Lithium For Anxiety Disorders: An Unconventional, Underinvestigated Intervention

Elemental lithium was first discovered by Johann August Arfvedson in 1817 and was later isolated via electrolysis of lithium oxide (Li2O) through a joint effort of William Thomas Brande and Sir Humphrey Davy.  In the 19^th century, scientists discovered that lithium was capable of dissolving uric acid crystals isolated from kidneys, and for this reason, it underwent trials as a treatment for gout.  Testing revealed that the quantity of lithium necessary to dissolve uric acid within the body was toxic, hence it was abandoned as a gout medication.

That said, since excess uric acid production was linked to neuropsychiatric conditions such as bipolar disorder, Carl Lange and William Alexander Hammond began administering lithium in the 1870s as a treatment of mania.  The popularity of lithium as an intervention for mania increased in the late 1940s when John Cade, an Australian psychiatrist, discovered that lithium ions facilitated tranquilizing effects in animal models.  Eventually, Cade tested the effect of lithium in humans with bipolar mania and documented a marked antimanic effect.

In 1970, lithium was officially approved by the FDA for the treatment of manic illness, and in 1974, it was also approved as a mania prophylactic.  These days, lithium salts are ubiquitously prescribed for the management of bipolar disorder, and on occasion, as an antidepressant adjunct among individuals with refractory major depressive disorder.  Moreover, due to the calming or tranquilizing effect of lithium, some have reported that it may be useful as an anxiolytic among persons with anxiety disorders.

How Lithium May Treat Anxiety Disorders (Mechanisms of Action)

There are numerous mechanisms by which lithium may prove useful as an intervention for anxiety disorders.  Potential anxiolytic mechanisms of lithium’s action include: serotonergic modulation (e.g. increasing extracellular levels, stimulating 5-HT receptors, etc.), downregulation of norepinephrine, inhibition of GSK-3 enzymes, and inositol modulation.  As of current, it is unclear as to which mechanisms are chiefly responsible for the induction of an anxiolytic effect following administration of lithium.

It is possible that a specific mechanism such as upregulation of extracellular serotonin is the single most important anxiolytic mechanism of lithium’s action.  On the other hand, it’s also possible that all mechanisms of lithium’s action contribute (in varying, weighted degrees) to an anxiolytic effect reported by certain users.  That said, since not all individuals with anxiety disorders exhibit the same underlying neurobiological expressions (i.e. signatures), it’s fair to speculate that the most substantial anxiolytic mechanisms of lithium’s action may be subject to individual variation.

For example, two people with completely different underlying causes of anxiety may benefit equally in terms of subjective anxiety reduction after taking lithium, yet one individual may have benefitted primarily from the upregulation of serotonin, whereas the other may have reaped most benefit from a reduction in norepinephrine – despite the similar outcomes.  A third individual may benefit most from decreased neuroinflammation and/or epigenetic modification.  On the other hand, a fourth person may derive no benefit from lithium because it failed to significantly target neurobiological causes implicated in their specific anxiety disorder.  Included below is a list of many possible mechanisms by which lithium could reduce anxiety.

Serotonergic modulation: The chief mechanism by which lithium may reduce symptoms of anxiety is through modulation of the serotonin system.  As most know, there are strong associations between serotonin system abnormalities and anxiety disorders.  Specifically, anxiety disorders are linked to irregular: extracellular serotonin levels, 5-HT receptor activity, 5-HT receptor density, serotonin synthesis, metabolism and reuptake, as well as serotonin turnover – within specific areas of the brain.

While not all anxiety disorders are caused by serotonergic abnormalities, a bulk of anxiety suffers derive clinically-relevant therapeutic benefit from ongoing administration of serotonergically-acting compounds (e.g. SSRIs).  This suggests that, regardless of the underlying cause of a person’s anxiety, modulation of serotonin can reduce it.  A considerable amount of data indicate that lithium significantly modulates the serotonin system.

Research by Treiser, Cascio, O’Donohue, et al. (1981) shows that long-term lithium administration substantially increases serotonin release and downregulates specific serotonin receptors.  A paper by Price, Charney, Delgado, and Heninger (1990) reveals that lithium may modify an array of serotonergic processes such as: precursor uptake, synthesis, storage, catabolism, release, and receptors of serotonin – for a net effect of enhanced serotonin function.  Perhaps the unique combination of enhanced serotonergic tone and modified 5-HT receptor activation resulting from administration of lithium effectively treats anxiety in some individuals.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/6269180
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5-HT1B receptors: The pharmacodynamics of lithium involves interaction with central 5-HT1B receptors, possibly contributing to its anxiolytic effect in a subset of persons with anxiety.  For reference, the 5-HT1B receptors are encoded by the HTR1B gene and are located in areas of the brain such as the: frontal cortex, basal ganglia, striatum, and hippocampus.  Most data indicate that 5-HT1B receptors function primarily by inhibiting the release of neurotransmitters, however, the specific neurotransmitters inhibited appear to vary based on regional positioning of 5-HT1B.

For example, 5-HT1B in the frontal cortex acts by inhibiting the release of dopamine, whereas 5-HT1B in the basal ganglia and striatum act by inhibiting the release of serotonin and glutamate.  Despite the inhibitory effect of 5-HT1B on neurotransmitter release, it has been discovered that modulation of 5-HT1B receptor activity yields anxiolytic effects in animal models.  A study by Nautiyal, Tritschler, Ahmari, et al. (2016) found that removal of 5-HT1B autoreceptors in rats facilitates a pronounced anxiolytic effect, evidenced by behavioral changes on open-field and forced-swim tests.

Researchers also noted that removing 5-HT1B autoreceptors from animals leads to significant increases in serotonin within hippocampal subregions of animals.  Tests by Tatarczyńska, Kłodzińska, Stachowicz, and Chojnacka-Wójcik (2004) revealed that 5-HT1B modulators (agonists and antagonists) can facilitate anxiolytic effects in animal models of anxiety and depression.  Though animal data does not automatically mean that 5-HT1B receptor modulation will decrease anxiety in humans, it suggests a possible anxiolytic mechanism.

A report by Massot, Rousselle, Fillion, et al. (1999) indicates that lithium acts upon 5-HT1B receptors.  More evidence to suggest action of lithium upon 5-HT1B is presented in a human study by Januel, Massot, Poirier, et al. (2002).  Based on the fact that lithium modulates 5-HT1B activity, as well as preclinical data suggesting that 5-HT1B modulation can facilitate anxiolytic effects, there’s reason to believe that lithium might treat anxiety through action upon 5-HT1B within the CNS.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/27353308
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5-HT2A receptors: To a lesser extent than its action upon 5-HT1B receptors, lithium appears to modify 5-HT2A receptor activity, possibly contributing to an anxiolytic effect.  Research by Weisstaub, Zhou, Lira, et al. (2006) discovered that 5-HT2A receptor signaling can modulate certain anxiety-like behaviors in animal models.  Particularly, global disruption of 5-HT2A receptor signaling decreases conflict-related anxiety among mice.

A study by Mora, Netto, and Graeff (1997) reported that select 5-HT2A antagonists appear to alter anxiety-like behaviors in animal models.  These researchers also suggest that the 5-HT2A receptor might modulate aspects of a conditioned-fear response.  Though links between 5-HT2A receptor dysfunction and anxiety disorders in humans aren’t strong, it’s possible that 5-HT2A irregularities may be implicated in a subset of anxiety disorders.

Work by Basselin, Chang, Seemann, et al. (2005) indicated that chronic lithium administration alters 5-HT2A receptor-mediated signaling through arachidonic acid (AA).  It’s possible that lithium exerts similar effects upon 5-HT2A sites in humans as it does within animals.  Although the primary anxiolytic mechanism of lithium isn’t 5-HT2A receptor modulation, it’s reasonable to theorize that 5-HT2A modulation could modestly contribute to the overall anxiolytic effect observed in certain users.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/16873667
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5-HT1A receptors: Another neurobiological target by which lithium may act upon to facilitate an anxiolytic effect is the 5-HT1A receptor.  A paper by Celada, Bortolozzi, and Artigas (2013) suggests that modulation of 5-HT1A receptor activity might prove useful as a treatment for neuropsychiatric conditions, including anxiety disorders.  Animal model data indicate that increased activation of presynaptic 5-HT1A receptors leads to decreases in anxiety-like behavior.

Furthermore, knocking out the 5-HT1A receptor in mice leads to significant increases in anxiety and avoidant behaviors.  In humans, administration of 5-HT1A partial agonists such as buspirone and gepirone are well-understood to alleviate certain types of anxiety disorders.  A study by Goodwin, DeSouza, Wood, and Green (1986) suggested that administration of lithium affects 5-HT1A receptor function in animals.

Additional animal research by Blier, de Montigny, and Tardif (1987) discovered that short-term administration of lithium enhances sensitivity of certain postsynaptic 5-HT1A receptors implicated in the firing of serotonergic neurons.  Nugent, Carlson, Bain, et al. (2013) documented that neuropsychiatric disorders are associated with irregular 5-HT1A receptor binding.  Specifically, high stress leads to decreased expression of 5-HT1A in animal models, possibly through heightened secretion of sympathomimetic hormones.

That said, chronic administration of lithium to stressed animals bolsters 5-HT1A receptor function to offset stress-mediated decreases in 5-HT1A receptor expression.  Neuroimaging research in humans diagnosed with bipolar disorder revealed that administration of lithium significantly increases 5-HT1A binding potential.  Lithium-mediated increases in 5-HT1A binding potential appear most noticeable within regions such as the amygdala and hippocampus.

It was speculated that lithium (and other mood stabilizers) function in part through enhancing the expression of 5-HT1A receptors.  Understanding that 5-HT1A receptor activity can influence anxiety, as well as that lithium administration may modulate 5-HT1A expression, sensitivity, and/or binding potential – it is reasonable to speculate that lithium facilitates an anxiolytic effect through 5-HT1A receptors.  Further research is necessary in humans to confirm this theoretic anxiolytic mechanism.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/23757185
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5-HT2C receptors: Lithium may exert an anxiolytic effect in a subset of persons through modulation of 5-HT2C receptor activity.  The 5-HT2C receptor is a binding site for serotonin and 5-HT2C activation is associated with inhibition of catecholamine secretion in various regions of the brain. Not only are 5-HT2C receptors implicated in feeding, reproduction, and mood regulation, but they also can significantly affect levels of anxiety.

In particular, it seems as though overactivation of 5-HT2C receptors causes a combination of anxiety and depression in some individuals.  Individuals reporting increased anxiety when initiating treatment with a serotonergic antidepressant (e.g. an SSRI) are thought to exhibit excess 5-HT2C receptor-mediated signaling.  Research by Heisler, Zhou, Bajwa, et al. (2007) indicates that 5-HT2C receptors play a role in regulation of anxiety behaviors in mice.

Additionally, a study by Kimura, Stevenson, Carter, et al. (2009) discovered that transgenically-induced overexpression of 5-HT2C receptors in the forebrain of mice leads to increases in anxiety and decreases in feeding.  What’s more, a report by Wood (2003) highlights the fact that the substance mCPP (m-chlorophenylpiperazine) provokes anxiogenic effects in both humans and animals via agonism of the 5-HT2C receptor.  The finding that mCPP agonizes 5-HT2C receptors to cause anxiety supports the hypothesis that 5-HT2C abnormalities may be implicated in a subset of human anxiety disorders.

Based on findings that 5-HT2C receptor activation and its overexpression in certain areas of the brain can cause anxiety, some researchers theorize that strategic modulation of 5-HT2C receptors could facilitate an anxiolytic effect.  In a report by Millman (2005), it pharmacological interventions targeting the 5-HT2C receptor were discussed as potential treatments for anxiety and depression.  The report by Millman notes that 5-HT2C receptor modulation with selective antagonists, inverse agonists, allosteric modulators, and ligands – could prove effective in the treatment of anxious states.

Furthermore, we already know that serotonergic antidepressants such as Mirtazapine and Nefazodone act upon 5-HT2C receptors, both of which are sometimes useful for the treatment of anxiety.  Although it is unclear as to whether the 5-HT2C action of of the aforementioned pharmaceuticals plays a significant role in the alleviation of anxiety, it’s a possibility to consider.  Intriguingly, there’s evidence to suggest that lithium might interact with 5-HT2C receptor sites.

A study by Moorman and Leslie (1998) discovered that lithium exerts a complex modulatory effect upon 5-HT2C receptors in animal models.  Later research by Basselin, Chang, Seemann, et al. (2005) reported that chronic administration of lithium modifies 5-HT2C receptor signaling through arachidonic acid (AA).  Though it remains unknown as to whether lithium modulates 5-HT2C sites in humans similar to its action in animals, 5-HT2C modulation should be regarded as a potential mechanism of lithium’s anxiolytic effect.

• Source: https://www.ncbi.nlm.nih.gov/pubmed/17451451
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Norepinephrine reduction: Lithium may help alleviate anxiety in a subset of individuals through reducing concentrations of norepinephrine.  Norepinephrine, sometimes referred to as noradrenaline, functions primarily as a stimulatory neurotransmitter and hormone within the central and peripheral nervous system.  Although the biologic actions of norepinephrine are complex, norepinephrine is most implicated in function of the sympathetic nervous system, a branch of the autonomic nervous system that evolved to increase likelihood of survival when faced with environmental threats.

When he sympathetic nervous system is activated, we experience the “freeze-fight-flight” response, in part, through secretion of central and peripheral norepinephrine.  Peripheral norepinephrine generates a surge of physical energy through mobilizing energy stores, decreasing digestion, and enhancing glucose uptake.  Other effects associated with increased norepinephrine include: blood pressure increases, heart rate increases, and pupil dilation.

The central release of norepinephrine occurs chiefly within the locus coeruleus to bolster vigilance, memory retrieval (short-term and long-term), and sensory processing.  Essentially, peripheral and central norepinephrine maximize physical and mental energy, respectively.  That said, elevated norepinephrine is directly associated with anxiety and fear – hence the response of an initial freeze, followed by fight or flight.

While transient norepinephrine elevations are useful in survival situations, chronic dysregulation of noradrenergic production, metabolism, regional turnover, and/or signaling – plays a role in the pathogenesis of some anxiety disorders.  Research by Hughes, Watkins, Blumenthal, et al. (2004) discovered a significant correlation between 24-hour norepinephrine secretion and symptoms of anxiety among women.  Although a correlation between 24-hour norepinephrine secretion and heightened anxiety doesn’t necessarily mean that elevated norepinephrine causes anxiety, it suggests that norepinephrine may be directly culpable for the anxiety.

A report by Goddard, Ball, Martinez, et al. (2010) further highlights the possibility that dysregulation of norepinephrine could induce anxiety disorders.  The report also mentions that targeting noradrenergic abnormalities with pharmacological compounds may prove useful for the treatment of anxiety disorders.  With the understanding that norepinephrine can cause anxiety, and increasing norepinephrine signaling can exacerbate anxiety, most professionals steer clear from prescribing drugs that upregulate extracellular norepinephrine signaling (e.g. NRIs and NDRIs) to patients with anxiety disorders.

On the other hand, medications that inhibit norepinephrine’s stimulation of adrenergic receptors are sometimes useful for the treatment of anxiety disorders.  Hence the reason a subset of individuals respond well to beta blockers for anxiety (e.g. clonidine, propranolol, etc.).  While lithium doesn’t act the same as a beta blocker, there’s evidence to suggest that it modulates norepinephrine.

Research by Eroglu and Atamer-Simsek (1980) discovered that administration of lithium to stress-exposed rats decreased brain levels of norepinephrine.  Additionally, a study by Linnoila, Karoum, Rosenthal, and Potter (1983) discovered that treatment with lithium carbonate significantly decreased excretion of norepinephrine and its metabolites, plus reduced norepinephrine turnover among humans with major depression.  Other evidence from Sastre, Nicolay, Bruguerolle, and Portugal (2005) indicated that lithium inactivates norepinephrine and decreases availability of norepinephrine to stimulate adrenergic receptors.  Overall, when considering that high norepinephrine often causes anxiety, any lithium-mediated decreases in noradrenergic tone may contribute to an anxiolytic effect.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/15518669
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GSK-3 inhibition: It is possible that lithium is an effective treatment for anxiety as a result of its ability to inhibit the GSK-3 (glycogen synthase kinase-3) enzyme.  GSK-3 is a serine/threonine protein kinase that regulates the addition of phosphate to serine and threonine amino acid residues.  Additionally, GSK-3 is implicated as a kinase in upwards of 40 distinct proteins throughout a multitude of biological pathways, and its activation has been linked to neuropsychiatric disorders in both humans and animal models.

Jope and Roh (2006) document that various intracellular signaling cascades and neurotransmitter systems (choline, dopamine, glutamate, and serotonin) influence GSK-3 activity.  They theorize that regulation of GSK-3 may prove useful as a treatment for depression, and mention that when GSK-3 is left unregulated, it may interfere with:  gene expression, neural architecture, neuroplasticity, neurogenesis, and responsiveness of neurons under stress.  Although it’s unclear as to whether targeted inhibition of GSK-3 could effectively treat anxiety disorders, there’s reason to think that it might.

As was already mentioned, low serotonin signaling in certain areas of the brain is associated with anxiety disorders.  Coincidentally, low serotonin signaling increases GSK-3 activation, whereas adequate serotonin signaling inhibits GSK-3 activity.  Given the relationship between serotonin and anxiety, as well as the relationship between serotonin and GSK-3, it’s apparent that there must be a relationship between increased GSK-3 activity and anxiety.

Although specific associations between GSK-3 and anxiety aren’t well-researched, it’s possible that GSK-3 is heavily implicated in the pathogenesis of certain anxiety disorders.  Knowing that GSK-3 activation may cause anxiety, it’s logical to assume that a GSK-3 inhibitor such as lithium could alleviate anxiety.  A study by Mines, Yuskaitis, King, et al. (2010) documented that GSK-3 appears hyperactive in the brains of FMR1 knockout mice, animal models of Fragile X Syndrome – a serious neurodevelopmental disorder in which anxiety is usually a symptom.

In the study, the FMR1 knockout mice exhibited noticeable anxiety-like behavior (e.g. digging, grooming, rearing) during social interactions compared to standard wild-type mice.  That said, following administration of lithium, a known inhibitor of GSK-3, anxiety-like behavior observed in the FMR1 knockout mice significantly decreased.  According to Jope (2003), lithium inhibits GSK-3 in multiple ways: directly and indirectly [by increasing inhibitory phosphorylation of GSK-3].  Anyone who notices a reduction in anxiety while taking lithium should consider its inhibitory effect upon GSK-3 as an anxiolytic mechanism.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/17100582
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Inositol modulation: Another mechanism of lithium’s action is thought to involve modulation of inositol, a sugar alcohol and glucose isomer.  Inositol is implicated in molecular signaling and the secondary messenger system.  Biologic processes in which inositol is utilized includes:  cell membrane potential maintenance, cytoskeleton assembly, fat catabolism, insulin signal transduction, and intracellular calcium regulation – to name a few.

There’s evidence indicating that concentrations of inositol can affect neurobiology and influence psychological status.  Some theorize that modulation of inositol concentrations through depletion and/or supplementation may prove useful for the treatment of certain neuropsychiatric conditions, including anxiety.  A study by Palatnik, Frolov, Fux, and Benjamin (2001) documented that administration of myo-inositol (up to 18 g/day) for 1 month alleviated symptoms of panic disorder equally as well as fluvoxamine, a pharmaceutical medication.

What’s more, treatment with inositol lead to overall improvements on the Hamilton Rating Scale for Anxiety and on an agoraphobia scale.  Countless anecdotal reports substantiate the theory that high-dose inositol for anxiety is sometimes an effective intervention.  Based on the aforementioned findings, it seems as though modifying inositol status could facilitate anxiolytic effects in a subset of individuals with anxiety disorders.

One way to modify inositol status, and consequently psychological status, is through administration of lithium.  Vadnal and Parthasarathy (1995) report that lithium functions as an inhibitor of myo-inositol monophosphatase (IMPase).  Inhibition of myo-inositol monophosphatase (IMPase) leads to increases in myo-inositol monophosphates and reductions in myo-inositol to resynthesize inositol phospholipids.

Agranoff and Fisher (2001) mention that lithium inhibits the enzymatic conversion of inositol phosphates to free inositol, whereby neural signal transduction is downregulated or suppressed.  Researchers believe that the suppression of neural signal transduction occurs as a result of lithium-induced inositol phosphate accumulation.  That said, another possible mechanism of impaired signal transduction is that free intracellular inositol decreases and the recycling of inositol-containing metabolites implicated in signal transduction slows.

The bottom line is that lithium-mediated changes in concentrations of inositol phosphates affects neurotransmission, which in turn, might prove helpful for the treatment of an anxiety disorder.  Furthermore, research by Sarkar, Floto, Berger, et al. (2005) suggests that inhibition of inositol monophosphatase (IMPase) by lithium induces autophagy.  Preliminary evidence suggests that inhibition of autophagy increases anxiety, so therefore, it’s possible that induction of autophagy may have the opposite effect of decreasing anxiety.

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Other Possible Mechanisms of Lithium for Anxiety

There are numerous other possible mechanisms of action by which lithium may reduce symptoms of anxiety.  These mechanisms include: cyclic AMP modulation, epigenetic modification, epinephrine reduction, neuroinflammation downregulation, and oxidative stress reduction.  It is also possible that administration of lithium may treat anxiety through the reversal of an underlying lithium deficiency.  Understand that some of these mechanisms of lithium’s anxiolytic action are currently speculative based on animal data and haven’t been confirmed in human trials.

Cyclic-AMP modulation: An anxiolytic effect may be generated by lithium partly through modulation of cyclic adenosine monophosphate (cAMP).  Cyclic AMP is a second messenger implicated in many biologic processes and its dysfunction has been linked to anxiety.  Many drugs that target cyclic AMP concentrations are effective as anxiolytics.

For example, the drug diazepam has been shown to inhibit PDE cAMP hydrolysis and upregulate cAMP activity plus activation within left frontal regions of the brain.  After exposure to stress, rats exhibit alterations in cAMP levels within the amygdala, frontal cortex, hippocampus, and hypothalamus.  What’s more, the intensity of various stressors administered to a rat correlates directly with increases in production of cAMP within certain regions of the brain.

Besides diazepam, agents such as caffeine and rolipram can facilitate anxiolytic effects through inhibition of PDE, which in turn, increases intracellular concentrations of cAMP.  An increase in intracellular cAMP leads to upregulation of CREB (cAMP response element binding protein), which binds to CRE, and then increases neuropeptide Y to directly reduce anxiety through action within regions such as the amygdala.  Montezinho, Duarte, Fonseca, et al. (2004) note that intraneuronal lithium concentrations affect cyclic AMP levels and vice-versa.  Any potential modulation of cyclic AMP as a result of increasing intraneuronal lithium could contribute to an anxiolytic effect.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/4402069
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Epigenetic modulation: A potentially-overlooked mechanism of lithium’s anxiolytic action may involve epigenetic modulation.  Research by Nieto, Patriquin, Nielsen, and Kosten (2016) mentions that simple environmental inputs such as diet, stress, and toxic exposures can significantly affect epigenetic mechanisms such as: chromatin remodeling, DNA methylation, and non-coding RNAs.  It was noted that, in animal models of anxiety, specific epigenetic alterations have been observed in cortical brain regions implicated in emotion and stress responses.

Murphy, O’Donovan, Mullins, et al. (2015) discovered that anxiety disorders are associated with higher levels of inflammatory cytokines (e.g. IL-6), and that these inflammatory cytokines induce expression of epigenetic enzymes DNMT1 and EZH2, each of which may be involved in the pathogenesis and/or exacerbation of anxiety.  Other research by Tran, Schulkin, Ligon, and Greenwood-Van Meerveld (2015) indicates that epigenetic expression within the amygdala, particularly involving histone modification, can affect anxiety levels.  Histone deacetylation within the central amygdala is thought to regulate corticosteroids, stimulation of glucocorticoid receptors, and corresponding levels of corticotropin-releasing factor (CRF).

When a histone deacetylase inhibitor is injected within the central amygdala, anxiety-like behavior resulting from corticosteroid exposure decreases, indicating that anxiety can be influenced by epigenetic factors.  Knowing that epigenetic factors may cause anxiety, it is possible that lithium attenuates symptoms of anxiety through epigenetic modulation.  Research by Weiner, Mallat, Papolos, and Lachman (1992) documented that acute treatment with lithium enhances the hippocampal expression of neuropeptide Y genes in rats, suggesting that lithium may exert therapeutic effects through modulation of gene expression.

As of current, it remains unknown as to whether lithium enhances the expression of hippocampal neuropeptide Y genes in humans.  That said, studies by Desai, Borkar, Nakhate, et al. (2014) suggest that inhibition of neuropeptide Y signaling in the brain might directly induce anxiety in animals, as well as humans.  Oppositely, upregulated neuropeptide Y expression is associated with the attenuation of anxiety-like behaviors in mice following exposure to an anxiogenic substance.

Considering that lithium may bolster neuropeptide Y concentrations in humans through enhancement of neuropeptide Y gene expression, it’s possible that this epigenetic mechanism yields an anxiolytic effect.  That said, the epigenetic impact of lithium is not limited to neuropeptide Y genes.  Research by Dwivedi and Zhang (2015) discovered that, in animals, lithium activates transcription of a specific exon to induce expression of BDNF, Bcl2, and Bcl-XL genes – each of which are implicated in neuroprotection.

In addition to increasing expression of genes involved in neuroprotection, lithium decreases expression of pro-apoptotic genes such as Bax, Bad, and capases 3.  Prior work by Emamghoreishi, Keshavarz, and Nekooeian (2015) reported that lithium increased proteins of BDNF and GDNF in rat neurons and astrocytes, indicating favorable epigenetic changes following lithium administration.  Considering the aforestated findings plus research indicating that expression of BDNF and GDNF can alter levels of anxiety, some might speculate that the anxiolytic effects of lithium can be attained through epigenetic modulation of BDNF and GDNF genes.

Other work by Lee, Pirooznia, Guintivano, et al. (2015) discovered that lithium alters histone H3 methylation and acetylation in LepR, a gene involved in leptin signaling.  Interestingly, research by Liu, Guo, and Lu (2015) indicates that signaling of LepRb (a leptin receptor in midbrain neurons) induces anxiolytic effects, whereas blockade of signaling generates anxiety-like behaviors.  Since leptin signaling has been shown to affect anxiety-like behaviors in mice, it’s possible that lithium-induced alterations in LepR gene expression alleviate anxiety.

Although it’s likely that various epigenetic modifications induced by lithium remain undiscovered, the cumulative epigenetic effect of lithium might be an important mechanism by which it decreases symptoms of anxiety in a subset of the population.  In other words, the combination of lithium-mediated enhancement of BDNF, GDNF, LepR, neuropeptide Y, et al. expression yields a net anxiolytic effect.

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Epinephrine reduction: The hormone and neurotransmitter epinephrine is secreted by the adrenal glands and specific neurons as part of a neurophysiologic reaction to environmental threats.  Although there are many important functions of epinephrine, it is primarily associated with activation of the sympathetic nervous system and the freeze-fight-flight response.  Secretion of epinephrine stimulates alpha and beta receptors to prime our neurophysiology for survival.

Analogous to norepinephrine, epinephrine increases blood flow to muscles, boosts heart rate, dilates pupils, and provides a significant jolt of energy for bursts of peak physical and mental performance.  That said, since it’s involved in the freeze-fight-flight response, excessive secretion of epinephrine and/or chronically high epinephrine may be associated with anxiety.  A study by Veltman, van Zijderveld, van Dyck, and Bakker (1998) notes that epinephrine infusions provoke panic in a majority of recipients.

Other research by van Zijderveld, Veltman, van Dyck, and van Doornen (1999) supports the idea of epinephrine-induced panic attacks.  Based on these findings, it is reasonable to speculate that persons with certain types of anxiety disorders (e.g. panic disorder) may be sensitive to epinephrine secretion and/or may secrete more epinephrine than non-anxious persons.  As an intervention for the management of anxiety, lithium may exert an anxiolytic effect through modulation of epinephrine concentrations.

Grof, Brown, Grof, and Van Loon (1986) documented that the administration of lithium carbonate over a 3-week duration significantly reduced plasma epinephrine concentrations.  They believe that lithium decreased epinephrine through modulation of the adrenal medulla and sympathetic nerve endings.  Though certainly not all individuals with anxiety will exhibit elevations in epinephrine, those for whom epinephrine induces anxious symptoms may derive therapeutic benefit from lithium through its ability to decrease epinephrine concentrations.

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Neuroinflammation decrease:  Salim, Chugh, and Asghar (2012) suggest that uptake of proinflammatory cytokines within the brain can deleteriously alter:  neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neural circuitry implicated in emotion.  They propose that the aforestated unwanted neurological alterations induced by cytokines (mediators of inflammation) may directly induce, or play a role in the induction of neuropsychiatric conditions, including anxiety disorders.  Research by Moons and Shields (2015) discovered that the specific emotion of “anxiety” triggers more inflammatory activity than the emotion of “anger.”

High anxiety lead to increased levels of inflammatory markers such as: interferon-γ (IFN- γ) and interleukin-1β (IL-1β).  A paper by Michopoulos, Powers, Gillespie, et al. (2016) highlighted a bidirectional relationship between anxiety and inflammation in that either one can cause and/or exacerbate the other.  In other words, unmanaged anxiety can lead to increased production of inflammatory cytokines, and excessive inflammation can disrupt brain activity to cause anxiety.

Considering the role of inflammation in anxiety disorders, it’s logical to suspect that anti-inflammatory agents may yield anxiolytic effects (of varying significance) in a subset of the population with anxiety.  Evidence from a study by De-Paula, Kerr, Scola, et al. (2016) suggests that subtherapeutic doses of lithium modulates pro-inflammatory and anti-inflammatory interleukin secretion in cultures of neurons and glial cells.  Yu, Wang, Tchantchou, et al. (2012) found that lithium attenuated neuroinflammation in animal models of stroke.

There are numerous ways by which lithium may reduce neuroinflammation including: GSK-3B inhibition, oxidative stress reduction, and net effect of neurotransmitter modulation (e.g. reducing glutamate excitotoxicity).  If a significant anti-inflammatory effect occurs among humans as a result of lithium administration, perhaps this mechanism contributes to an anxiolytic effect.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/22814704
• Source: http://www.ncbi.nlm.nih.gov/pubmed/26053247
• Source: http://www.ncbi.nlm.nih.gov/pubmed/27510423
• Source: http://www.ncbi.nlm.nih.gov/pubmed/26892291
• Source: http://www.ncbi.nlm.nih.gov/pubmed/21895523

Oxidative stress reduction: There are a myriad of links between elevated oxidative stress and neuropsychiatric conditions, including anxiety.  A report by Bouayed, Rammal, Soulimani (2009) extensively discusses the relationship between oxidative stress and anxiety disorders, plus highlights potential biologic pathways by which oxidative stress could induce anxiety.  In the report, researchers reflected upon animal model studies in which manipulation of antioxidant status and/or oxidative stress affected anxiety levels.

When oxidative stress accumulates, it is known to modify gene expression, protein conformation, and signaling of cells.  Researchers believe that chronic and/or exaggerated oxidative stress can also disrupt neurotransmission, neuronal activity, and overall brain function.  Furthermore, it was hypothesized that heightened oxidative stress may be neurotoxic, whereby it damages the brain, induces inflammation, and/or kills brain cells if unaddressed.

All of the aforestated effects resulting from oxidative stress could certainly directly or indirectly contribute to the pathogenesis of anxiety.  Worth mentioning are studies by Hovatta, Tennant, Helton, et al. (2005) in which the expression of glutathione reductase and glyoxalase reductase were manipulated in the cingulate cortex of rodents.  It was discovered that overexpression of each gene increased anxiety-like behavior, whereas inhibition of glyoxalase yielded low anxiety mice.

This research established a causal link between antioxidant status within rodent brains and anxiety. What’s more, it showed that by improving antioxidant status or reducing oxidative stress, mice became less anxious.  Research by Rammal, Bouayed, Younos, and Soulimani (2008) used a tracker to measure concentrations of oxidative stress in anxious and non-anxious mice, noting that anxiety level correlated with level of oxidative stress within the brain and peripheral of the mice.

If that’s not enough, Yan, Guo, Liu, et al. (2016) documented that ingestion of the phthalate ester DPB (dibutyl phthalate) induces oxidative damage within the brains of mice, leading to increased anxiety-like behavior.  Administration of an antioxidant protected against the severity of DPB-induced oxidative stress and attenuated corresponding anxiety-like behavior.  Overall, while oxidative stress is unlikely a cause of anxiety in all humans, it may be directly or indirectly culpable for some.

Assuming oxidative stress is contributing to a person’s anxiety, lithium is capable of reducing it.  An investigation by Bengesser, Lackner, Birner, et al. (2016) sought to measure oxidative parameters among patients who were taking lithium compared to those using antipsychotics.  Results indicated that lithium users exhibited significantly lower levels of oxidative stress (of various types) compared to the antipsychotic users, suggesting that lithium functions in part by lowering oxidative stress.

Testing by de Sousa, Zarate, Zanetti, et al. (2014) revealed that lithium exerts antioxidant effects among patients with bipolar disorder to combat oxidative stress.  Lithium’s ability to reduce oxidative stress is not unique to patients with bipolar disorder, similar effects are observed among healthy individuals.  Research by Khairova, Pawar, Salvadore, et al. (2012) found that administration of lithium for 2 to 4 weeks to healthy volunteers significantly reduced markers of oxidative stress.  Given the relationship between oxidative stress and anxiety, and the finding that lithium reduces oxidative stress, it’s possible that this is a means by which lithium facilitates an anxiolytic effect.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/20357926/
• Source: http://www.ncbi.nlm.nih.gov/pubmed/16244648/
• Source: http://www.ncbi.nlm.nih.gov/pubmed/18620042/
• Source: http://www.ncbi.nlm.nih.gov/pubmed/27262985
• Source: http://www.ncbi.nlm.nih.gov/pubmed/26996179
• Source: http://www.ncbi.nlm.nih.gov/pubmed/24332923
• Source: http://www.ncbi.nlm.nih.gov/pubmed/22200861

Reversal of lithium deficiency:  A paper by Schrauzer (2002) suggests that lithium should be considered an essential nutrient for the biological function of humans.  In the paper it was noted that trace quantities of lithium were first detected within human organs and tissues in the late 1800s, and suggested that lithium was likely essential for biological processes.  After the initial discovery of lithium within the human body, researchers conducted experiments to test the effects of lithium restriction in animals.

Experiments revealed that restriction of lithium intake in rats and goats yields higher mortality rates, reproductive dysfunction, and behavioral problems.  Although the outcomes from animal studies don’t provide conclusive evidence that lithium is essential for humans, the outcomes of these experiments support the theory that it might be.  Concentrations of lithium in the body are known to affect a host of biological processes including: enzyme function, hormonal secretion, growth factor production, and epigenetic expression.

What’s more, research reveals that low lithium contents in drinking water correlates directly with rates of suicide, homicide, and arrests.  Though correlation shouldn’t be considered causation, the possibility that a lithium deficiency induces and/or contributes to neuropsychiatric conditions, including anxiety disorders, cannot be dismissed.  Nonetheless, Schrauzer believes that there’s sufficient evidence to accept lithium as an essential element, and for this reason, he recommends a provisional recommended daily allowance (RDA) of 1,000 mcg/day for a 70 kg (154.32 lb) adult.

Dietary sources highest in lithium include grains, vegetables, and drinking water.  That said, the concentrations of lithium are subject to variation based on the sourcing of a person’s food and water, respectively.  This means that persons living in areas in which their grains, vegetables, and/or drinking water contains little or zero lithium – might experience a deficiency.

A report by Młyniec, Davies, de Agüero Sánchez, et al. (2014) suggests that a deficiency in any essential element, including lithium, may induce anxiogenic and/or depressive behaviors.  By correcting an essential element deficiency, researchers believe that the severity of a person’s anxiety and/or depression should decrease.  Additionally, it was suggested that, among persons with essential element deficiencies, administration of supplements to reverse the deficiency should augment pharmaceutical anxiolytics and/or antidepressants.

In other words, supplementing with lithium may prove effective as a standalone treatment for anxiety among those with deficient intakes because it reverses the deficiency to normalize biological functions.  Furthermore, regular supplementation of lithium to ensure that the provisional 1000 mcg/day requirement is being met could also potentiate the therapeutic efficacy of a pharmaceutical anxiolytic.  In summary, while a lithium deficiency is unlikely the root cause of most anxiety disorders, correction of the deficiency to improve lithium-mediated biological functions may be a mechanism by which anxiety is reduced for a subset of individuals.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/11838882
• Source: http://www.ncbi.nlm.nih.gov/pubmed/24948052

Benefits of Lithium for Anxiety (Possibilities)

There are numerous potential benefits to be derived from utilizing lithium as an intervention for anxiety disorders.  Arguably the most significant benefit to be attained from using lithium as an intervention for anxiety is that it might prove useful as an alternative pharmacological option among persons who respond inadequately to conventional anxiolytics.  Another benefit is evidence to suggest that lithium is relatively safe in humans, even when administered over a long-term.  Other benefits of using lithium to treat anxiety might include its:  adjunct potential, ability to manage neuropsychiatric comorbidities, neuroprotective properties, antisuicidal effect, and low cost.

• Adjunct potential: Available data from animal model trials and case reports suggest that lithium has significant therapeutic potential as an anxiolytic adjunct.  Animal model data indicate that subchronic lithium carbonate acts synergistically with serotonergic antidepressants (e.g. SSRIs, TCAs, MAOIs) to upregulate concentrations of extracellular serotonin in the CNS.  Specifically, increases in extracellular serotonin that occur after administration of lithium plus a serotonergic antidepressant exceed the increases that occur after administration of a standalone serotonergic antidepressant.  Additionally, the anxiolytic effect derived from co-administration of lithium plus a serotonergic antidepressant significantly exceeds that which is derived from standalone serotonergic antidepressants – in animal models.  The adjunct potential of lithium as an adjunct anxiolytic is best presented in a 1986 case report by Cournoyer.  In this case report, a 40-year-old woman with refractory panic disorder derives therapeutic relief only when lithium (600 mg/day) is added to clomipramine (225 mg/day).  When dosed correctly, lithium is often safe and well-tolerated as an adjunct.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/3085912).
• Alternative intervention: Another advantage associated with using lithium for anxiety is that it may prove effective as an anxiolytic when none of the conventional pharmacological approaches work, and might be safer than other options. Currently, the most popular first-line agents prescribed to persons with anxiety disorders are serotonergic antidepressants.  Although serotonergic antidepressants are regarded safe and effective, a subset of patients report zero and/or negligible relief from anxiety.  While there are many other anxiolytic medications to consider for the management of anxiety besides serotonergic antidepressants, many of them are risky – especially over the long-term.  For example, benzodiazepines are linked to dementia and drugs such as antipsychotics can lower brain volume over a long-term.  Furthermore, there’s a high potential for addiction, abuse, dependence, rapid tolerance onset, and dangerous discontinuation effects associated with most GABAergic anxiolytics.  Lithium isn’t addictive, has no potential for abuse, isn’t associated with dependence or rapid tolerance onset, and has a milder withdrawal than most medications.  Assuming an individual has tested many of the safer anxiolytics and nothing seems to provide sufficient symptomatic relief, lithium may be a useful alternative anxiolytic option.
• Antisuicidal agent: There’s evidence to suggest that ongoing lithium treatment may prevent suicidal ideation. A review by Lewitzka, Severus, Bauer, et al. (2015) documented that long-term lithium administration reduces suicide risk and attempts in patients with affective disorders.  Additionally, although higher mortality rates are expected among patients using lithium, the data indicate lower mortality rates among lithium users.  It is reasonable to believe that the antisuicidal properties of lithium may be beneficial among patients with anxiety disorders.  A meta-analytic review by Bentley, Franklin, Ribeiro, et al. (2016) reported that anxiety is a statistically significant predictor of suicidal ideation and attempts.  When considering that anxiety can increase suicidality, yet lithium may exert antisuicidal effects, it’s reasonable to speculate benefit among patients with anxiety disorders – especially individuals with a history of suicidal thoughts. (Source #1: http://www.ncbi.nlm.nih.gov/pubmed/26183461). (Source #2: http://www.ncbi.nlm.nih.gov/pubmed/26688478).
• Comorbid conditions: Lithium is understood to be most effective for the stabilization of mood, hence its longstanding approval for the management of bipolar disorder. There’s also quality evidence to suggest that lithium is effective as an adjunct for the treatment of refractory depression.  Preliminary, lower-quality evidence suggests that lithium could also be useful in select cases of autism and schizophrenia.  That said, it seems reasonable to test the effectiveness of lithium among patients diagnosed with bipolar disorder and comorbid anxiety, especially since lithium is a first-line intervention for bipolar disorder.  In a subset of bipolar disorder patients, the lithium may balance mood while simultaneously reducing anxiety.  Among persons with severe depression and comorbid anxiety, lithium might: attenuate depressive symptoms, decrease suicide risk, and possibly reduce anxiety.
• Efficacy: There are mounting data indicating that lithium may be effective for the treatment of anxiety. Fear-conditioned animal models show reductions in anxious behaviors from administration of lithium.  Additionally, human case reports have highlighted the efficacy of lithium for the management of anxiety disorders in a subset of persons.  Moreover, while anecdotes aren’t quality data, there are numerous anecdotes circulating around the internet noting that lithium (of various types such as aspartate, carbonate, and orotate) can alleviate anxiety when administered regularly or on an as-needed basis.  Based on the currently-available evidence, it’s not a stretch to speculate that lithium could be an effective anxiolytic.
• Essential nutrient: Lithium is classified as an essential nutrient in humans, meaning that some lithium is necessary to ensure optimal neurobiological function. Schrauzer (2002) documents that lithium is found in various foods such as grains and vegetables, and can also be ingested through drinking water.  Low lithium intake is associated with increased mortality rates, behavioral problems, and adverse reproductive consequences in animals.  In humans, low levels of lithium in drinking water is correlated with increased risk of suicides, homicides, and drug-related arrests.  Not only does lithium play a critical role in fetal development, adequate lithium is necessary to facilitate certain enzymatic and hormonal processes within the body.  For this reason, administration of lithium for anxiety may counteract a mild biologic deficiency to improve overall health.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/11838882).
• Low cost: Many patients struggle to afford medications to manage neuropsychiatric disorders, including anxiety. Some newer antidepressant drugs prescribed to patients with anxiety can cost hundreds of dollars for a 30-day prescription.  Lithium is among the cheapest pharmaceutical medications on the market.  The cost of lithium carbonate ranges between $5 and $10 for 90 capsules at 300 mg.  Alternative formats of lithium such as lithium orotate can be purchased from online vendors at a price under $25 for 120 capsules.  Overall, lithium is an extremely affordable treatment option for most patients.
• Multiple formats: There are many different formats of lithium being sold. The only format utilized by medical professionals for the management of neuropsychiatric disorders is lithium carbonate.  That said, lithium can be purchased as a dietary supplement in the forms of lithium orotate and lithium aspartate.  The advantage of access to multiple formats of lithium has to do with individual tolerability.  A subset of individuals may find that they are unable to tolerate one format of lithium, but respond remarkably well to another format without side effects.
• “Natural” treatment: Just because a substance is natural does not mean that it’s safe or healthy to consume. Nonetheless, many patients subscribe to the belief that natural compounds and/or supplements are always safer and healthier than synthetic pharmaceuticals.  For this reason, a subset of persons may refuse and/or never seek treatment for serious neuropsychiatric conditions, including a debilitating anxiety disorder.  Convincing these individuals to try lithium may prove fruitful upon presentation of facts that lithium is an essential element and/or that lithium can be purchased online as a “natural” dietary supplement.  While it is never recommended to take lithium without guidance from a medical professional, some may like the fact that they don’t need to book doctor’s appointments to attain a supply of lithium.
• Neuroprotective agent: At certain doses, lithium functions as a neuroprotective agent in a subset of individuals. Forlenza, De-Paula, and Diniz (2014) document that lithium exerts a neuroprotective effect through the modulation of autophagy, inflammation, mitochondrial function, and oxidative stress.  This may lead to favorable long-term neurological outcomes in patients at risk for neurodegeneration as a result of their respective neuropsychiatric disorders.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/24766396).
• Neurodevelopmental normalization: It’s possible that properly-dosed lithium might counteract genetically and/or environmentally-mediated neurodevelopmental irregularities implicated in neuropsychiatric disorders. While more evidence is needed, preclinical studies in animal models of Fragile X syndrome indicate that properly-dosed lithium combats dendritic morphology to improve neurodevelopmental outcomes.  Based on this finding, it can be theorized that a subset of patients with neurodevelopmental disorders and comorbid anxiety may benefit from lithium in that it ameliorates dysfunctional neurodevelopment implicated in various disorders.
• Refractory anxiety: It is understood that between 50% and 60% of patients treated for anxiety disorders attain significant symptomatic reductions from medication. While over half of patients are benefitting from first-line anxiolytics, around 40% won’t respond sufficiently to conventional medications.  Even of the 50-60% of patients who respond to medications, approximately 20% of those individuals experience a symptomatic relapse within 5 years of an initially-successful treatment.  Though the exact number of patients with refractory anxiety disorders isn’t well-documented in the literature, it may be greater than expected.  For this reason, unconventional and/or off-label pharmacology warrants testing.  When considering the established safety of lithium in humans, case studies suggesting that adjunct lithium alleviates panic disorder, and data from animal models indicating that lithium can reduce fear behaviors – it’s rational to believe that lithium may be useful for a subset of persons with refractory anxiety.  Lithium may be the only intervention that sufficiently alleviates debilitating anxiety in a subset of patients.
• Safety: Many consider low doses of lithium, especially in supplemental form, to be extremely safe. While high doses of lithium carbonate can be unsafe, close monitoring of patients taking lithium by medical professionals can reduce safety concerns.  It could be argued that lithium-based anxiolytic interventions are safer than atypical antipsychotics and benzodiazepines, each of which are sometimes used to treat anxiety.  Unlike atypical antipsychotics, lithium isn’t known to shrink brain volume, plus its side effect profile is more tolerable and discontinuation symptoms are easier to manage.  Additionally, unlike benzos, lithium isn’t habit forming and doesn’t appear to increase risk of dementia.  Despite the fact that lithium can be a dangerous psychiatric drug if administered at too high of a dose or in the wrong scenario, it’s fairly safe when administered with accurate medical instruction.
• Tolerability: Though some side effects are reported during lithium treatment (as with any medication), especially during initial titration of dosing, it is generally well-tolerated. Additionally, evidence suggests that tolerability can be improved through once-daily dosing protocols and/or dosage reductions.  If lithium is administered for anxiety as an adjunct to conventional antidepressants, it may turn out that patients respond to lower doses of lithium than are needed to treat other conditions such as bipolar disorder, whereby tolerability is further improved.

Drawbacks of Lithium for Anxiety (Possibilities)

Although there may be some benefits attained from lithium as an anxiolytic, there are also some potentially serious drawbacks to contemplate.  Perhaps the single biggest drawback associated with using lithium for the treatment of anxiety is that it hasn’t undergone randomized controlled testing for anxiety disorders.  Not only is lithium’s efficacy for the management of anxiety disorders unknown, there are safe, clinically-tested anxiolytic interventions available that are likely to work for most patients.  Other possible drawbacks associated with using lithium include: its side effect profile, toxicity concerns, the need to regularly monitor blood levels, and discontinuation symptoms.

• Cognitive deficits: A serious drawback associated with taking lithium as an anxiolytic is that it may induce mild cognitive dysfunction. Some lithium users report experiencing “brain fog” or clouded thinking and impaired executive function throughout treatment.  A meta-analysis conducted by Wingo, Wingo, Harvey, and Baldessarini (2009) documented significant cognitive deficits in various domains of cognition including: verbal learning, memory, and creativity – among lithium users.  Assuming cognitive impairment occurs as a result of lithium, this may detrimentally affect one’s ability to function in occupational and/or academic settings.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/19689922).
• Contraindications: Lithium is not devoid of contraindications, and may induce severe health complications if taken by a subset of the population. Medical sources suggest that lithium should be avoided among persons with: Brugada Syndrome, cardiovascular disease, dehydration, electrolyte depletion, or renal dysfunction.  There may be other medical conditions in which lithium administration could cause a medical emergency.  For more information regarding lithium contraindications, consult a medical professional.
• Ineffective: As of current, lithium hasn’t undergone so much as a proof of concept trial in humans for the treatment of anxiety disorders.  Before lithium can be suggested as effective for the treatment of anxiety, we need some quality evidence from multiple large-scale, randomized controlled trials (RCTs).  No quality research has been conducted to evaluate the safety, dosing, efficacy, and practicality of lithium as an anxiolytic intervention.  Moreover, even if lithium was regarded as clinically effective for the treatment anxiety, it wouldn’t be universally effective for all persons.  There are many neurobiological signatures of anxiety, some of which would either: not respond to lithium and/or end up worse off with lithium treatment.
• Interactions: There are hundreds of drugs and/or supplements that may interact with lithium pharmacokinetically or pharmacodynamically. For example, lithium may increase serotonin to an abnormally high level when administered with certain antidepressants, thereby inducing serotonin syndrome, a dangerous medical condition.  Lithium can interact with SSRIs, SNRIs, TCAs, and MAOIs – depending on the specific drug and dose.  Examples of some other agents that can interact with lithium include: ACE inhibitors, anticonvulsants, calcium-channel blockers, dextromethorphan, diuretics, meperidine, methyldopa, methylxanthines, muscle relaxants, NSAIDs, phenothiazines, and tramadol.  It should also be noted that co-administration of lithium with antipsychotics can cause neuroleptic malignant syndrome, and co-administration of lithium older neuroleptic agents can induce irreversible toxic encephalopathy.  Due to the potentially deleterious interaction effects resulting from co-administration of lithium and another medication, other anxiolytics may be preferred over lithium.
• Emotional numbness: It is possible to experience blunted affect (emotional numbness) while taking lithium. Lithium can work wonders for persons with bipolar disorder because it prevents manic highs and reduces likelihood of depressive lows.  A person’s emotional range is somewhat restricted when taking lithium and they may feel as though they’re stuck in an emotional flatline.  Those with anxiety disorder devoid of a bipolar diagnosis may dislike the numbing or zombified effect that is occasionally caused by lithium.  Even if lithium were effective for anxiety, its anxiolytic efficacy may not outweigh the emotional restriction.
• Monitoring: Anyone receiving lithium from a medical doctor will need to receive regular blood tests. These blood tests will help monitor lithium levels to ensure that they are within a non-toxic, therapeutic range.  Individuals who dislike blood tests and/or frequent doctor visits may immediately reject the idea of receiving lithium for the treatment of their anxiety.  There are many anxiolytic treatments that require zero blood draws.  What’s more, patients receiving lithium often require thyroid and kidney tests to ensure that lithium hasn’t disrupted their respective functions.
• Neurodevelopmental impairment: While there’s preclinical research suggesting that lithium may normalize morphological outcomes in animal models of severe neurodevelopmental disorders, there’s also some evidence suggesting that it may harm development of those without neurodevelopmental disorders. Therefore, lithium probably isn’t a favorable treatment option for children, adolescents, or young adults with standalone diagnoses of anxiety.  It’s possible that regular administration of lithium throughout critical developmental years may adversely affect neural development in a subset of individuals.
• Side effects: The side effects of lithium are downright unbearable for certain individuals. Among the most common lithium side effects include: confusion, constipation, diarrhea, dry mouth, frequent urination, headache, heartbeat changes, leukocytosis, memory impairment, nausea, renal dysfunction, thirstiness, tremor, twitching, vomiting, weakness, and weight gain.  Other fairly common side effects include: acne, extrapyramidal effects, hair loss, hypothyroidism, and goiter.  Even if lithium works well for one’s anxiety, if side effects remain severe and fail to subside after several months of treatment, most users will opt to discontinue.  In addition to general side effects, there’s a chance that individuals may endure deleterious, perhaps permanent, long-term effects from usage of lithium over an extended duration (e.g. several years).  The bottom line is that a majority of pharmaceutical anxiolytics exhibit favorable side effect profiles over lithium.
• Superior options: Any anxiolytic drug that’s prescribed by a medical professional for the treatment of an anxiety disorder has undergone extensive evaluation via randomized controlled trials to ensure safety, tolerability, and efficacy in the general population. Since lithium hasn’t been subject to any randomized controlled trials specifically for the treatment of anxiety, we cannot know whether it might be useful as an anxiolytic.  Although lacking randomized controlled trial testing doesn’t render lithium an ineffective anxiolytic by default, it does mean that lithium would be a poor treatment choice compared to drugs that have proven track records of anxiolytic efficacy in randomized controlled trials.  Professionals prescribe medications that have strong scientific support for treating anxiety so that patients get relief as quickly as possible, hence the reason it’s fairly negligent, in most circumstances, to prescribe lithium as an anxiolytic.  Only when all FDA-approved and evidence-based off-label medications have been exhausted, and a patient exhibits refractory anxiety, could lithium warrant consideration as an anxiolytic adjunct.  Overall, there are so many superior anxiolytic interventions that lithium is unlikely to ever get prescribed for the treatment of anxiety.
• Toxicity: Another of the most serious drawbacks associated with prescription lithium carbonate is that it can induce toxicity. Evidence suggests that serum lithium concentrations between 0.4 mmol/L and 1.2 mmol/L are therapeutic, non-toxic, and well-tolerated for most individuals.  However, long-term users may accumulate lithium in the serum and exhibit levels between 1.8 mmol/L and 2.5 mmol/L.  In the event of an overdose, serum concentrations of lithium may rise between 3 mmol/L and 10 mmol/L.  Serum concentrations above 1.5 mEq increases toxicity risk and serum concentrations exceeding 2.5 mEq/L nearly guarantees toxicity.  Lithium can cause both neurotoxicity (brain damage) and renal toxicity (kidney damage).  While conservative dosing can reduce likelihood of lithium toxicity, it’s not a guarantee.  Acute lithium toxicity is understood to affect neurons implicated in coordination and causes overt symptoms such as tremor and dyscoordination of extremities.  Higher levels of toxicity can cause the following: delirium, extrapyramidal effects, slurring of speech, seizures – and even death.  Moreover, lithium toxicity can be permanent (irreversible) as a result of high-doses causing demyelination at multiple sites within the CNS, particularly the cerebellum.  For this reason, professional monitoring of serum lithium levels is required, which can be a hassle for patients.  Given the life-altering consequences of lithium-induced irreversible toxicity, most persons with anxiety disorders likely prefer safer treatments.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/26644952).
• Unclear administration guidelines: If lithium were to be administered for the management of anxiety, it is unclear what dosage would be necessary. Perhaps the therapeutic blood concentrations of lithium necessary to treat anxiety disorder would be much lower than those needed for bipolar disorder.  In this case, administration of lithium at the range necessary to stabilize mood may have no favorable effect upon patients with anxiety.  It is also necessary to note that some individuals may take lithium orotate and/or lithium aspartate supplements – neither of which haven’t been thoroughly investigated by medical researchers as neuropsychiatric interventions.  For this reason, it may be even more difficult to recommend dosing for the lithium orotate and lithium aspartate formats compared to lithium carbonate.  Until legitimate randomized controlled trials are conducted to test multiple lithium formats and determine an effective dosing range, anyone using lithium as an anxiolytic won’t know the optimal quantity to administer.
• Withdrawal symptoms: Although lithium is considered easier to discontinue than many other neuropsychiatric medications, a subset of patients will experience unwanted lithium withdrawal symptoms. A paper by King and Hullin (1983) documents several prominent withdrawal symptoms from lithium such as: anxiety, emotional lability, and irritability.  Furthermore, the paper suggests that around 20% of persons might notice some discontinuation effects following cessation of lithium.  For some individuals, the fact that there’s a withdrawal that might make their anxiety worse may be reason enough to avoid lithium.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/6882990).
• Worsening of anxiety: Though most preclinical data from animal model studies suggest lithium might reduce anxiety, other data indicate that lithium could exacerbate anxiety. For example, a study by Youngs, Chu, Meloni, et al. (2006) administered lithium to preadolescent rats and concluded that lithium treatment induced long-term anxiety-like behavior.  It was also revealed that lithium administration altered the expression of gene transcripts within the synapse and cytoskeleton of the rats, which in turn, adjusted synapses and modified neurodevelopment – likely culpable for the long-term anxiety-like behavior.  Though this study was conducted in animal models and may not apply to humans, it is possible that administration of lithium, especially during critical periods of brain development, might induce similar morphological changes to induce long-term anxiety in humans.  What’s more, a study by Bschor, Baethge, Adli, et al. (2003) evaluated concentrations of stress hormones among patients receiving adjunct lithium for the treatment of refractory depression.  Findings indicated that lithium significantly upregulated levels of ACTH and cortisol – suggestive of increased HPA axis activity.  Since overactivation of the HPA axis is linked to anxiety disorders, it’s likely that lithium could exacerbate anxiety in some persons.  (Source #1: http://www.ncbi.nlm.nih.gov/pubmed/16738246/).  (Source #2: http://www.ncbi.nlm.nih.gov/pubmed/12577277).

Lithium for Anxiety (Review of Research)

To determine whether lithium might be useful for the treatment of anxiety, it’s necessary to search the medical literature for studies investigating the anxiolytic potential of lithium.  As of current, there don’t seem to be any randomized controlled trials that have evaluated lithium as a standalone intervention for anxiety disorders.  That said, there are data from animal model trials and human case studies suggestive that lithium may facilitate an anxiolytic effect.  Moreover, a subset of trials in which lithium is tested for the treatment of neuropsychiatric disorders (e.g. bipolar disorder, depression, schizophrenia) have documented reductions in anxiety following lithium administration.

2015: Subchronic lithium treatment increases the anxiolytic-like effect of mirtazapine on the expression of contextual conditioned fear.

An, Inoue, Kitaichi, et al. (2015) reported that lithium not only acts as a mood stabilizer, but can enhance mood when administered along with antidepressants.  Though it was believed that lithium could effectively bolster the therapeutic properties of mirtazapine, its efficacy when administered along with mirtazapine was never formally evaluated.  For this reason, researchers set up a trial in which they tested the effects of mirtazapine plus lithium in animal models conditioned to fear.

The fear-conditioned rats (animal models of anxiety) received systemically-administered mirtazapine and subchronic doses of lithium carbonate (added to the rats’ food).  All rats underwent a contextual fear conditioning test prior to receiving mirtazapine plus lithium, followed by another test after treatment.  Results indicated that mirtazapine (10 mg/kg) dose-dependently attenuated freezing behavior within 1 day after fear conditioning, however, the anxiolytic effect of mirtazapine was relatively poor when the time gap between fear conditioning and the conditioning test increased to 1-week.

Surprisingly, an anxiolytic effect was observed even after a 1-week time gap (between conditioning and the testing) when a subchronic quantity of lithium carbonate (0.2%) was added to mirtazapine (10 mg/kg).  Smaller doses of lithium carbonate (e.g. 0.05%) failed to generate an anxiolytic effect when administered with mirtazapine in the fear-conditioned rats.  Researchers concluded that subchronic lithium carbonate (0.2%) augments the anxiolytic effects of mirtazapine.

Thereafter, they suggested that lithium may be effective for the treatment of anxiety disorders when administered as an adjunct.  It is also reasonable to speculate that standalone lithium may have been equally as effective as mirtazapine for the attenuation of anxiety in the fear-conditioned rats, but since it wasn’t tested as a standalone intervention, there’s no way of knowing its anxiolytic efficacy.  While results from animal trials aren’t always similar in humans, this provides preliminary data indicating that low-dose lithium might improve symptoms of anxiety.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25438255

2014: Anxiogenic and anxiolytic effects of lithium chloride under preventive and therapeutic treatments of male mice with repeated experience of aggression.

Smagin and Kudryavtseva (2014) documented repeated aggression in daily agonistic interactions can lead to deleterious behavioral and psychological changes.  Furthermore, exposure to aggression on a regular basis often leads the exposed individual to develop aggressive behaviors, which often become challenging to treat with serenic or antiaggressive agents.  In this report, researchers assessed the preliminary efficacy of lithium chloride as an antiaggressive agent in animal models.

Male mice received lithium chloride (100 mg/kg/day, intraperitoneally) within 7 days of exposure to agonistic interactions as a prophylactic.  Another group of male mice with a 21-day history of agonistic interactions received lithium chloride during periods devoid of aggression.  Lithium chloride was also administered chronically to a control group of male mice that hadn’t been exposed to agonistic interactions.

Behavior of all mice was assessed using elevated plus maze, social interaction test, partition test, and agonistic interaction test.  Results indicated that administration of lithium chloride to male mice repeatedly exposed to agonistic interactions induces an anxiogenic effect.  On the other hand, when lithium chloride is administered therapeutically and/or to the control group (devoid of aggressive experiences), it yields a significant anxiolytic effect.

Overall, this research supports that idea that lithium administration yields serenic and/or anxiolytic effects in a subset of animal models.  Based on the results of this study, we could hypothesize that a subset of humans, especially those devoid of aggressive exposures, might derive a serenic and/or anxiolytic effect from the administration of lithium.  A follow-up study evaluating the serenic and/or anxiolytic potential of humans with neuropsychiatric conditions may be useful.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25975141

2014: Essential elements in depression and anxiety. Part I.

Młyniec, Davies, de Agüero Sánchez, et al. (2014) highlight the fact that essential elements are conducive to general health and are necessary to ensure optimal neurobiological function in humans.  Basic processes such as cell division, cell differentiation, and synthesis of proteins are disrupted when persons are lacking in essential elements.  Furthermore, any chronic and/or severe essential element deficiency can cause debilitating neuropsychiatric symptoms such as anxiety and depression, and if severe enough, may lead to premature death.

Authors of this paper suggest that supplementation with essential elements could reverse an underlying deficiency that caused anxiety and/or depression.  It was also mentioned that supplementation with essential elements can facilitate synergistic anxiolytic and antidepressant effects when administered along with neuropsychiatric medications.  What’s more, essential element supplementation as an adjunct to a neuropsychiatric medication may yield fewer unwanted side effects in patients.

The reduction of unwanted side effects may be partly related to the fact that essential elements directly attenuate side effects and/or decrease dosing needs of the neuropsychiatric drug (which should also reduce side effects).  In this report, lithium is one of the essential elements listed as holding therapeutic potential for the treatment of anxiety and depression.  While more research is necessary to evaluate the anxiolytic potential of lithium, this paper implies that it could reduce anxiety in a subset of persons.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/24948052

2013: Prescribing patterns of lithium or lithium+valproate in manic or mixed episodes: a naturalistic study.

A study by Muti, Del Grande, Musetti, et al. (2013) sought to determine prescribing patterns of lithium (as a standalone agent), versus lithium plus valproate among patients with bipolar disorder.  For the study, researchers analyzed 75 patients who had been diagnosed with bipolar disorder (type 1) and were experiencing mania or a mixed episode.  In a naturalistic setting, researchers documented the treatment each patient received (lithium OR lithium plus valproate) and corresponding therapeutic outcomes.

Additionally, researchers evaluated whether there were correlations between concentrations of lithium in the serum and symptomatic reductions.  Results indicated that patients with serum lithium concentrations of 0.60 mEq/L or higher, exhibited the highest rates of remission and greatest symptomatic reduction compared to those with lower serum lithium concentrations.  What’s more, patients receiving a combination of lithium plus valproate exhibited the greatest improvements in: anxiety, mixed, and psychotic symptoms – compared to those receiving standalone lithium.

When lithium is co-administered with valproate, serum concentrations within the range of 0.40 and 0.60 mEq/L appear sufficiently therapeutic for the treatment of bipolar disorder.  In other words, when simultaneously administered, valproate reduces the dosing needs of lithium required for a therapeutic effect.  Despite the fact that the primary aim of this study wasn’t to investigate the anxiolytic effect of lithium, it was noted that lithium (at serum concentrations of 0.60 mEq/L or higher) reduced anxiety in patients with bipolar disorder.

What’s more, the combination of lithium plus valproate generated greater anxiolytic effects than standalone lithium.  Based on the finding that optimal serum concentrations of lithium decreases anxiety among patients with bipolar disorder, it’s reasonable to speculate that lithium might also treat anxiety among patients with other neuropsychiatric conditions (e.g. anxiety disorders).  Moreover, there’s reason to believe that usage of lithium plus another neuropsychiatric medication (e.g. valproate) yields stronger anxiolytic effects than standalone lithium.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/23873290

2011: Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome.

Fragile X syndrome is a genetic condition in which the FMR1 gene is mutated, thereby disrupting the process in which the protein FMRP is manufactured.  Lack of FMRP is problematic because it is responsible for regulating production of other proteins and facilitating the formation of synapses (connections between cells).  Unfortunately, those with the condition experience cognitive deficits, learning disabilities, speech and language difficulties, plus exhibit symptoms such as: anxiety, hyperactivity, and delayed speech.

Liu, Chuang, and Smith (2011) conducted a study utilizing a mouse model of Fragile X syndrome to test the therapeutic potential of lithium.  For their study, they utilized knockout (KO) mice devoid of the FMR1 gene and compared them to standard wild-type (WT) mice.  Both types of mice were assigned to receive either: standard chow OR chow-enriched with lithium carbonate (0.3%).

To gauge the efficacy of the lithium carbonate intervention, 8-to-12-week-old mice underwent behavioral evaluations in tests such as: open field, social interaction, elevated plus maze, elevated zero plus maze, and passive avoidance.  After 13 weeks, researchers analyzed dendritic spine morphology in the medial prefrontal cortex (mPFC).  Results indicated that the untreated FMR1 knockout mice exhibited longer and increased numbers of dendritic spines (in the mPFC).

Furthermore, untreated FMR1 knockout mice exhibited anxiety, social deficits, and learning difficulty compared to the wild-type (WT) controls.  Comparatively, the FMR1 knockout mice receiving lithium exhibited: reduction in hyperactivity, reversal of social interaction deficits, partial decreases in general anxiety, and morphological improvements of dendritic spines.  Based on results of this study, one would theorize that lithium may prove useful as a treatment among humans with Fragile X syndrome.

It is necessary to highlight the fact that administration of lithium reduced social and generalized anxiety behaviors in both the knockout (KO) and wild-type (WT) mice, however, the anxiolytic effect was most pronounced in the knockout (KO) mice.  Reduced generalized anxiety was evidenced by behavioral changes in open field tests, the elevated plus maze, and the elevated zero maze – following the administration of lithium.  Decreased social anxiety was evidenced by significantly increased social behavior in a 3-chambered apparatus after lithium treatment.

When considering that lithium treatment attenuates behaviors associated with generalized and social anxiety in animals, it’s logical to theorize that similar outcomes may occur in humans.  Knowing that lithium can be safely administered to humans for the treatment of bipolar disorder, one may question why it hasn’t been tested as an intervention for anxiety disorders.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/20497624

2009: Epidemiology and management of anxiety in patients with bipolar disorder.

It is understood that patients with bipolar disorder frequently experience symptoms of anxiety during mania, depression, and/or mixed episodes.  Although anxiety may be disconcerting to patients with bipolar disorder, in many cases, it isn’t quite severe enough to meet necessary diagnostic criteria for a specific anxiety disorder.  Nonetheless, Kauer-Sant’Anna, Kapczinski, and Vieta (2009) highlight the fact that anxiety disorders are the single most diagnosed comorbidity among patients with bipolar disorder.

For this reason, researchers reviewed clinical and epidemiological data from studies documenting links between bipolar disorder and symptoms of anxiety OR comorbid diagnosis of an anxiety disorder.  Next, researchers analyzed the efficacies of various anxiolytic interventions among patients with bipolar disorder and anxiety.  Evidence suggested that quetiapine OR olanzapine administered along with either lithium OR fluoxetine – effectively attenuated symptoms of bipolar disorder and comorbid anxiety.

Other findings suggested that administration lamotrigine plus lithium was an effective combination for the treatment of bipolar disorder with comorbid anxiety.  Knowing that combinations of lithium plus lamotrigine OR atypical antipsychotics (quetiapine or olanzapine) can treat bipolar disorder with comorbid anxiety, one might speculate that lithium facilitates an anxiolytic effect.  Although the anxiolytic effect of lithium may be limited to bipolar patients receiving adjunct antipsychotics or mood stabilizers, it may be worth investigating the anxiolytic potential of lithium in non-bipolar patients with anxiety disorders.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/19845416

2008: Olanzapine or lamotrigine addition to lithium in remitted bipolar disorder patients with anxiety disorder comorbidity: a randomized, single-blind, pilot study.

Maina, Albert, Rosso, and Bogetto (2008) conducted a randomized, single-blinded, pilot trial to evaluate the therapeutic potential of adjunct olanzapine OR lamotrigine when administered along with lithium to patients who met DSM-IV criteria for bipolar disorder plus comorbid anxiety disorders.  All participants had been on lithium maintenance therapy for at least 2 months to control their bipolar symptoms, but had exhibited scores on the Hamilton Rating Scale for Anxiety (HAM-A) of 12 or higher.  Participants were assigned at random to receive either: 5-10 mg/day of olanzapine (24 patients) OR 50-200 mg/day of lamotrigine (23 patients) – in addition to their lithium.

After 12 weeks of treatment, participants were assessed using the HAM-A, CGI-S, and GAF scales.  Results indicated that 40 participants completed the trial; 22 of 24 in the olanzapine group and 18 of 23 in the lamotrigine group.  Results indicated that augmentation of lithium with olanzapine and lamotrigine significantly reduced HAM-A scores from pre-treatment baseline.  Moreover, both augmentation options significantly improved scores on the CGI-S and GAF, each of which were used as secondary outcome measures.

Olanzapine exhibited a quicker onset of anxiolytic action when augmenting lithium compared to lamotrigine, however, after 12 weeks, neither was more effective than the other.  It was concluded that augmenting lithium with either olanzapine or lamotrigine is effective for attenuating anxiety among patients with bipolar disorder plus anxiety disorders.  Based on the results, it is unclear as to whether lithium facilitated any of the anxiolytic effect observed in patients.

Perhaps it would’ve been useful to assess for reductions in anxiety levels after initiation of lithium treatment to determine whether it provided any preliminary anxiolytic effect prior to augmentation with olanzapine or lamotrigine.  It’s possible that lithium alleviates anxiety only when administered in combination with olanzapine or lamotrigine – through a synergistic effect.  Moreover, another possibility is that lithium only helps with mood stabilization and has zero significant effect on anxiety level.

It might’ve also been interesting to recruit patients with bipolar disorder receiving standalone olanzapine and/or lamotrigine for sufficient duration to stabilize mood.  Then filter out patients with HAM-A scores above 12, indicative of anxiety, and test the therapeutic efficacy of lithium for treating anxiety as an adjunct.  By adding lithium later, we’d have a better understanding as to whether it contributes to an anxiolytic effect.

There are some limitations associated with this study including small sample sizes and the lack of a placebo control.  It is possible that the pronounced anxiolytic effect observed in patients was partly associated with a placebo effect.  Overall, it is fair to hypothesize that lithium plus another mood stabilizer act in synergy to produce an anxiolytic effect.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/18294024

2006: Effect of co-administration of subchronic lithium pretreatment and acute MAO inhibitors on extracellular monoamine levels and the expression of contextual conditioned fear in rats.

Kitaichi, Inoue, Nakagawa, et al. (2006) conducted a study using fear-conditioned rats, an animal model of anxiety.  For this study, subchronic doses of lithium carbonate at either 0.2% or 0.05% were received by some of the rats via diet, whereas others received a standard-chow diet.  After 1-week of the lithium administration, researchers administered clorgyline (a selective MAO-A inhibitor) and lazabemide (a selective MAO-B inhibitor).

Throughout the trial, researchers measured extracellular concentrations of dopamine, norepinephrine, and serotonin within the medial prefrontal cortex (mPFC) and monitored fear behaviors.  Prior research suggested that concentrations of extracellular serotonin are inversely correlated with the expression of fear behavior; the greater the extracellular serotonin, the less fearful the rats.  Measures collected in this study indicated that subchronic lithium carbonate significantly increased extracellular serotonin at the 0.2% dose.

That said, subchronic lithium carbonate administered at the 0.05% dose had no effect on extracellular serotonin.  It was further noted that clorgyline (10 mg/kg) as an adjunct to subchronic 0.2% lithium carbonate substantially increased extracellular serotonin levels compared to standalone clorgyline.  Moreover, the combination of subchronic 0.2% lithium carbonate plus clorgyline facilitated synergistic effects in reducing conditioned freezing behavior, a sign of anxiety.

Reductions in freezing behaviors were not observed after administration of the 0.05% lithium carbonate, nor after administration of lazabemide (10 mg/kg).  It was noted that lazabemide had no significant effect on extracellular monoamine levels.  Researchers concluded that subchronic 0.2% lithium carbonate yields adjunct anxiolytic effects when administered with MAO-A inhibitors in animal models of fear.

When considering that subchronic 0.2% lithium carbonate significantly increased extracellular concentrations of serotonin, and that extracellular serotonin levels correlated with anxiolytic effects, it’s possible that standalone lithium carbonate may prove useful as a treatment for anxiety.  Still, since we know that subchronic 0.05% lithium carbonate failed to reverse fear behaviors, more research may be helpful to determine optimal dosing for anxiety.  Perhaps administration of lithium carbonate at a level above 0.2% would’ve facilitated a more pronounced increase in extracellular serotonin, as well as corresponding anxiolytic outcomes – when compared to the 0.2% lithium carbonate.

Nonetheless, it was shown that subchronic 0.2% lithium carbonate synergistically elevated extracellular serotonin concentrations upon co-administration with the inhibitor of MAO-A.  For this reason, we could hypothesize that low-dose lithium plus an inhibitor of MAO-A would treat anxiety in humans.  Moreover, it may be worth evaluating the safety and efficacy of low-dose lithium as an adjunct to non-contraindicated serotonergic anxiolytics in humans with refractory anxiety disorders.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/16487506/

1999: Effect of subchronic lithium carbonate treatment on anxiolytic-like effect of citalopram and MKC-242 in conditioned fear stress in the rat.

Muraki, Inoue, Hashimoto, et al. (1999) administered the SSRI citalopram and the 5-HT1A agonist MKC-242 to fear-conditioned male Sprague-Dawley rats that had been treated with subchronic lithium carbonate for 1 week (at either 0.2% or 0.05% via diet).  Findings suggested that administration of standalone citalopram significantly attenuated freezing behaviors at a high dose (30 mg/kg), but not at lower ones (3 mg/kg and 10 mg/kg).  The standalone administration of MKC-242 reduced freezing behaviors in a dose-dependent manner.

When subchronic lithium (0.2% or 0.05%) was administered as a standalone, zero reductions in freezing behavior were observed.  The augmentation of subchronic lithium carbonate with citalopram and MKC-242 yielded significant decreases in freezing behavior.  What’s more, the combined effect of subchronic lithium plus the serotonergic agents generated a significantly more robust anxiolytic effect compared to each serotonergic compound as a standalone.

It was concluded that subchronic lithium carbonate enhances the anxiolytic efficacy of serotonergic agents through upregulation of serotonergic transmission in the CNS.  Though the findings from this animal model study cannot be generalized to humans, they suggest that lithium may be an underexplored anxiolytic adjunct.  For this reason, it may be worth investigating the anxiolytic potential of lithium plus an SSRI among humans with severe anxiety.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/10594313/

1986: Rapid response of a disorder to the addition of lithium carbonate: panic resistant to tricyclic antidepressants.

An intriguing case report was documented by Cournoyer (1986) in which lithium carbonate was successfully utilized to treat a refractory case of panic disorder.  Cournoyer opens the report by suggesting that panic disorder and major depression may exhibit neurobiological commonalities.  It is logical to speculate that panic and depression share neurobiological commonalities on the basis that most antidepressant drugs can be used interchangeably for the treatment of panic or depression.

In this particular case report, a 40-year-old woman had suffered from panic disorder.  She had been taking lorazepam for an extended duration, but discontinued and incurred debilitating Ativan withdrawal symptoms, one of which was the onset of severe depression.  Medical professionals prescribed amitriptyline at a dose of 150 mg/day, but her panic failed to subside.

Within 12 weeks, her amitriptyline was substituted with clomipramine at a dose of 150 mg/day, followed by a titration up to 225 mg/day.  Despite the increased dose of clomipramine, symptoms of anxiety remained unchanged.  Approximately 2 weeks later, lithium carbonate at a dosage of 900 mg/day was added-on to the clomipramine.

In less than 3 days, the concentration of lithium within her plasma rose to 0.8 mEq/L and her symptoms of anxiety significantly decreased.  Unfortunately, the woman experienced tremors upon initiation of the lithium and she was advised to cease administration.  Around 4 days after discontinuing lithium, a resurgence of debilitating anxiety and panic occurred.

Professionals agreed that she should reinstate lithium carbonate at a lower dose of 600 mg/day.  Around 2 days after resumption of lithium carbonate, a marked anxiolytic effect was observed.  Upon publishing of the case study, the woman remained symptom free with the combination of clomipramine (225 mg/day) and lithium carbonate (600 mg/day).

Cournoyer highlighted the fact that there were previous case reports suggesting prominent antidepressant effects from lithium plus TCAs among persons with refractory depression.  That said, prior to this report, there were no studies showing that adjunct lithium could effectively treat anxiety and/or panic when administered with a TCA.  Based on the fact that lithium hasn’t been well-researched for the treatment of anxiety, it may be an underrated adjunctive option for refractory patients.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/3085912

Limitations of Research associated with Lithium for Anxiety

There are some serious limitations associated with research of lithium for anxiety.  The biggest limitation is that lithium has never undergone quality (randomized controlled) testing in a large sample of humans with anxiety disorders.  Another limitation is the mixed data regarding lithium’s anxiolytic efficacy in animal models.  Moreover, the administration details, dosing, and formatting of lithium necessary to attenuate symptoms of anxiety remains unknown.

• Administration details: There haven’t been any trials comparing modalities of lithium administration (e.g. oral, intravenous, etc.) to determine whether one mode may be more effective than another. Additionally, it is unknown as to whether the frequency of dosing may matter in regards to anxiolytic efficacy.  Perhaps administering lithium on an “as-needed” basis could be effective for the treatment of acute anxiety and/or panic.  It is also possible that lithium may be ineffective when administered “as-needed.”  Other administration details to consider include: time of day administered (e.g. morning, afternoon, night) and whether administered with food vs. on an empty stomach.  If lithium were effective for anxiety, further research should elucidate the optimal administration parameters.
• Anxiety subtypes: There are many different neurobiological signatures of anxiety, each of which may require different treatments. Some individuals might experience anxiety due to lack of serotonergic transmission in specific areas of the brain, whereas others may feel anxious due to brain damage inflicted via a traumatic brain injury.  Another subset of persons may be anxious from an overactive amygdala and/or HPA axis.  Given the fact that anxiety is complex and no 2 individuals exhibit the exact same neurobiologic causal underpinnings, it’s likely that lithium would only be effective in certain individuals.  Assuming lithium is effective as an anxiolytic, researchers should aim to determine the general neurobiologic subtypes of anxiety are most likely to benefit from its administration.
• Dosage: The dosage of lithium needed to treat anxiety disorders is unclear, and likely contingent upon the type of lithium administered. In a case report, a 40-year-old woman found that a dosage of 600 mg per day of lithium carbonate reduced her symptoms of anxiety as an adjunct to clomipramine (225 mg/day).  It’s possible that the dosage of lithium needed may be contingent upon the type of anxiety that a person is dealing with (e.g. panic disorder may require a higher dose than generalize anxiety disorder).  We also must consider that doses between 300 mg and 600 mg of lithium carbonate per day may be effective for most types of anxiety.  That said, since the dosages of lithium needed to treat anxiety hasn’t been investigated, no dosage guidelines have been established.
• Formatting: As was mentioned elsewhere in this article, there are several formats of lithium available to consumers. Medical doctors prescribe lithium carbonate for the management of bipolar disorder and as an adjunct for major depression, however, lithium orotate and lithium aspartate can be purchased online from supplement companies.  It is possible that certain formats are more effective and/or safer than others in the specific domain of anxiety disorders.  Keep in mind there are many other potential formats of lithium (e.g. lithium-l-threonate) that haven’t been synthesized or studied, possibly yielding slightly different effects.  More investigation should aim to compare the various types of lithium in regards to effect on psychological status.
• Lack of human trials: The chief limitation associated with using lithium for anxiety is the lack of human trials. Subchronic lithium administration has been tested in animal models as both a standalone and adjunct, both of which suggest its ability to generate an anxiolytic effect.  That said, substances that work in animals can be ineffective and/or worsen symptoms in people.  Researchers haven’t yet conducted a proof of concept trial testing the anxiolytic effects of lithium.
• Mixed data: While most data from animal models indicate that lithium reduces anxiety, not all data are congruent. One animal study found that lithium provoked long-term anxiety by remodeling brain architecture in preadolescent rats.  A study conducted in humans found that lithium augmenting an antidepressant significantly increased concentrations of stress hormones ACTH and cortisol, suggestive of increased anxiety.  Then again, a case report found that lithium at 600 mg/day effectively treated refractory panic disorder when administered with clomipramine (225 mg/day).
• Reverse causality: It’s possible that some individuals may have anxiety due to an underlying lithium deficiency. If an internal lithium deficit is the cause of an anxiety disorder, supplementation with lithium should alleviate anxious symptoms.  In the event that researchers test lithium for anxiety and suggest that it’s effective, they may also wish to evaluate whether individuals with anxiety disorders are more likely to exhibit lithium deficits compared to healthy, non-anxious persons.  If a deficiency was to blame, reversal and corresponding treatment of anxiety may only require a very small dose (much smaller than the dosages need to treat bipolar disorder).
• Safety: When administered above a particular dosing threshold, lithium can be unsafe and induce [potentially irreversible] neurological and renal damage. Though risk of lithium toxicity is low when ingested in small quantities, even a low risk may not outweigh the benefit for patients with anxiety.  All it takes is one dosing error, interaction, or contraindication for lithium to induce irreversible toxicity.  If lithium was proven efficacious for the management of anxiety, a cost-benefit analysis would be warranted for each patient in terms of toxicity potential vs. therapeutic effect.
• Study designs: There are no human trials investigating the anxiolytic potential of lithium. One case report exists in which lithium carbonate was effective as an adjunct to clomipramine for the attenuation of panic disorder.  To truly understand whether lithium might be useful for the treatment of anxiety, it is necessary to conduct trials that implement randomized, placebo-controlled, double-blinded designs with a large number of participants.

Verdict: Lithium may help a subset of individuals with anxiety disorders

Upon review of the available literature, it seems as though lithium has likely never undergone any randomized controlled trials for the treatment of anxiety disorders.  There are likely many reasons lithium has never been tested as an anxiolytic, including: requirement of frequent serum monitoring, unwanted side effects, adverse long-term effects, and lack of preexisting data indicating that it could be an effective anxiolytic.  That said, there is some evidence from a 1986 case report to suggest that lithium may prove useful for the management of refractory panic disorder.

In this case report by Cournoyer, it was reported that a 40-year-old patient had been treated with clomipramine (225 mg/day) for depression experienced unremitting panic disorder.  Adjuvant lithium administration (600 mg/day) effectively treated the panic.  Other than this lone case report, there are animal model data indicating that lithium reduces anxiety-like behavior in fear-conditioned rats.

It may be worth noting that there are anecdotal reports circulating throughout the internet suggesting that lithium is effective for the alleviation of anxiety.  Though anecdotal reports do not qualify as legitimate scientific data, they support the hypothesis that lithium could reduce anxiety in a subset of the population.  Nonetheless, with new anxiety medications (2015) in the pipeline and the abundance of safe and effective currently-available anxiolytics, lithium may never be properly evaluated for the treatment of anxiety.

Given the available research, one would surmise that lithium is a reasonable first-line agent for patients with bipolar disorder plus comorbid anxiety due to the fact that it is an effective mood stabilizer and may facilitate an additional anxiolytic effect.  Among patients with refractory depression plus comorbid anxiety, lithium seems to be a decent intervention in that it’s an effective for the adjunct alleviation of depression, and might synergistically reduce anxiety with an antidepressant.  While it may be a stretch, off-label administration of lithium could be regarded as a last-resort adjunct among persons with treatment-resistant anxiety.

Overall, lithium should only be considered for the treatment of anxiety when all practical pharmacological approaches have been tested without any benefit.  Additionally, it should be emphasized that while lithium could help a subset of patients with their anxiety, it won’t help everyone.  Certain individuals will find that lithium exerts zero therapeutic effect in helping them control their anxious symptoms, and others will report that lithium worsens their anxiety (possibly due to increased HPA axis activity).

What type and dosage of lithium should be taken for anxiety?

Many individuals with anxiety wonder the type of lithium and dosage they should utilize for anxiety.  Since there are no clinical data on the usage of lithium for anxiety, no recommendations for lithium type and dosing can be made by professionals.  It should be emphasized to avoid following dosing recommendations made by anecdotal reports online, as these could yield dangerous adverse effects and/or outcomes for you as an individual.

If for whatever reason you want to test lithium as an intervention for your anxiety, it is strongly advised to work with a psychiatrist who understands lithium.  Furthermore, you’ll want the psychiatrist to help you rule out potential interactions and contraindications with your current medical status and medication and/or supplement regimen.  Some individuals may find that lithium carbonate works well as an adjunct to serotonergic antidepressants for their anxiety.

Interestingly, a subset of reports online suggest that medically-unconventional formats such as lithium orotate or lithium aspartate can reduce anxiety when administered on an “as-needed” basis in low-dose or micro-dose quantities.  Although lithium is available as a supplement, anyone going the supplement route should consult a doctor before doing so, proceed with caution, and be cognizant of potential side effects.  Overall, unless you’re taking lithium for bipolar disorder or refractory depression, you should use the minimal effective dose needed to reduce anxiety; this amount can be determined based on starting with a micro-dose amount and slowly titrating upwards with your doctor until you notice symptomatic improvement.

Have you tried Lithium for anxiety?

If you’ve tested the efficacy of lithium for anxiety, share your experience in the comments section below.  Mention whether you found lithium to be effective, partially-effective, or completely ineffective for the treatment of your anxiety – or if it somehow made your anxiety worse.  In your subjective experience, what would you rate lithium’s efficacy on a numeric scale of 1 to 10 (with “1” being totally ineffective and “10” being highly effective) for the treatment of your anxiety?

To help others get a better understanding of your situation, provide details such as:  the manufacturer and type of lithium you take (e.g. carbonate, orotate, aspartate), your average lithium dosage (e.g. 300 mg), frequency of administration (e.g. “as needed” vs. daily), and the cumulative duration over which you’ve been taking it (e.g. 2 months).  Also document things like: your anxiety diagnosis (e.g. generalized anxiety disorder), neuropsychiatric comorbidities (e.g. bipolar disorder), and other substances that you regularly administer (e.g. pharmaceuticals, supplements, etc.) with lithium.  If you derived therapeutic benefit from lithium, how long did it take for the anxiolytic effect to kick in after initiation of treatment?

For persons who take lithium with other psychiatric medications and/or supplements, have you considered that you might be misattributing anxiolytic effects to lithium when they’re likely being generated by another substance?  Furthermore, do you believe that lithium might be acting synergistically with another substance you’re taking to reduce your anxiety OR do you attribute your anxiety reduction entirely to lithium?  What prompted you to give lithium a try for the treatment of your anxiety?

Throughout your term of lithium usage, note whether you’ve experienced side effects, tolerance onset, and/or adverse long-term effects.  In your personal experience, has the anxiolytic efficacy of lithium outweighed its side effects?  Overall, although lithium isn’t an evidence-based treatment for anxiety, a subset of individuals may find it effective as an off-label and/or supplemental intervention.  More research is needed to elucidate the efficacy of lithium among persons with anxiety disorders.

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