As a medical treatment for bipolar, lithium has a tarnished reputation. Many patients and providers view the drug as side-effect prone or downright dangerous. And yet, lithium remains one of the most effective drugs for treating bipolar disorder with researchers often recommending using the drug more, rather than less (Severus 2018).
Beyond its use for bipolar, lithium also has potential for other conditions. One area receiving at least some recent attention due to the pandemic is lithium’s effect on helping prevent or treat viral infections. While most of the evidence is preliminary and comes from cell culture work, there are indications derived from human trials that appear to indicate clinical effects of note.
Lithium has been shown to have potential benefits for treating:
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Herpes virus
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Human Immunodeficiency Virus
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Coronavirus infections
Lithium and Herpes Family Viruses
In cell culture, lithium has been shown to inhibit herpes viral replication (Ziaie 1994, Hartley 1993, Cernescu 1988, Skinner 1980). The effect was present at levels that did not interfere with cellular replication (Skinner 1980). In addition, lithium appeared to interfere with viral protein synthesis, inhibiting viral messenger RNA (mRNA), while mostly not interfering with cellular mRNA (Ziaie 1994).
While a rabbit study using lithium to treat herpes reactivation appeared to show no benefit (Trousdale 1984), case studies in patients already taking lithium for bipolar with herpes infections were noting benefits with treatment (Bschor 1999, Gillis 1983 Lieb 1979). A review article noted “greatly reduced frequency of labial viral recurrences” in bipolar patients with herpes infections on lithium for maintenance therapy (Rybakowski 2000).
A small placebo controlled clinical trial using lithium for recurrent herpes outbreaks noted reductions in the number of episodes per month, duration of each episode, the number of days with infections and the maximum severity, while placebo subjects had mostly worsening outcomes (Amsterdam 1996). Most likely due to the study being so small the results were only trends and didn’t achieve a fully significant outcome (p = .08). A previous study by the same group using lithium for herpes labialis did show significant improvement in patients with lithium treatment (Amsterdam 1990).
Lithium and Human Immunodeficiency Virus
While the data on lithium and herpes virus appears a little more clear cut, the benefits with human immunodeficiency virus (HIV) probably still remains to be fully characterized. Early research suggested that lithium helped improve immune responses of white blood cells from HIV+ patients in response to antigenic stimulation (Sztein 1987). A small clinical trial using lithium in an attempt to treat HIV directly, however, ended in failure with the majority of patients developing lithium toxicity and none of the patients showing decreased viral load (Parenti 1988).
Two early case reports in patients with bipolar and HIV+ treated with lithium have been described. In both patients T-cell counts improved with lithium treatment, with one patient having worsening T-cell counts after withdrawal of the medication and improvement upon re-initiation (Jordan 1992). Later studies showed reduced viral load in patients on lithium before other antiretroviral therapy, with viral loads that increased with decreasing doses of lithium (Kumar 2008). In patients on antiretroviral therapy, the addition of lithium carbonate reduced the remaining pool of HIV infected cells (Puertas 2014).
One of the effects of HIV infection is long-term cognitive side effects, including dementia. The damage to neurons is likely, at least in part, mediated through the HIV glycoprotein gp120 that directly damages neurons. Initial animal studies suggested that lithium can protect from HIV gp120 induced neuronal damage (Everall 2002). The animal studies were followed by a 12 week human trial in 12 HIV patients struggling with HIV-induced cognitive impairment. All eight patients had improvements, with six eliminating their cognitive impairment with the use of lithium (Letendre 2006). A separate study attempted to replicate the findings and found improvements visible upon imaging, yet no significant cognitive improvements at ten weeks (Schifitto 2009). The largest and most recent controlled trial of lithium for cognitive impairment in HIV patients showed no difference with lithium compared to placebo. Interestingly, both treatment and placebo groups had significant cognitive improvement over the course of 24 weeks, cutting their global deficit scores in half (Decloedt 2016).
Lithium and Coronavirus
Based on earlier work showing antiviral effects, studies on lithium’s ability to inhibit coronavirus replication in-vitro has been explored. Coronaviruses are common viruses that can cause mild to serious infections in farm animals (and humans), making their treatment of economic interest.
Initial cell culture studies on porcine epidemic diarrhea virus, transmissible gastrointestinal coronavirus and avian coronavirus have all shown potential for lithium as a possible treatment (Li 2018, Ren 2011, Li 2009, Harrison 2007). Based on the promising data for animal coronaviruses, numerous reviews have suggested using lithium as a treatment for COVID-19 (Gomez-Bernal 2020, Murru 2020, Nowak 2020).
Since lithium appears to arrest viral reproduction and downregulate the potentially lethal inflammatory cascade initiated by infection, researchers have advocated for clinical trials or a review of patients on lithium for bipolar disorder and outcomes of COVID-19 (Rudd 2020). However, amidst the excitement, it is worth remaining cautious, since viral infections, including coronavirus, appears to increase risks of lithium toxicity (Suwanwongse 2020). Likely, safe dosing during infection is less than standard dosing used for treating bipolar disorder.
Lithium’s Benefits for Increasing Low White Blood Cell Counts
Lithium is generally considered the treatment of choice in bipolar disorder (Goodwin 2016). Yet, as a mineral, lithium has a number of interesting and less well known effects. One effect often seen with lithium treatment is a potential change in white blood count. Listed under the common side effects from taking prescription lithium is reversible leukocytosis (Epocrates 2021). Lithium’s effects on white blood cells is fairly well known and has been explored for potential therapeutic benefits.
Hematopoietic Effects of Lithium
Even before lithium’s widespread use for mania, researchers had noted increased white blood cells in individuals taking the mineral, initially as a salt substitute (Radomski 1950). Unfortunately, due to lethal side effects in overdose, using lithium chloride to replace table salt was halted for safety concerns in the 1950s.
Most often, neutrophils are the primary white blood cell increased with the use of lithium (Hager 2002). Early investigations of these changes in mice demonstrated that lithium increased granulocyte colony stimulating factor (GCSF). In cell culture, the addition of lithium was able to double production of granulocyte colonies (Harker 1977). Studies in patients taking lithium have broadly confirmed the effect. A small human trial in eight patients with bipolar disorder showed that lithium treatment increased neutrophils by, on average 88% (Ballin 1998).
Lithium and Low White Counts from Cancer Treatment
Interestingly, early studies in the 1970s found decreased rates of leukemia in areas of Texas with higher levels of lithium in the local water supply. While the results have been disputed (Budd 1980), it raised interests in lithium and cancer. GCSF is often used for treating patients after chemotherapy to raise white cell counts due to suppression common in cancer therapy (Morstyn 1988). And since lithium is known to raise GCSF, it has been seen as a cheap, effective and well-tolerated alternative for helping increase white counts in cancer patients (Hager 2002).
A number of human trials in cancer patients have demonstrated the benefits of lithium for treating induced low white blood counts. Initial studies showed a decreased dip in white blood cells with lithium treatment during chemotherapy (Greco 1977). Follow on studies showed that lithium appeared to protect bone marrow cells during chemotherapy as well (Stein 1977). Studies for both radiation and chemotherapy induced low white counts showed that lithium more than halved the time for restoration of white blood cell counts after treatment from 12 to 5 days (Chang 1989). While some studies have refuted the effects (Horns 1984), on the whole lithium does appear to support white blood cell levels in cancer therapy (Scanni 1980, Richman 1984). In addition, lithium also appears to help treat cancer patients with low platelet levels as well (Hager 2001).
The use of short-term lithium for treating cancer patients with low white blood cell counts to protect from infections appears safe and effective. And yet, this cheap therapy is widely ignored with almost no recent studies exploring its utilization.
Lithium and Other Low White Blood Cell Conditions
For other conditions with low white blood counts, lithium appears to work best when there’s evidence for reduced GCSF (Focosi 2009). A number of rare conditions, including Felty’s syndrome, a low white count associated with rheumatoid arthritis, appears to respond well to lithium treatment. Patient’s with Felty’s syndrome treated with lithium increased their white count from between 138% and 617% (Gupta 1975). In response to lithium treatment, patients develop less infections, improving overall outcomes (Schapira 1977).
Aplastic anemia is a rare condition where stem cells are damaged in the bone marrow and fail to produce adequate blood cells. The condition is difficult to treat and can be fatal. Two case studies showed at least initial benefits in aplastic anemia, with one patient making a sustained recovery with restoration of normal levels of neutrophils. Based on the results, the researchers hypothesized that there needed to be enough stem cells left in the bone marrow for lithium treatment to be effective (Barrett 1977). Other cases were similarly documented, with one patient refractory to almost all treatment responding with remarkable improvement after the addition of lithium (Blum 1979) and a separate case of aplastic anemia responding with improvements in both white blood cells and platelets (Pi 1980).
Due to the safety of short courses of lithium, a review recommended trials of lithium carbonate in aplastic anemia patients, especially those patients who were less severe and likely still had cells in the bone marrow that could produce GCSF (Silver 1980). Additional case studies accrued, with some showing profound improvements with lithium (Barrios 1989, Amano 1999). Interestingly, separate research of patients with aplastic anemia were shown to have lower levels of a number of trace minerals, including lithium (Wang 1994).
Other than a recent mouse study, very little research has been done furthering the potential use of lithium for aplastic anemia (Zhang 2012). Considering the cost, safety and sometimes startling efficacy in treating these patients, it’s unfortunate that research has not been further pursued.
Conclusion
While the benefits of lithium for bipolar disorder are well known and well researched, lithium has potentially untapped potential in other areas. It’s been repeatedly observed that lithium increases white blood cell counts through increased GCSF production. This effect appears to be potentially therapeutic in a number of conditions, including low white counts caused by cancer therapy, Felty’s syndrome and aplastic anemia.
Lithium has antiviral effects that have been documented for a number of different viruses relevant for human health. And with the current COVID-19 pandemic, it may have a place in treatment. Further studies are necessary to better understand dosing regimens and outcomes for different viral conditions.
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