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. Lithium is the 32nd most abundant element in the Earth and distribution in nature is variable.
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 amyloid- β protein (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. 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 patients 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 commonest reasons for lithium toxicity in people taking pharmaceutical doses include water and salt imbalances like dehydration, drug-drug interactions, and improper dosing and/or monitoring.
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 about a lack of reproducibility 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:
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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.
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The paper suggests that Li may be a critical
micronutrient in terms of brain function.
AD:
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TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in
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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
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“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.”
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“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.”
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“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,
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“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,
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Multiple System Atrophy (MSA)
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MCI:
21: Damiano RF,
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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
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MS:
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clinical effects of lithium in progressive multiple sclerosis. Heliyon. 2020
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Machado Joseph Disease:
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Russo AD, Furtado GV, Gheno TC, Souza DO, Saraiva-Pereira ML, Portela LV, Camey
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Spinocerebellar Ataxia Type 2:
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Huntington’s Disease:
29: Aminoff MJ,
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