drink one liter of water you will be one kilo heavier — physics! Their analysis is irrational.
These data indicate that the tight regulation of Se Li levels at endogenous Li intakes of 0.1-3 mg/day breaks down once intake reaches around 5-20 mg/day, when it becomes proportional to the daily dose, as it is when Li is used therapeutically for BPD at doses of around 1,000 mg/day.
Tap-water: small proportion of daily intake
The above data demonstrate that dietary Li intake below ~5 mg/day is tightly regulated and variations within this range will not much affect serum Li levels.
Furthermore, all the epidemiological research relates to average levels in the reticulated water supply (viz. tap-water). But that tap-water constitutes only a minor proportion of typical daily dietary Li intake. That is clear from data in the Second French TDS (18) which has produced a figure for daily Li intake of 0.05 mg/day, and water contributed only 35% of Li intake in adults, i.e. only 0.015 mg — not all of which is ‘tap-water’ — a significant % is bottled water (which, of course, does not come from the area where the subject lives, it may even come from a different continent).
It is reasonable to deduce from those data that tap-water constitutes only about 10% of total daily Li intake in most people, and less in many others (e.g. those people who drink mainly bottled water).
It should be noted that the consumption of bottled spring-water is a multi-billion-dollar industry throughout the ‘western’ world and bottled waters have five times higher average Li concentrations: viz. median level of bottled waters is 0.010 mg/L vs. 002 mg/L for tap-water (19-24). Sales figures indicate that about one thousand bottles of ‘mineral’ water are sold per person per year (USA: 30 billion bottles in 2008). In Europe the consumption figure varies between 50-200 L per person/year. Source (European Federation of Bottled Waters): http://efbw.eu/bwf.php?classement=07 .
The extensive data that now exist on Li levels in reticulated water (which usually comes from surface water, rather than subterranean water) is reviewed elsewhere. It is notable that psychiatric publications are unaware of these data (the seminal citations herein do not appear in the ‘Psych’ literature — poor research and 3rd-rate refereeing yet again). Levels in surface water are generally extremely low, usually a few thousandths of a mg/L (<0.002 mg/L) and often as low a few millionths of a mg/L (0.000,005 mg/L) (19-21, 25), but levels in bottled mineral water from springs and underground supplies can be quite high: this has been assessed at 884 different European sites which had a median level of 0.010 mg/L. Thus, a typical bottled mineral water is equivalent to 5 L of tap-water which indicates that even low levels of consumption would substantially alter the Li intake from ‘water’. A large proportion of subjects live in areas where the concentration in tap-water is only a few millionths of mg/L, and they therefore do not ingest a significant amount of Li from tap-water.
These data demonstrate that it is certain a majority of the subjects in these samples will have been ingesting far more Li from bottled mineral/spring-water than from tap-water. That is, without any doubt whatsoever, enough to make a complete and utter nonsense of this supposed ‘epidemiological’ data.
Two fatal flaws
In summary, there are two fatal flaws invalidating research concerning endogenous Li in tap-water and its effect on humans.
First, at endogenous levels of intake serum Li is not proportional to intake, it is tightly regulated within a narrow range.
Second, even if the ingested amount of Li made a difference, it would not be as a result of varying Li levels in the reticulated tap-water supply, because that is a minor contributor to total dietary Li intake.
Therefore, trying to correlate Li in tap-water with suicide, or any other state or condition, in different geographical areas with different water supplies is, a priori, irrational and without any scientific basis.
For those out there who still think that the refereeing system for scientific articles in journals is functioning adequately I suggest the example of the multiple papers that have been refereed (obviously inadequately) on this subject constitutes a solid refutation of that notion. Serotonin toxicity, my area of special expertise, proves this proposition even more decisively — the literature in this field has become a stream of utter nonsense; e.g. see here for the most egregious example to cross my desk for some time:
Further publications about Lithium and Suicide
Here are yet more recent publications (subsequent to my initial posted comment a few years ago) about Li and suicide etc. to add to the steady trickle from the last two decades, which now seems to be turning into a flood (26-48)
The only critical and negative study I recall seeing was Parker et al. (27). There are yet more studies and comments, but since they are largely pointless, and mostly a waste money, and paper, it is hardly worth expending the effort to search multiple databases for them.
All sorts of ill-considered suggestions have been aired, and picked-up by the media: e.g. McGrath and Berk recently stated: ‘… the prospect that a relatively safe, simple, and cheap intervention (i.e. optimizing lithium concentrations in the drinking water) could lead to the primary prevention of dementia is a tantalizing prospect (30): and there are other similarly ill-informed and ill-judged comments, which will have the social conspiracy theorists in a frenzy in no time (cf. fluoride).
Lastly, the failure to measure serum levels of Li in a sample of subjects in different areas (exposed to different levels of Li in their tap-water) and to (attempt to) establish a correlation between the two variables, is a quite extraordinary omission which speaks to the lack of methodological competence of these various authors. One has to wonder where these researchers learnt their science and what they were thinking when they planned their projects. I will not even comment on the perspicacity of reviewers who approved the grants for these projects, or the fact that it is likely few, if any, of these papers underwent expert statistical review. Some of these projects/papers must have cost a great deal of money — all utterly wasted.
The irony is that they did not even need to do those measurements for themselves, because, as explained above, it has already been done for them, in more than 1000 subjects (11, 12). But none of these researchers recognized that fact.
1. Greenland, S, Senn, SJ, Rothman, KJ, Carlin, JB, et al., Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur. J. Epidemiol., 2016. 31(4): p. 337-50.
2. Phillips, CV and Goodman, KJ, The missed lessons of Sir Austin Bradford Hill. Epidemiol Perspect Innov, 2004. 1(1): p. 3.
3. Gillman, PK, Neuroleptic Malignant Syndrome: Mechanisms, Interactions and Causality. Mov. Disord., 2010. 25(12): p. 1780-1790.
4. Gillman, PK, Neuroleptic malignant syndrome: half a century of uncertainty suggests a Chimera. Pharmacoepidemiol Drug Saf, 2010. 19(8): p. 876-7.
5. Hernan, MA and Robins, JM, Estimating causal effects from epidemiological data. J. Epidemiol. Community Health, 2006. 60(7): p. 578-86.
6. Muthen, B and Brown, HC, Estimating drug effects in the presence of placebo response: causal inference using growth mixture modeling. Stat. Med., 2009. 28(27): p. 3363-85.
7. Maldonado, G and Greenland, S, Estimating causal effects. Int. J. Epidemiol., 2002. 31(2): p. 422-9.
8. Subramanian, KS, Determination of metals in biofluids and tissues: sample preparation methods for atomic spectroscopic techniques. Spectrochimica Acta Part B: Atomic Spectroscopy, 1996. 51(3): p. 291-319.
9. Lu, Y, Kippler, M, Harari, F, Grandér, M, et al., Alkali dilution of blood samples for high throughput ICP-MS analysis—comparison with acid digestion. Clin. Biochem., 2015. 48(3): p. 140-147.
10. Clarke, WB, Guscott, R, Downing, RG, and Lindstrom, RM, Endogenous lithium and boron red cell-plasma ratios: normal subjects versus bipolar patients not on lithium therapy. Biol. Trace Elem. Res., 2004. 97(2): p. 105-16.
11. Seidlerova, J, Staessen, JA, Maillard, M, Nawrot, T, et al., Association between arterial properties and renal sodium handling in a general population. Hypertension, 2006. 48(4): p. 609-15.
12. Bochud, M, Staessen, JA, Woodiwiss, A, Norton, G, et al., Context dependency of serum and urinary lithium: implications for measurement of proximal sodium reabsorption. Hypertension, 2007. 49(5): p. e34.
13. Cwynar, M, Gasowski, J, Gluszewska, A, Krolczyk, J, et al., Blood pressure, arterial stiffness and endogenous lithium clearance in relation to AGTR1 A1166C and AGTR2 G1675A gene polymorphisms. J Renin Angiotensin Aldosterone Syst, 2016. 17(2): p. 1470320316655669.
14. Miller, NL, Durr, JA, and Alfrey, AC, Measurement of endogenous lithium levels in serum and urine by electrothermal atomic absorption spectrometry: a method with potential clinical applications. Anal. Biochem., 1989. 182(2): p. 245-9.
15. Folkerd, E, Singer, DR, Cappuccio, FP, Markandu, ND, et al., Clearance of endogenous lithium in humans: altered dietary salt intake and comparison with exogenous lithium clearance. Am. J. Physiol., 1995. 268(4 Pt 2): p. F718-22.
16. Nunes, MA, Viel, TA, and Buck, HS, Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimers disease. Curr Alzheimer Res, 2012.
17. Shiotsuki, I, Terao, T, Ogami, H, Ishii, N, et al., Drinking spring water and lithium absorption: a preliminary study. German Journal of Psychiatry, 2008. 11: p. 103-106.
18. Kalonji, E, Sirot, V, Noel, L, Guerin, T, et al., Nutritional Risk Assessment of Eleven Minerals and Trace Elements: Prevalence of Inadequate and Excessive Intakes from the Second French Total Diet Study. European Journal of Nutrition & Food Safety, 2015. 5(4): p. 281-296.
19. Krachler, M and Shotyk, W, Trace and ultratrace metals in bottled waters: Survey of sources worldwide and comparison with refillable metal bottles. Sci. Total Environ., 2009. 407: p. 1089–1096.
20. Demetriades, A, Reimann, C, and Birke, M, European Ground Water Geochemistry Using Bottled Water as a Sampling Medium in Clean Soil and Safe Water. 2012, Springer Netherlands: Dordrecht. p. 115-139.
21. Reimann, C and M, B, Geochemistry of European bottled water. 268 pp. Available online at:
http://www.schweizerbart.de/publications/detail/artno/001201002. 2010, Stuttgart: Borntraeger Science Publishers.
22. Levei, E, Hoaghia, M, and Savastru, R, Quality assessment of Romanian bottled mineral water and tap water. Environmental monitoring and assessment, 2016. 188(9): p. 521.
23. González-Weller, D, Rubio, C, Gutiérrez, ÁJ, González, GL, et al., Dietary intake of barium, bismuth, chromium, lithium, and strontium in a Spanish population (Canary Islands, Spain). Food Chem. Toxicol., 2013. 62: p. 856-868.
24. Harari, F, Åkesson, A, Casimiro, E, Lu, Y, et al., Exposure to lithium through drinking water and calcium homeostasis during pregnancy: a longitudinal study. Environ. Res., 2016. 147: p. 1-7.
25. Salminen, R, Batista, M, Bidovec, M, Demetriades, A, et al., Geochemical atlas of Europe. Part 1 – Background information, methodology and maps. Geological Survey of Finland, Espoo, Finland, 2005: p. http://www.gtk.fi /.
26. Shimodera, S, Koike, S, Ando, S, Yamasaki, S, et al., Lithium levels in tap water and psychotic experiences in a general population of adolescents. Schizophr. Res., 2018.
27. Parker, WF, Gorges, RJ, Gao, YN, Zhang, Y, et al., Association Between Groundwater Lithium and the Diagnosis of Bipolar Disorder and Dementia in the United States. JAMA Psychiatry, 2018.
28. Ishii, N and Terao, T, Trace lithium and mental health. J Neural Transm (Vienna), 2018. 125(2): p. 223-227.
29. Brown, EE, Gerretsen, P, Pollock, B, and Graff-Guerrero, A, Psychiatric benefits of lithium in water supplies may be due to protection from the neurotoxicity of lead exposure. Med. Hypotheses, 2018. 115: p. 94-102.
30. McGrath, JJ and Berk, M, Could Lithium in Drinking Water Reduce the Incidence of Dementia? JAMA Psychiatry, 2017. 74(10): p. 983-984.
31. Knudsen, NN, Schullehner, J, Hansen, B, Jørgensen, LF, et al., Lithium in Drinking Water and Incidence of Suicide: A Nationwide Individual-Level Cohort Study with 22 Years of Follow-Up. International Journal of Environmental Research and Public Health, 2017. 14(6): p. 627.
32. Liaugaudaite, V, Mickuviene, N, Raskauskiene, N, Naginiene, R, et al., Lithium levels in the public drinking water supply and risk of suicide: a pilot study. J. Trace Elem. Med. Biol., 2017.
33. Kessing, L, Gerds, T, Knudsen, N, Jørgensen, L, et al., Lithium in drinking water and the incidence of bipolar disorder: A nation-wide population-based study. Bipolar disorders, 2017.
34. Fajardo, VA, Fajardo, VA, LeBlanc, PJ, and MacPherson, RE, Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer’s Disease Mortality in Texas. Journal of Alzheimer’s Disease, 2017(Preprint): p. 1-10.
35. Kavanagh, L, Keohane, J, Cleary, J, Garcia Cabellos, G, et al., Lithium in the Natural Waters of the South East of Ireland. Int J Environ Res Public Health, 2017. 14(6).
36. Kessing, LV, Gerds, TA, Knudsen, NN, Jorgensen, LF, et al., Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry, 2017. 74(10): p. 1005-1010.
37. Kessing, LV, Gerds, TA, Knudsen, NN, Jorgensen, LF, et al., Lithium in drinking water and the incidence of bipolar disorder: A nation-wide population-based study. Bipolar Disord, 2017. 19(7): p. 563-567.
38. Grof, P, Old treatment and new curiosity: Lithium in drinking water. Bipolar Disord, 2017. 19(7): p. 597-598.
39. Kanehisa, M, Terao, T, Shiotsuki, I, Kurosawa, K, et al., Serum lithium levels and suicide attempts: a case-controlled comparison in lithium therapy-naive individuals. Psychopharmacology, 2017. 234(22): p. 3335-3342.
40. Ando, S, Koike, S, Shimodera, S, Fujito, R, et al., Lithium Levels in Tap Water and the Mental Health Problems of Adolescents: An Individual-Level Cross-Sectional Survey. J Clin Psychiatry, 2017. 78(3): p. e252-e256.
41. Devadason, P, Is there a role for lithium orotate in psychiatry? Aust NZ J Psychiatry, 2018: p. 0004867418810185.
42. Szklarska, D and Rzymski, P, Is Lithium a Micronutrient? From biological activity and epidemiological observation to food fortification. Biol. Trace Elem. Res., 2019. 189(1): p. 18-27.
43. Pompili, M, Gonda, X, Serafini, G, Innamorati, M, et al., Epidemiology of suicide in bipolar disorders: a systematic review of the literature. Bipolar Disord, 2013. 15(5): p. 457-90.
44. Pompili, M, Serafini, G, Innamorati, M, Ambrosi, E, et al., Antidepressants and Suicide Risk: A Comprehensive Overview. Pharmaceuticals (Basel), 2010. 3(9): p. 2861-2883.
45. Pompili, M, Vichi, M, Dinelli, E, Pycha, R, et al., Relationships of local lithium concentrations in drinking water to regional suicide rates in Italy. World J Biol Psychiatry, 2015: p. 1-8.
46. Vita, A, De Peri, L, and Sacchetti, E, Lithium in drinking water and suicide prevention: a review of the evidence. Int. Clin. Psychopharmacol., 2015. 30(1): p. 1-5.
47. Shiotsuki, I, Terao, T, Ishii, N, Takeuchi, S, et al., Trace lithium is inversely associated with male suicide after adjustment of climatic factors. J Affect Disord, 2016. 189: p. 282-6.
48. Ishii, N, Terao, T, Araki, Y, Kohno, K, et al., Low risk of male suicide and lithium in drinking water. J Clin Psychiatry, 2015. 76(3): p. 319-26.