What is NADH

NADH is short for reduced nicotinamide adenine dinucleotide. NADH is a coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). NADH is the reduced form of NAD+ and NAD+ is the oxidized form of NADH ¹. NAD+ and NADH participate in reactions such as glycolysis, the tricarboxylic acid cycle (citric acid cycle), and oxidative phosphorylation,  participating in multiple redox reactions in cells ². In addition, it serves as a substrate for several enzymes involved in DNA damage repair, such as the sirtuins (silent information regulator 2 or Sir2) and poly (ADP-ribose) polymerases (PARPs) ³. The human serum NADH concentration was found to be in very small amount (50 nM to 1.2 μM) ⁴.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in all living cells. NAD+ (nicotinamide adenine dinucleotide) serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate–ribose) polymerases. Cellular NAD+ concentrations change during aging, and modulation of NAD+ usage or production can prolong both health span and life span.

The NAD⁺/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb’s cycle (also known as tricarboxylic acid cycle or citric acid cycle), and fatty acid oxidation ⁵. Intracellular NAD⁺ is synthesized de novo from L-tryptophan, although its main source of synthesis is through salvage pathways from dietary vitamin B3 (Niacin) as precursors. NAD⁺ is utilized by various proteins including sirtuins (silent information regulator 2), poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases. The NAD⁺ pool is thus set by a critical balance between NAD⁺ biosynthetic and NAD⁺ consuming pathways. Raising cellular NAD⁺ content by inducing its biosynthesis or inhibiting the activity of poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases via genetic or pharmacological means lead to sirtuins activation. Sirtuins (silent information regulator 2) modulate distinct metabolic, energetic and stress response pathways, and through their activation, NAD⁺ directly links the cellular redox state with signaling and transcriptional events. NAD⁺ levels decline with mitochondrial dysfunction and reduced NAD⁺/NADH ratio is implicated in mitochondrial disorders, various age-related pathologies as well as aging.

Sirtuins (silent information regulator 2 or Sir2) proteins are a family of evolutionarily conserved nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacylases harboring lysine deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity ⁶ or an ADP-ribosyltransferase activity ⁷. Mammals contain seven sirtuins (SIRT1–7) that are locacted in different subcellular compartments i.e. nucleus (SIRT1, SIRT6 and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3, SIRT4 and SIRT5) ⁸ and are implicated in a wide variety of biological functions including control of cellular metabolism and energy homeostasis, aging and longevity, transcriptional silencing, cell survival, proliferation, differentiation, DNA damage response, stress resistance, and apoptosis ⁹. Since sirtuins are NAD⁺-dependent enzymes, the availability of NAD⁺ is one of the key mechanisms that regulate their activity. Sirtuins therefore serve as “metabolic sensors” of the cells as their activity is coupled to changes in the cellular NAD⁺/NADH redox state, which is largely influenced by the availability and breakdown of nutrients ¹⁰. Thus, NAD⁺ is not only a vital cofactor/coenzyme but also a signaling messenger that can modulate cell metabolic and transcriptional responses. Changes in cellular NAD⁺ levels can occur due to modulation of pathways involved in NAD⁺ biosynthesis and consumption. Reduced NAD⁺ levels have been reported in mitochondrial and age-related disorders, and NAD⁺ levels also decline with age ¹¹. Boosting cellular NAD⁺ levels serves as a powerful means to activate sirtuins, and as a potential therapy for mitochondrial as well as age-related disorders.

Figure 1. NADH redox reaction

Figure 2. NADH and NAD+ redox metabolism

It is known, as aging progresses, nicotinamide adenine dinucleotide (NAD⁺) levels decrease and are involved in age-related metabolic decline and mitochondrial dysfunction ¹². Elevated NADH to NAD+ ratio further suggests that older individuals of both sexes are unable to utilize NADH as effectively as the younger adults. This observation has direct bearing on the mitochondrial oxidation. NADH is perhaps not oxidized efficiently in the older and female adults than the younger individuals, i.e. less of the energy pool (ATP) in the older adults. Recent studies have shown that a reduction in NAD⁺ is a key factor for the development of age-associated metabolic decline. Increased NAD⁺ levels in vivo results in activation of pro-longevity and health span-related factors. Also, it improves several physiological and metabolic parameters of aging, including muscle function, exercise capacity, glucose tolerance, and cardiac function in mouse models of natural and accelerated aging.

It has been shown that the cellular NAD⁺ pool is determined by a balance between the activity of NAD-synthesizing and NAD-consuming enzymes ¹³. In previous publications, it was demonstrated that expression and activity of the NADase CD38 increases with age and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity (see Figure 3 below) ¹⁴. It was also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo. That indicates that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases ¹⁴. CD38 was originally identified as a cell-surface enzyme that plays a key role in several physiological processes such as immune response, inflammation, cancer, and metabolic disease ¹⁵.

Type 2 diabetes has become an epidemic due to calorie-rich diets overwhelming the adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD⁺ biosynthesis and the NAD⁺-dependent protein deacetylase SIRT1. The results presented in this study in mice demonstrated that nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD⁺ biosynthesis is severely compromised by high fat diet and aging, contributing to the pathogenesis of type 2 diabetes ¹⁶. Strikingly, nicotinamide mononucleotide (NMN), a product of the nicotinamide phosphoribosyltransferase (NAMPT) reaction and a key NAD⁺ intermediate, ameliorates glucose intolerance by restoring NAD⁺ levels in high fat diet-induced type 2 diabetes mice. Nicotinamide mononucleotide (NMN) also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD⁺ and NAMPT levels show significant decreases in multiple organs during aging, and nicotinamide mononucleotide (NMN) improves glucose intolerance and lipid profiles in age-induced type 2 diabetes mice ¹⁶.

The recent development of potent and specific CD38 inhibitors ¹⁷, together with the novel findings highlighting the role of NAD⁺ replacement therapy and CD38 in age-related diseases such as hearing loss and Alzheimer’s ¹⁸, indicate that CD38 inhibition combined with NAD precursors may serve as a potential therapy for metabolic dysfunction and age-related diseases.

Figure 3. NAD decline due to increases in CD38/NADase during aging

[Source ¹²]

NAD+ biosynthesis, consumption and compartmentalization

The mammalian NAD⁺ biosynthesis occurs via de novo and salvage pathways, and involves four major substrates including the essential amino acid l-tryptophan (Trp), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR) ¹⁹. De novo biosynthesis of NAD⁺ starts from dietary L-tryptophan (Trp) which is catalytically converted to N-formylkynurenine by either indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO) and is the first rate limiting step. N-formylkynurenine is then converted by a series of four enzymatic reactions to α-amino-β-carboxymuconate-ε-semialdehyde (ACMS) which is unstable and hence undergoes either complete enzymatic oxidation or non-enzymatic cyclization to quinolinic acid (see Figure 4). The second rate limiting step involves the catalytic conversion of quinolinic acid to nicotinic acid mononucleotide (NAMN) by quinolinate phosphoribosyl transferase (QPRT). Next, NAMN is converted to nicotinic acid adenine dinucleotide (NAAD) by one of the three isoforms of nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme. The human NMNAT1 is localized in the nucleus, NMNAT2 is found in the Golgi and cytosol, whereas NMNAT3 is localized in both mitochondria and cytosol ²⁰. The final step of de novo biosynthesis is the amidation of NAAD by NAD synthase (NADS) enzyme (see Figure 4) ¹⁹. The de novo pathway contributes only a minor fraction to the total NAD⁺ pool, however, its importance is stressed by the human disease pellagra which is caused by dietary deficiency of Trp and NAM intermediate, leading to diarrhea, dermatitis, dementia and ultimately death ²¹. However, pellagra is easily treated by dietary supplementation of L-tryptophan (Trp) or niacin (vitamin B3) (i.e. nicotinic acid, nicotinamide and nicotinamide riboside). The primary source of NAD⁺ biosynthesis is the salvage or Preiss-Handler pathway which utilizes dietary niacin as precursors (Figure 4). The salvage pathway involves catalytic conversion of nicotinic acid to nicotinic acid mononucleotide by nicotinic acid phosphoribosyltransferase (NAPT), which is subsequently converted to NAD⁺ by the action of nicotinamide mononucleotide adenylyltransferase (NMNAT) and NAD synthase (NADS) enzymes. The nicotinamide and nicotinamide riboside are converted to nicotinamide mononucleotide (NMN) by the action of nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside kinase (NRK) enzymes respectively. Finally, nicotinamide mononucleotide (NMN) is enzymatically converted to NAD⁺ by nicotinamide mononucleotide adenylyltransferase (NMNAT).

The cellular abundance of NAD⁺ is also regulated by its breakdown since NAD⁺ serves as a degradation substrate for multiple enzymes including sirtuins, poly ADP-ribose polymerases (PARPs) and cyclic ADP (cADP) ribose synthases which cleave NAD⁺ to produce nicotinamide and an ADP-ribosyl product ²². For instance, the deacetylase activity of mammalian sirtuins uses NAD⁺ to cleave the acetyl group from ε–acetyl lysine residues of target proteins to generate nicotinamide and 2′O-acetyl-ADP-ribose. Sirtuins are activated in response to nutrient deprivation or energy deficit which triggers cellular adaptations to improve metabolic efficiency. Poly ADP-ribose polymerases’s are activated in response to DNA damage (e.g. DNA strand breaks) and genotoxic stress, and use NAD⁺ to catalyze a reaction in which the ADP ribose moiety is transferred to a substrate protein. The cADP-ribose synthases (e.g. CD38 and CD157) use NAD⁺ to generate cADP-ribose which serves as an intracellular second messenger. The members of poly ADP-ribose polymerases and cADP-ribose synthase family show increased affinity and lower K_m for NAD⁺ compared to sirtuins, indicating that their activation critically impacts intracellular NAD⁺ levels and determines if it reaches a permissive threshold for sirtuin activation ²³. Multiple studies also suggested that PARP activity constitutes the main NAD⁺ catabolic activity, which drives cells to synthesize NAD⁺ from de novo or salvage pathways ²⁴.

The intracellular NAD⁺ levels are typically between 0.2 and 0.5 mM in mammalian cells, and change during a number of physiological processes ²³. Since the nucleus, cytosol and mitochondria are equipped with NAD⁺ salvage enzymes, the compartment-specific NAD⁺ production activates distinct sirtuins to trigger the appropriate physiological response. The NAD⁺/NADH levels also vary with the availability of dietary energy and nutrients. For instance, tissue NAD⁺ levels decrease with energy overload such as high-fat diet ²⁵ and display circadian oscillations with a 24 hour rhythm in the liver, which is regulated by feeding ²⁶. During energetic stress such as exercise, calorie restriction and fasting in mammals, the NAD⁺ levels increase leading to sirtuin activation, which is associated with metabolic and age-related health benefits (Figure 5) ²⁷. Decreased sirtuins (e.g. SIRT1 and SIRT3) expression is associated with various age-related pathologies ²⁸ and their overexpression has been reported to enhance overall mitochondrial and metabolic health in age-related disorders as well as mitochondrial diseases ²⁹.

Figure 4. NAD⁺ biosynthesis

Footnotes: Schematic representation of de novo and salvage pathways for NAD⁺ biosynthesis. In mammals, the de novo biosynthesis starts from l-tryptophan (Trp) which is enzymatically converted in a series of reactions to quinolinic acid (QA). Through quinolinate phosphoribosyltransferase (QPRT) enzyme activity, QA is converted to nicotinic acid mononucleotide (NAMN), which is then converted to nicotinic acid adenine dinucleotide (NAAD) by nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme. The final step in de novo biosynthesis is the amidation of NAAD by NAD synthase (NADS) which generates NAD⁺. The salvage pathway involves NAD⁺ synthesis from its precursors, i.e. Nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR). NA is catalytically converted to NAMN by the action of nicotinic acid phosphoribosyltransferase (NAPT). NAM is converted by nicotinamide phosphoribosyltransferase (NAMPT) to nicotinamide mononucleotide (NMN), which is also the product of phosphorylation of NR by nicotinamide riboside kinase (NRK) enzyme. Finally, NAMN is converted to NAD by the action of NMNAT and NADS enzymes, whereas NMN is converted to NAD by the NMNAT enzyme. Multiple enzymes break-down NAD⁺ to produce NAM and ADP-ribosyl moiety, however only sirtuins are depicted in this figure

[Source ³⁰]

Figure 5. Boosting NAD+ levels is beneficial for health and lifespan

Footnotes: NAD⁺ is a rate-limiting cofactor for the enzymatic activity of sirtuins. Boosting intracellular NAD⁺ levels by physiological (e.g. exercise, calorie restriction, fasting) or pharmacological [e.g. resveratrol, sirtuin activating compounds (STACs)] interventions, and inducing NAD⁺ biosynthesis through supplementation with precursors (e.g. NA, NAM, NR) or inhibition of NAD⁺ consuming enzymes (e.g. PARP-1, CD38) leads to activation of sirtuins (e.g. SIRT1, SIRT3). SIRT1 deacetylates and activates transcriptional regulators (e.g. PGC-1α, FOXO1), whereas SIRT3 deacetylates and activates multiple metabolic gene targets (e.g. succinate dehydrogenase, superoxide dismutase 2), which in turn regulate mitochondrial biogenesis and function. Supplementation with NR or PARP inhibitors extends lifespan in worms by inducing the UPR^mt stress signaling response via Sir-2.1 activation, which then triggers an adaptive mitohormetic response to stimulate mitochondrial function and biogenesis. Improved mitochondrial function associated with mitohormesis or metabolic adaptation can attenuate the impact of mitochondrial diseases, aging as well as age-related metabolic and neurodegenerative disorders. The physiological and pharmacological interventions that boost NAD⁺ levels are highlighted in yellow and pink respectively whereas the pathways that produce and consume/decrease NAD⁺ levels are highlighted in green and red respectively

[Source ³⁰]

What does NADH do?

NAD⁺ and its phosphorylated and reduced forms including NADP⁺, NADH, and NADPH (reduced nicotinamide adenine dinucleotide phosphate) are vital in regulating cellular metabolism and energy production. NAD⁺ functions as an oxidoreductase cofactor in a wide range of metabolic reactions and modulates the activity of compartment-specific pathways such as glycolysis in the cytosol, and tri-carboxylic acid (TCA) cycle, OXPHOS, fatty acid and amino acid oxidation in the mitochondria. For instance, NAD⁺ is converted to NADH at the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step of glycolysis, a pathway that generates pyruvate from glucose ³¹. In the mitochondrial compartment, NAD⁺ is converted to NADH at multiple steps in the tricarboxylic acid cycle (citric acid cycle) in which acetyl-coenzyme A is oxidized to carbon dioxide. Mitochondrial NADH is then oxidized by furnishing reducing equivalents to complex I in the ETC through a series of redox reactions that generate ATP from ADP by OXPHOS. The NAD⁺/NADH ratio thus regulates multiple metabolic pathway enzymes including glyceraldehyde 3-phosphate dehydrogenase (GAPDH), pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase. In contrast to NAD⁺/NADH, the NADPH/NADP⁺ ratios are maintained high in both cytosol and mitochondrial compartments, to maintain a reducing environment ³². NADPH plays a key role in reductive biosynthesis and cellular defense against oxidative damage ³³. For instance, NADPH serves as a cofactor for P450 enzymes that detoxify xenobiotics, acts as a terminal reductant for glutathione reductase which maintains reduced glutathione levels during oxidative defense, and also serves as a substrate for NADPH oxidase that generates peroxides for release during oxidative burst processes in the immune system ³³.

Increased NAD+ levels protects against mitochondrial and age-related disorders

Mitochondrial disorders represent one of the most common forms of heritable metabolic disease in children ³⁴. Reduced NAD⁺/NADH ratio is strongly implicated in mitochondrial disorders and, age-related disorders including diabetes, obesity, neurodegeneration and cancer ³⁵. NAD⁺ levels also decline during aging in multiple models including worms, rodents and human tissue ³⁶. Increasing evidence suggests that boosting NAD⁺ levels could be clinically beneficial, as it activates the NAD⁺/sirtuin pathway which yields beneficial effects on multiple metabolic pathways.

Pharmacological activation of NAD⁺ production has recently been used to treat mouse models of mitochondrial diseases. For instance, treatment of cytochrome c oxidase (COX) deficiency caused by SURF1, SCO2 or COX15 genetic mutations in mice, with AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), partially rescued mitochondrial dysfunction and improved motor performance ³⁷. These findings could be explained by the fact that AMPK stimulates NAD⁺ production, consequently activating SIRT1 which promotes energy production and homeostasis ²⁸. Oral administration of NAD⁺ precursor, NR in mitochondrial myopathy mice harboring a pathogenic mutation in the mtDNA helicase—Twinkle, effectively delayed myopathy progression, by increasing mitochondrial biogenesis, preventing mitochondrial ultrastructural abnormalities, mtDNA deletion formation and activating the mitochondrial unfolded protein (UPR^mt) response ³⁸. In addition, NR supplementation and reduction of NAD⁺ consumption by a specific PARP inhibitor significantly improved mitochondrial respiratory chain defect and exercise intolerance, in a mouse model of COX deficiency caused by SCO2 mutation ²⁹.

Besides improving mitochondrial function, boosting NAD⁺ levels with resveratrol, nicotinamide riboside or nicotinamide mononucleotide (NMN) also corrects metabolic disturbances in mice caused by high fat diet ²⁸. Nicotinamide mononucleotide (NMN) administration ameliorates glucose intolerance and insulin resistance in diet- and age-induced type 2 diabetic mice ³⁹ and rectifies glucose-stimulated insulin secretion and glucose intolerance in NAMPT-deficient animals, by restoring NAD⁺ levels ⁴⁰. Interventions using NAD⁺ precursors or poly ADP-ribose polymerase inhibitors were also shown to be neuroprotective. For instance treatment with nicotinamide mononucleotide (NMN) or nicotinamide riboside precursors, protected against axonal degeneration and hearing loss in mice ⁴¹. Raised NAD⁺ levels after calorie restriction, nicotinamide or nicotinamide riboside treatment attenuated increase in β-amyloid content and oxidative damage, preventing cognitive decline and neurodegeneration in rodent models of Alzheimer’s disease ⁴². PARP-1 (poly ADP-ribose polymerase 1) activation also occurs in neurodegenerative DNA repair disorders including xeroderma pigmentosum group A (XPA) and Cockayne syndrome group B, and treatment with specific PARP inhibitors rescues defective phenotypes in XPA mutant worms and Cockayne syndrome group B mutant mice respectively ⁴³. However, PARP-2 (poly ADP-ribose polymerase 2) deleted mice were glucose intolerant and exhibited pancreatic dysfunction, implying that these results may interfere with other beneficial consequences of PARP inhibition, and hence warrant further investigation on the safe clinical use of these inhibitors ⁴⁴. Because poly ADP-ribose polymerase inhibitors enhance oxidative metabolism and improve metabolic flexibility, these compounds are being tested in phase III trials as anti-cancer agents ⁴⁵.

Increasing NAD⁺ levels by treatment with nicotinic acid and nicotinamide precursors has been shown to inhibit metastasis and breast cancer progression in response to mitochondrial complex I defect in mice ⁴⁶. However, reducing NAD⁺ bioavailability is reported to have an antineoplastic effect in various tumor cell types, as cancer cells rely on increased central carbon metabolism and biomass production to sustain an unrestricted growth ⁴⁷. The exact role of sirtuins in cancer remains controversial with dichotomous functions being reported, for example multiple studies have shown that SIRT1, SIRT3 and SIRT5 can act as tumor promoters or tumor suppressors under different cellular conditions, tumor stage and tissue of origin ⁴⁸. However, SIRT4 is only shown to have a tumor suppressor function ⁴⁹. Further research is needed to understand why and how certain sirtuins have both oncogenic or tumor-suppressive roles, and how this dual action may be best exploited for cancer management.

Declining NAD⁺ levels during aging compromise mitochondrial function in multiple model organisms, which can be restored via NAD⁺ precursor supplementation or poly ADP-ribose polymerase inhibition. For instance, nicotinamide mononucleotide or nicotinamide riboside administration in aged mice or worms respectively, reversed mitochondrial dysfunction by restoring NAD⁺ levels ⁵⁰. Moreover, nicotinamide riboside administration or poly ADP-ribose polymerase inhibition in worms extended lifespan by activating the UPR^mt response via Sir-2.1 (worm SIRT1 ortholog) and mitonuclear protein imbalance, which in turn induced a mitohormetic response to improve mitochondrial function (Figure 5) ⁵¹. Inducing UPR^mt genes such as Hsp60 paralogs in Drosophila also prevented mitochondrial and age-dependent muscle dysfunction, thereby promoting longevity ⁵².

Modulation of NAD+ levels by pharmacological compounds

Besides physiological processes, NAD⁺ levels can be modulated pharmacologically. Resveratrol—a polyphenolic compound found in red wine has been shown to indirectly stimulate NAD⁺ production by activating the energy sensor AMP-activated protein kinase (AMPK) ⁵³. Increased NAD⁺ subsequently stimulates SIRT1 activity, which in turn activates PGC-1α and FOXO family of proteins that govern mitochondrial biogenesis and function (Figure 5) ⁵³. SIRT1 is also amenable to intervention by small molecules such as SIRT1-activating compounds (STACs) that exert beneficial effects on age-related metabolic abnormalities ²⁸. NAD⁺ levels can be directly raised by supplying NAD⁺ biosynthetic precursors/intermediates, or by inhibiting NAD⁺ consuming enzymes with specific inhibitors (Figure 5). For instance, supplementation of nicotinic acid, nicotinamide riboside or nicotinamide mononucleotide compounds increase NAD⁺ levels in both cultured cells and mouse tissues²⁸. Because nicotinamide riboside can be metabolized both in the nucleus and mitochondria, its supplementation raises the nuclear and mitochondrial NAD⁺ levels, thereby activating nuclear SIRT1 and mitochondrial SIRT3 respectively ²⁸. Pharmacological activation of NAD⁺ thus stimulates the activity of multiple sirtuin in a compartment-specific manner to exert its beneficial effects on multiple metabolic pathways which is in contrast to SIRT1 activating compounds’s that specifically stimulate the activity of SIRT1 pathway. Treatment of mice or cultured cells with poly ADP-ribose polymerase and CD38 specific inhibitors has also been shown to induce NAD⁺ levels that activate sirtuins ⁴⁵.

Summary

Based on the current evidence, both NAD⁺ precursors and poly ADP-ribose polymerase inhibitors seem as promising candidates for boosting NAD⁺ levels in cell culture and animal models. However, there are several key questions that remain unanswered ⁵⁴.

1. First, whether different pharmacological, genetic and physiological manipulations that boosts NAD⁺ production lead to enhanced activity of all sirtuin enzymes or whether only a few family members are activated, especially considering the fact that some sirtuins may have opposing actions?
2. Second, how sirtuins located in different subcellular compartments differ in their enzyme kinetics towards NAD⁺ availability?
3. Third, what may be the optimal dosages, routes of administration, efficacy and bioavailability of compound drugs that raise intracellular NAD⁺ levels for human application?

Future studies that are directed towards understanding these would be highly relevant in designing therapeutic strategies aimed at selective activation of specific sirtuins, and would also aid in translating the results for human clinical application. It is possible that some of the NAD⁺ boosting drugs show adverse side effects in humans which could preclude their use and/or may be acceptable for only those inherited conditions that are highly devastating. It is also important to determine if nicotinamide riboside could be valid substitute to avoid undesirable side effects of other NAD⁺ precursors such as nicotinic acid and nicotinamide, for instance when used as lipid lowering drugs ⁵⁵.

In addition, future studies are required to examine the UPR^mt pathway in vivo in mammalian models to identify key signaling molecules involved in mitochondrial protective mechanisms, which will further advance our understanding of the diseases associated with mitochondrial dysfunction, and will allow discovery of new targets to modulate this pathway. Finally, it remains to be determined whether or not boosting NAD⁺ levels could extend lifespan in higher organisms. Although much remains to be done, based on the steadily growing evidence, the pharmacological modulation of NAD⁺ levels via NAD⁺ precursors and poly ADP-ribose polymerase inhibitors appears to be an attractive and valid strategy to enhance oxidative metabolism and mitochondrial biogenesis, and holds a significant therapeutic potential in the clinical management of mitochondrial and age-related disorders.

References

1. NAD. https://www.ncbi.nlm.nih.gov/mesh/68009243
2. Kanamori KS, de Oliveira GC, Auxiliadora-Martins M, Schoon RA, Reid JM, Chini EN. Two Different Methods of Quantification of Oxidized Nicotinamide Adenine Dinucleotide (NAD+) and Reduced Nicotinamide Adenine Dinucleotide (NADH) Intracellular Levels: Enzymatic Coupled Cycling Assay and Ultra-performance Liquid Chromatography (UPLC)-Mass Spectrometry. Bio-protocol. 2018;8(14):e2937. doi:10.21769/BioProtoc.2937. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086385/
3. NAD⁺ in aging, metabolism, and neurodegeneration. Verdin E. Science. 2015 Dec 4; 350(6265):1208-13. http://science.sciencemag.org/content/350/6265/1208.long
4. NAD+ and NADH Concentrations in younger and older human adults. FASEB Journal Vol. 20, No. 5, March 2006 https://www.fasebj.org/doi/10.1096/fasebj.20.5.A1357
5. Srivastava S. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clinical and Translational Medicine. 2016;5:25. doi:10.1186/s40169-016-0104-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963347
6. Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011;334:806–809. doi: 10.1126/science.1207861
7. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006;126:941–954. doi: 10.1016/j.cell.2006.06.057
8. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253–295. doi: 10.1146/annurev.pathol.4.110807.092250
9. Anderson KA, Green MF, Huynh FK, Wagner GR, Hirschey MD. SnapShot: mammalian sirtuins. Cell. 2014;159(956–956):e951
10. Canto C, Auwerx J. NAD+ as a signaling molecule modulating metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:291–298. doi: 10.1101/sqb.2012.76.010439
11. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS ONE. 2011;6:e19194. doi: 10.1371/journal.pone.0019194
12. Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism. Cell metabolism. 2016;23(6):1127-1139. doi:10.1016/j.cmet.2016.05.006. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911708/
13. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Yoshino J, Mills KF, Yoon MJ, Imai S. Cell Metab. 2011 Oct 5; 14(4):528-36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204926/
14. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN. Cell Metab. 2016 Jun 14; 23(6):1127-1139. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911708/
15. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S. Physiol Rev. 2008 Jul; 88(3):841-86.
16. Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell metabolism. 2011;14(4):528-536. doi:10.1016/j.cmet.2011.08.014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204926/
17. Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors. Haffner CD, Becherer JD, Boros EE, Cadilla R, Carpenter T, Cowan D, Deaton DN, Guo Y, Harrington W, Henke BR, Jeune MR, Kaldor I, Milliken N, Petrov KG, Preugschat F, Schulte C, Shearer BG, Shearer T, Smalley TL Jr, Stewart EL, Stuart JD, Ulrich JC. J Med Chem. 2015 Apr 23; 58(8):3548-71.
18. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Blacher E, Dadali T, Bespalko A, Haupenthal VJ, Grimm MO, Hartmann T, Lund FE, Stein R, Levy A. Ann Neurol. 2015 Jul; 78(1):88-103. https://www.ncbi.nlm.nih.gov/pubmed/25893674/
19. Canto C, Menzies KJ, Auwerx J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 2015;22:31–53. doi: 10.1016/j.cmet.2015.05.023
20. Berger F, Lau C, Dahlmann M, Ziegler M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem. 2005;280:36334–36341. doi: 10.1074/jbc.M508660200
21. Hegyi J, Schwartz RA, Hegyi V. Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol. 2004;43:1–5. doi: 10.1111/j.1365-4632.2004.01959.x
22. Chini EN. CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr Pharm Des. 2009;15:57–63. doi: 10.2174/138161209787185788.
23. Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev. 2010;31:194–223. doi: 10.1210/er.2009-0026
24. Berger NA. Poly(ADP-ribose) in the cellular response to DNA damage. Radiat Res. 1985;101:4–15. doi: 10.2307/3576299
25. Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15:838–847. doi: 10.1016/j.cmet.2012.04.022
26. Asher G, Reinke H, Altmeyer M, Gutierrez-Arcelus M, Hottiger MO, Schibler U. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell. 2010;142:943–953. doi: 10.1016/j.cell.2010.08.016
27. Canto C, Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab. 2009;20:325–331. doi: 10.1016/j.tem.2009.03.008
28. Canto C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev. 2012;64:166–187. doi: 10.1124/pr.110.003905
29. Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W, Leoni V, Schon EA, Dantzer F, Auwerx J, et al. NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab. 2014;19:1042–1049. doi: 10.1016/j.cmet.2014.04.001
30. Srivastava S. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clinical and Translational Medicine. 2016;5:25. doi:10.1186/s40169-016-0104-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963347/
31. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5. New York: W.H. Freeman; 2002.
32. Tischler ME, Friedrichs D, Coll K, Williamson JR. Pyridine nucleotide distributions and enzyme mass action ratios in hepatocytes from fed and starved rats. Arch Biochem Biophys. 1977;184:222–236. doi: 10.1016/0003-9861(77)90346-0
33. Pollak N, Dolle C, Ziegler M. The power to reduce: pyridine nucleotides—small molecules with a multitude of functions. Biochem J. 2007;402:205–218. doi: 10.1042/BJ20061638
34. Morava E, van den Heuvel L, Hol F, de Vries MC, Hogeveen M, Rodenburg RJ, Smeitink JA. Mitochondrial disease criteria: diagnostic applications in children. Neurology. 2006;67:1823–1826. doi: 10.1212/01.wnl.0000244435.27645.54
35. Mouchiroud L, Houtkooper RH, Auwerx J. NAD(+) metabolism: a therapeutic target for age-related metabolic disease. Crit Rev Biochem Mol Biol. 2013;48:397–408. doi: 10.3109/10409238.2013.789479
36. Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Canto C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, et al. The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 2013;154:430–441. doi: 10.1016/j.cell.2013.06.016
37. Viscomi C, Bottani E, Civiletto G, Cerutti R, Moggio M, Fagiolari G, Schon EA, Lamperti C, Zeviani M. In vivo correction of COX deficiency by activation of the AMPK/PGC-1alpha axis. Cell Metab. 2011;14:80–90. doi: 10.1016/j.cmet.2011.04.011
38. Khan NA, Auranen M, Paetau I, Pirinen E, Euro L, Forsstrom S, Pasila L, Velagapudi V, Carroll CJ, Auwerx J, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med. 2014;6:721–731
39. Ramsey KM, Mills KF, Satoh A, Imai S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell. 2008;7:78–88. doi: 10.1111/j.1474-9726.2007.00355.x
40. Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, et al. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007;6:363–375. doi: 10.1016/j.cmet.2007.09.003
41. Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci. 2006;26:8484–8491. doi: 10.1523/JNEUROSCI.2320-06.2006.
42. Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A. Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1-42)-induced rat model of Alzheimer’s disease. Free Radic Res. 2014;48:146–158. doi: 10.3109/10715762.2013.857018
43. Scheibye-Knudsen M, Fang EF, Croteau DL, Bohr VA. Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders. Autophagy. 2014;10:1468–1469. doi: 10.4161/auto.29321
44. Bai P, Canto C, Brunyanszki A, Huber A, Szanto M, Cen Y, Yamamoto H, Houten SM, Kiss B, Oudart H, et al. PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab. 2011;13:450–460. doi: 10.1016/j.cmet.2011.03.013
45. Bai P, Canto C, Oudart H, Brunyanszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011;13:461–468. doi: 10.1016/j.cmet.2011.03.004
46. Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, Yagi T, Felding-Habermann B. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 2013;123:1068–1081. doi: 10.1172/JCI64264
47. Chiarugi A, Dolle C, Felici R, Ziegler M. The NAD metabolome—a key determinant of cancer cell biology. Nat Rev Cancer. 2012;12:741–752. doi: 10.1038/nrc3340
48. Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30:2986–2996. doi: 10.1038/onc.2011.37
49. Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell. 2013;23:450–463. doi: 10.1016/j.ccr.2013.02.024
50. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155:1624–1638. doi: 10.1016/j.cell.2013.11.037
51. Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013;497:451–457. doi: 10.1038/nature12188
52. Owusu-Ansah E, Song W, Perrimon N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell. 2013;155:699–712. doi: 10.1016/j.cell.2013.09.021
53. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458:1056–1060. doi: 10.1038/nature07813
54. Srivastava S. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clinical and Translational Medicine. 2016;5:25. doi:10.1186/s40169-016-0104-7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963347/
55. Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD⁺ precursor vitamins in human nutrition. Annu Rev Nutr. 2008;28:115–130. doi: 10.1146/annurev.nutr.28.061807.155443

What is lithium orotate

Lithium orotate is a salt of orotic acid and lithium. Lithium orotate is widely available over the internet and marketed as a dietary supplement for conditions such as bipolar disorder, alcoholism, and aggression, although it is NOT U.S. Food and Drug Administration (FDA) approved for the treatment of any medical condition. Lithium orotate is available in some drug stores and health food stores under various brand names. Lithium orotate are advertised without regulation, and they are purchased and used without medical supervision or monitoring. The widespread availability of herbal and “dietary supplement” products from internet sources has increased the potential for poisonings. Patients who obtain Lithium orotate are subject to toxicity, drug-drug interactions, and other adverse effects.

• Proper medical diagnosis and a clear description of all possible treatment options should always be the first plan of action when treating mental disorders.

While lithium orotate is capable of providing lithium to the body, like lithium carbonate and other lithium salts, there are no systematic clinical study reviews supporting the efficacy of lithium orotate and it is only barely researched between 1973–1986 to treat certain medical conditions, such as alcoholism ¹.

Animal models suggest that lithium orotate has similar pharmacokinetics, but the lithium orotate may achieve higher tissue concentrations at the same dosages than commonly prescribed for lithium carbonate and lithium citrate formulations ². This may be secondary to lower renal clearance of the lithium orotate salt ³.

In 1973, Nieper ⁴ reported that lithium orotate contained 3.83 mg of elemental lithium per 100 mg and lithium carbonate contained 18.8 mg of elemental lithium per 100 mg. Nieper went on to claim that lithium did not dissolve from the orotate carrier until it passed through the blood–brain barrier ⁴; however, a 1976 study documented that lithium concentrations within the brains of rats were not statistically different between equivalent dosages of lithium from lithium orotate, lithium carbonate, or lithium chloride ⁵. While this study was conducted with rats, it directly contradicts the aforementioned assumptions made by Nieper and others ⁵. The pharmacokinetics of lithium orotate in human brains is poorly documented and further inquiry is needed to affirm that lithium concentrations in the brain are higher with lithium orotate. Major medical research has not been conducted on lithium orotate since the 1980s due to its patent status and the abundant availability of lithium carbonate. As previously stated, lithium intake appears to be effective even at low doses, and this may account for lithium orotates claimed effectiveness ⁶.

Do not use lithium without telling your doctor if you are pregnant. It could cause harm to the unborn baby. Use an effective form of birth control, and tell your doctor if you become pregnant during treatment. Early voluntary reports to international birth registries suggested an increase in cardiovascular malformations, especially for Ebstein’s anomaly, with first trimester use of Lithium. Subsequent case-control and cohort studies indicate that the increased risk for cardiac malformations is likely to be small; however, the data are insufficient to establish a drug-associated risk. There are concerns for maternal and/or neonatal Lithium toxicity during late pregnancy and the postpartum period. Published animal developmental and toxicity studies in mice and rats report an increased incidence of fetal mortality, decreased fetal weight, increased fetal skeletal abnormalities, and cleft palate (mouse fetuses only) with oral doses of Lithium that produced serum concentrations similar to the human therapeutic range. Other published animal studies report adverse effects on embryonic implantation in rats after Lithium administration. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

You should not breast-feed while using this medicine. Limited published data reports the presence of Lithium carbonate in human milk with breast milk levels measured at 0.12 to 0.7 mEq or 40 to 45% of maternal plasma levels. Infants exposed to Lithium during breastfeeding may have plasma levels that are 30 to 40% of maternal plasma levels. Signs and symptoms of Lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some breastfed neonates and infants. Increased prolactin levels have been measured in lactating women, but the effects on milk production are not known. Breastfeeding is not recommended with maternal Lithium use; however, if a woman chooses to breastfeed, the infant should be closely monitored for signs of Lithium toxicity. Discontinue breastfeeding if a breastfed infant develops Lithium toxicity. Consider regular monitoring of Lithium levels and thyroid function in a breastfed infant.

Is lithium orotate safe?

Lithium orotate’s safety remains in question. There have been numerous case reports of patients requiring medical attention after taking lithium orotate supplements ⁷, ⁸, ⁹.

Orotic acid can be mutagenic in mammalian somatic cells. It is also mutagenic for bacteria and yeast ¹⁰.

An 18-year-old woman presented to our emergency department after ingesting 18 tablets of Find Serenity Now®; each tablet contained, according to the listing, 120 mg of lithium orotate [3.83 mg of elemental lithium per 100 mg of (organic) lithium orotate compared to 18.8 mg of elemental lithium per 100 mg of (inorganic) lithium carbonate] ⁷. The patient complained of nausea and reported one episode of emesis (vomiting). Her examination revealed normal vital signs. The only finding was a mild tremor without rigidity. Almost 90 minutes after the ingestion, her serum lithium level was 0.31 mEq/L, a urine drug screen was negative, and an electrocardiogram (ECG) showed a normal sinus rhythm. The patient received intravenous fluids and an anti-emetic; one hour later, her repeat serum lithium level was 0.40 mEq/L. After 3 hours of observation, nausea and tremor were resolved, and she was subsequently transferred to a psychiatric hospital for further care.

Lithium’s widespread use and its narrow therapeutic index can lead to adverse effects in up to 90% of all users ¹¹. Most toxicity is mild and includes lethargy, vomiting, ataxia, and myoclonus, but massive, acute ingestions or severe chronic toxicity can lead to coma or seizures ⁷. Other adverse effects include thyroid and parathyroid abnormalities, serotonergic crisis, cardiovascular abnormalities, and nephrogenic diabetes insipidus ¹².

Onset and severity of symptoms vary upon the timing of ingestion and product formulation. The risk of toxicity increases with increased age, renal insufficiency, hyponatremia, volume depletion, drug-drug interactions, and comorbidities or co-ingestions ¹³. Significant toxicity tends to occur when levels are well above the upper therapeutic level (1.5 mEq/L); however, lithium’s variable absorption and delayed tissue concentrations make interpretation of serum levels difficult. Toxicity may also occur at lower levels, especially in the setting of chronic use ¹⁴.

Lithium orotate vs Lithium carbonate

Lithium Carbonate is a white, light, alkaline powder with molecular formula Li2CO3 and molecular weight 73.89. Lithium Carbonate is the carbonate salt of lithium, a soft alkali metal, with antimanic and hematopoietic activities. Lithium interferes with transmembrane sodium exchange in nerve cells by affecting sodium, potassium-stimulated adenosine triphosphatase (Na+, K+-ATPase); alters the release of neurotransmitters; affects cyclic adenosine monophosphate (cAMP) concentrations; and blocks inositol metabolism resulting in depletion of cellular inositol and inhibition of phospholipase C-mediated signal transduction. While lithium has no psychotropic effects in normal individuals, it has potent mood stabilizing properties in patients with bipolar disorders, mania and recurrent depression. The mechanism of action of lithium is unknown, but is thought to be mediated by its replacement of sodium ions and disruption of membrane potentials in the central nervous system. It may also act by differential effects on neurotransmitter induced depolarization of membranes or interference with phosphatidylinositol pathways. In addition, lithium stimulates granulocytopoiesis and appears to increase the level of pluripotent hematopoietic stem cells by stimulating the release of hematopoietic cytokines and/or directly acting on hematopoietic stem cells.

Lithium was approved for use in bipolar illness for the treatment of mania for more than 50 years in the United States since 1970 and it is still widely used for this indication. Manic symptoms include hyperactivity, rushed speech, poor judgment, reduced need for sleep, aggression, and anger. Lithium also helps to prevent or lessen the intensity of manic episodes. Lithium has also been used in therapy of schizophrenia, alcohol dependence, attention deficit disorder and migraine headaches. Lithium is available as capsules or tablets of 150, 300, 450 and 600 mg in generic forms as well in several brand names including Carbolith, Duralith and Eskalith. A typical maintenance dose regimen is 600 to 900 mg daily. Lithium levels are generally monitored because of the narrow therapeutic window between toxicity and effectiveness aiming for levels between 0.6 and 1.2 mEq/L in chronic situations (higher in acute). Common side effects include metallic taste, nausea, tremor, polyuria, polydipsia and weight gain. Uncommon side effects include hypothyroidism.

Concurrent administration of lithium carbonate and potassium iodide or other iodine-containing compounds may enhance hypothyroid and goitrogenic effects of either drug ¹⁵.

Lithium can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Call your doctor at once if you have any early signs of lithium toxicity, such as nausea, vomiting, diarrhea, drowsiness, muscle weakness, tremor, lack of coordination, blurred vision, or ringing in your ears.

Lithium is not approved for use by anyone younger than 12 years old.

Liver test abnormalities have been reported to occur in a small proportion of patients on long term therapy with lithium. These abnormalities are usually asymptomatic and transient, reversing even with continuation of medication. Instances of more marked elevations in serum aminotransferases have been reported in patients taking overdoses of lithium, but the other metabolic and systemic effects of lithium overdose generally overshadow hepatic adverse effects. Lithium has not been associated with instances of clinically apparent acute liver injury with jaundice.

Before taking lithium

You should not use lithium if you are allergic to it.

Lithium may be used to treat manic episodes associated with bipolar disorder; however, there is a fine line between too much and too little and ongoing monitoring is needed to prevent lithium toxicity.

Obtain serum Lithium concentration assay after 4 days, drawn 12 hours after the last oral dose. Adjust daily dosage based on serum Lithium concentration and clinical response. Fine hand tremor, polyuria and mild thirst may occur during initial therapy for the acute manic phase, and may persist throughout treatment. Transient and mild nausea and general discomfort may also appear during the first few days of Lithium administration. These adverse reactions may subside with continued treatment, concomitant administration with food, temporary reduction or cessation of dosage.

• Lithium is usually taken two to three times daily with food.
• There is a fine line between too much and too little lithium. Always take lithium exactly as directed and go to your scheduled appointments. Never take any herbal supplements or over the counter remedies without consulting your doctor or pharmacist first as many drugs may affect blood levels of lithium.
• If you miss a dose of lithium, take it as soon as you remember. If it is close to your next dose, do not double up on the dose.
• Do not crush or chew extended-release tablets; swallow whole.
• Too much caffeine may decrease the amount of lithium in your body.
• Lithium may affect your mental alertness or make you drowsy. Do not drive until you know how lithium will affect you. Avoid alcohol.
• Ensure you keep adequately hydrated while taking lithium and maintain an adequate salt intake (your doctor will discuss this requirement). The risk of side effects of lithium is increased if you are dehydrated, or if you are excessively hydrated. Excessive sweating or diarrhea may also upset the balance of lithium in the blood.
• Contact your doctor if you become ill or have an infection as your dosage of lithium may need to be altered or temporarily discontinued.
• Seek urgent medical attention if symptoms similar to diabetes (such as excessive thirst or excessive urine production), or serotonin syndrome ( occur.
• Stop lithium and contact your doctor urgently if symptoms of lithium toxicity such as diarrhea, vomiting, tremor, drowsiness, muscle weakness or confusion occur.
• Seek urgent medical advice if symptoms consistent with serotonin syndrome (such as agitation, hallucinations, fast heart rate, dizziness, flushing, nausea, diarrhea) develop.
• You will need to go for regular blood tests while you are taking lithium to ensure that the dosage is appropriate for you.
• May affect your mental and physical abilities so be careful driving or operating machinery until you know how lithium affects you.
• Do not take any other medications, including those bought over the counter, without first checking with your doctor or pharmacist that they are compatible with lithium.

Tell your doctor if you have ever had:

• an abnormal electrocardiograph or ECG (sometimes called an EKG);
• fainting spells;
• a family history of death before age 45;
• kidney disease;
• heart disease;
• a debilitating illness;
• a thyroid disorder;
• low levels of sodium in your blood; or
• if you are dehydrated.

Some medicines can interact with lithium and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take stimulant medicine, opioid medicine, herbal products, or medicine for depression, mental illness, Parkinson’s disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

Other drugs that will affect lithium

Tell your doctor about all your current medicines. Many drugs can interact with lithium, especially:

• a diuretic or “water pill”;
• fluoxetine (Prozac);
• metronidazole;
• potassium iodide thyroid medication;
• heart or blood pressure medication;
• seizure medicine; or
• nonsteroidal anti-inflammatory drugs – aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete and many other drugs may interact with lithium. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

How long does it take for lithium to work?

A reduction in manic symptoms should be noticed within one to three weeks. Your doctor will determine if your symptoms have improved enough to warrant lithium long-term.

Lithium is completely absorbed in the gastrointestinal tract with peak levels occurring 0.25 to 3 hours after oral administration of immediate-release preparations and two to six hours after sustained-release preparations.

Lithium dosing information

Adult Dose of Lithium for Mania

Comments:

• Dosing must be individualized according to serum levels and the response to treatment.
• Obtain serum Lithium concentrations regularly until the serum concentration and clinical condition of the patient has stabilized. Adjust daily dosage based on serum Lithium concentration and clinical response.
• Alternative extended release formulation doses are 600 mg 3 times a day (acute control) and 300 mg 3 to 4 times a day (long-term control).

Uses:

• Treatment of manic episodes of bipolar disorder
• Maintenance treatment for individuals with bipolar disorder

Acute Control:

• Titrate to serum Lithium concentrations between 0.8 and 1.2 mEq/L.
• Usual dose: 1800 mg/day
• Extended release formulations: 900 mg orally in the morning and at nighttime
• Regular release formulations: 600 mg orally 3 times a day, in the morning, afternoon, and nighttime

Long-term Control:

• Titrate to serum Lithium concentrations between 0.8 and 1 mEq/L
• Maintenance dose: 900 to 1200 mg/day
• Extended release formulations: 600 mg orally in the morning and at nighttime
• Regular release formulations: 300 mg orally 3 to 4 times a day

Adult Dose of Lithium for Bipolar Disorder

Comments:

• Dosing must be individualized according to serum levels and the response to treatment.
• Alternative extended release formulation doses are 600 mg 3 times a day (acute control) and 300 mg 3 to 4 times a day (long-term control).

Uses:

• Treatment of manic episodes of bipolar disorder
• Maintenance treatment for individuals with bipolar disorder

Acute Control:

• Usual dose: 1800 mg/day
• Extended release formulations: 900 mg orally in the morning and at nighttime
• Regular release formulations: 600 mg orally 3 times a day, in the morning, afternoon, and nighttime

Long-term Control:

• Maintenance dose: 900 to 1200 mg/day
• Extended release formulations: 600 mg orally in the morning and at nighttime
• Regular release formulations: 300 mg orally 3 to 4 times a day

Pediatric 12 years and older dose of Lithium for Mania

Comments:

• Dosing must be individualized according to serum levels and the response to treatment.
• Alternative extended release formulation doses are 600 mg 3 times a day (acute control) and 300 mg 3 to 4 times a day (long-term control).
• Maintenance therapy reduces the frequency of manic episodes and diminishes the intensity of the episodes.

Uses:

• Treatment of manic episodes of bipolar disorder
• Maintenance treatment for individuals with bipolar disorder

12 years and older acute control:

Usual dose: 1800 mg/day

• Extended release formulations: 900 mg orally in the morning and at nighttime
• Regular release formulations: 600 mg orally 3 times a day, in the morning, afternoon, and nighttime

Long-term Control:

• Maintenance dose: 900 to 1200 mg/day
• Extended release formulations: 600 mg orally in the morning and at nighttime
• Regular release formulations: 300 mg orally 3 to 4 times a day

Pediatric 12 years and older dose of Lithium for Bipolar Disorder

Comments:

• Dosing must be individualized according to serum levels and the response to treatment.
• Alternative extended release formulation doses are 600 mg 3 times a day (acute control) and 300 mg 3 to 4 times a day (long-term control).
• Maintenance therapy reduces the frequency of manic episodes and diminishes the intensity of the episodes.

Uses:

• Treatment of manic episodes of bipolar disorder
• Maintenance treatment for individuals with bipolar disorder

12 years and older acute control:

• Usual dose: 1800 mg/day
• Extended release formulations: 900 mg orally in the morning and at nighttime
• Regular release formulations: 600 mg orally 3 times a day, in the morning, afternoon, and nighttime

Long-term Control:

• Maintenance dose: 900 to 1200 mg/day
• Extended release formulations: 600 mg orally in the morning and at nighttime
• Regular release formulations: 300 mg orally 3 to 4 times a day

Lithium side effects

Get emergency medical help if you have signs of an allergic reaction to lithium: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Fine hand tremor, frequent urination, and mild thirst commonly occur during lithium initiation. Sometimes these effects may persist throughout treatment.
• Nausea during initiation is common but usually subsides with continued administration.
• Diarrhea, vomiting, drowsiness, muscular weakness, loss of appetite and coordination difficulties may be an early sign of lithium toxicity. Dizziness, blurred vision, ringing in the ears and excessive production of dilute urine may occur with higher (toxic) lithium levels. Seek urgent medical advice.
• Lithium may also cause irregular heartbeat, drying and thinning of hair, alopecia, dry mouth, weight gain, itchiness, and other side effects. Long-term use may lead to hypothyroidism or other thyroid problems.
• Dosing may be difficult because there is not much of a margin between an adequate dose of lithium and a toxic dose.
• Monitoring is required, particularly during therapy initiation but also long-term.
• Not suitable for people with significant renal or cardiovascular disease, in those who are frail, dehydrated, taking diuretics or with low levels of sodium. Not recommended for children aged less than 12.
• Full effects of lithium in pregnancy have not been fully determined so advice is to avoid lithium, particularly in the first trimester.
• May interact with several other medications including diuretics (water pills), NSAIDs and ACE inhibitors.
• Interaction or overdosage may cause serotonin syndrome (symptoms include mental status changes [such as agitation, hallucinations, coma, delirium]), fast heart rate, dizziness, flushing, muscle tremor or rigidity and stomach symptoms (including nausea, vomiting, and diarrhea).

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;
• irregular heartbeats, shortness of breath;
• fever, increased thirst or urination;
• weakness, dizziness or spinning sensation;
• confusion, memory problems, hallucinations;
• uncontrolled muscle movements, slurred speech;
• loss of bowel or bladder control;
• a seizure (blackout or convulsions);
• dehydration symptoms – feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin; or
• increased pressure inside the skull – severe headaches, ringing in your ears, dizziness, nausea, vision problems, pain behind your eyes.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Common lithium side effects may include:

• drowsiness;
• tremors in your hands;
• dry mouth, increased thirst or urination;
• nausea, vomiting, loss of appetite, stomach pain;
• changes in your skin or hair;
• cold feeling or discoloration in your fingers or toes;
• feeling uneasy; or
• impotence, loss of interest in sex.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Nervous system

Frequency not reported: Abnormal reflex convulsions, acute dystonia, ataxia, benign intracranial hypertension, blackout spells, choreoathetotic movements, cerebellar syndrome, clonic movements of whole limbs, coarse tremor of the extremities and lower jaw, cogwheel rigidity, coma, convulsions, diffuse slowing of EEG, dizziness, downbeat nystagmus, drowsiness, dysarthria, dysgeusia/taste distortion, encephalopathy, encephalopathic syndrome, epileptiform seizures, extrapyramidal syndrome, fine hand tremor, giddiness, headache, hyperactive deep tendon reflexes, hypertonicity, impaired consciousness, lack of coordination, lethargy, metallic/salty taste, myoclonus, nystagmus, peripheral sensorimotor neuropathy, poor memory, potentiation and disorganization of EEG background rhythm, pseudotumor cerebri (increased intracranial pressure and papilledema), psychomotor retardation, seizures, serotonin syndrome, slowed intellectual functioning, slurred speech/speech disorder, somnolence, startle response, stupor, tendency to sleep, tongue movements, transient electroencephalogram (EEG), tremor, vertigo, widening of EEG frequency spectrum

• Drowsiness and lack of coordination may be early signs of lithium toxicity, and may occur at lithium levels below 2 mEq/L.
• Ataxia and giddiness occurred at levels above 2 mEq/L.
• Fine hand tremor may occur during initial therapy for the acute manic phase, and may persist during therapy.
• The development of transient EEG changes, headache, dysgeusia/taste distortion, and metallic taste were unrelated to dosage.
• Peripheral neuropathy may occur in patients on long-term treatment, but is usually reversible after discontinuation of therapy.

Cardiovascular

The development of transient ECG changes, chest tightness, and edematous swelling of ankles/wrists were unrelated to dosage.

Painful discoloration of the fingers/toes and coldness of extremities (resembling Raynaud’s syndrome) occurred within one day of initiation; the patient recovered after discontinuation. The exact mechanism for this side effect is unknown.

Frequency not reported: Atrioventricular block, bradycardia, cardiac arrhythmia, cardiomyopathy, chest tightness, conduction disturbance, ECG changes, edema, hypotension, inversion of T-waves, isoelectricity of ECG, peripheral circulatory collapse, peripheral edema/edematous swelling of ankles or wrists, peripheral vasculopathy, QT prolongation, Raynaud’s phenomena/syndrome, reversible flattening of ECG, sinus node dysfunction with severe bradycardia and/or sinoatrial block (may result in syncope), transient ECG changes, unmasking of Brugada syndrome, ventricular tachyarrhythmia

Gastrointestinal

Frequency not reported: Abdominal pain/discomfort, constipation, dental caries, diarrhea, dry mouth, excessive salivation, flatulence, gastritis, incontinence of feces, indigestion, nausea/transient and mild nausea, salivary gland swelling, swollen lips, vomiting

• Diarrhea and vomiting may be early signs of lithium toxicity, and may occur at lithium levels below 2 mEq/L.
• Transient and mild nausea may occur within the first few days of therapy.
• The development of metallic/salty taste, dental caries, and swollen lips were unrelated to dosage.

Dermatologic

Frequency not reported: Acne/acneform eruptions, alopecia, anesthesia of skin, chronic folliculitis/folliculitis, cutaneous ulcers, drying and thinning of hair, generalized pruritus with/without rash, papular skin disorders, pruritus, psoriasis onset/exacerbation, urticaria, xerosis cutis

The development of generalized pruritus with/without rash and cutaneous ulcers were unrelated to dosage.

Endocrine

Frequency not reported: Diffuse nontoxic goiter with/without hypothyroidism, euthyroid goiter, hyperparathyroidism, hyperthyroidism, hypothyroidism (including myxedema), iodine 131 uptake increased, lower T3 and T4 levels, thyrotoxicosis

Hyperthyroidism has been rarely reported, and may persist after discontinuation of treatment.

Hyperparathyroidism may persist after discontinuation of treatment.

The development of diffuse nontoxic goiter with/without hypothyroidism and hyperparathyroidism were unrelated to dosage.

Musculoskeletal

Muscular weakness develops early in lithium toxicity, and may occur at lithium levels below 2 mEq/L.

Muscle hyperirritability includes fasciculations, twitching, clonic movements of whole limbs.

The development of swollen/painful joints and polyarthralgia were unrelated to dosage.

Frequency not reported: Arthralgia/polyarthralgia, muscle hyperirritability, muscular weakness, myalgia, myasthenia gravis, myoclony, rhabdomyolysis, swollen/painful joints, twitching

Renal

Frequency not reported: Decreased creatinine clearance, glycosuria, histological renal changes with interstitial fibrosis, lithium-induced chronic kidney disease, microcysts, nephrogenic diabetes insipidus, nephrotic syndrome, oliguria, renal dysfunction

Diabetes insipidus may persist after discontinuation of treatment.

Histological renal changes with interstitial fibrosis occurred in patients on prolonged treatment, and was usually reversible upon discontinuation. Long-term treatment may cause permanent kidney changes and impairment of renal function; high serum concentrations and/or acute lithium toxicity may worsen these changes.

Metabolic

Frequency not reported: Anorexia, dehydration, excessive weight gain, hypercalcemia, hypermagnesemia, hyponatremia, polydipsia, thirst/mild thirst, transient hyperglycemia/hyperglycemia, weight loss

The development of transient hyperglycemia, hypercalcemia, and excessive weight gain were unrelated to dosage.

Other side effects

Tinnitus occurred at levels above 2 mEq/L.

Mild thirst may occur during initial therapy for the acute manic phase, and may persist during therapy; in some cases, thirst resembled diabetes insipidus. The development of thirst was unrelated to dosage.

General discomfort may also appear within the first few days of therapy.

The development of fever was unrelated to dosage.

Frequency not reported: Fall, fasciculations, fatigue, feeling dazed, fever, general discomfort, lithium toxicity, tinnitus

Genitourinary

Frequency not reported: Albuminuria, impotence/sexual dysfunction, incontinence of urine, large output of dilute urine, lithium-induced polyuria/polyuria

At levels above 2 mEq/L, patients excreted a large output of dilute urine.

Polyuria may occur during initial therapy for the acute manic phase, and may persist during therapy; in some cases, polyuria resembled diabetes insipidus. The development of polyuria was unrelated to dosage.

The development of albuminuria was unrelated to dosage.

Psychiatric

Frequency not reported: Confusion, delirium, hallucinations, restlessness, tics, worsening of organic brain syndromes

The worsening of organic brain syndromes was unrelated to dosage.

Hypersensitivity

Frequency not reported: Allergic rashes, angioedema

Ocular

Frequency not reported: Blindness, blurred vision, enlargement of the blind spot, exophthalmos, optic atrophy, transient scotomata/scotoma, visual field constriction

Blurred vision occurred at levels above 2 mEq/L.

Oncologic

Frequency not reported: Collecting duct renal carcinoma, oncocytoma

Collecting duct renal carcinoma occurred in patients on long-term therapy.

Hematologic

Frequency not reported: Leukocytosis

The development of leukocytosis was unrelated to dosage.

Lithium-Induced Polyuria

Chronic Lithium treatment may be associated with diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. The concentrating defect and natriuretic effect characteristic of this condition may develop within weeks of Lithium initiation. Lithium can also cause renal tubular acidosis, resulting in hyperchloremic metabolic acidosis. Such patients should be carefully managed to avoid dehydration with resulting Lithium retention and toxicity. This condition is usually reversible when Lithium is discontinued, although for patients treated with long-term Lithium, nephrogenic diabetes insipidus may be only partly reversible upon discontinuation of Lithium. Amiloride may be considered as a therapeutic agent for Lithium-induced nephrogenic diabetes insipidus.

Hyponatremia

Lithium can cause hyponatremia by decreasing sodium reabsorption by the renal tubules, leading to sodium depletion. Therefore, it is essential for patients receiving Lithium treatment to maintain a normal diet, including salt, and an adequate fluid intake (2500 to 3000 mL) at least during the initial stabilization period. Decreased tolerance to Lithium has also been reported to ensue from protracted sweating or diarrhea and, if such occur, supplemental fluid and salt should be administered under careful medical supervision and Lithium intake reduced or suspended until the condition is resolved. In addition, concomitant infection with elevated temperatures may also necessitate a temporary reduction or cessation of medication.

Symptoms are also more severe with faster-onset hyponatremia. Mild hyponatremia (i.e., serum Na > 120 mEq/L) can be asymptomatic. Below this threshold, clinical signs are usually present, consisting mainly of changes in mental status, such as altered personality, lethargy, and confusion. For more severe hyponatremia (serum Na < 115 mEq/L), stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and death can result. During treatment of hyponatremia, serum sodium should not be elevated by more than 10 to 12 meq/L in 24 hours, or 18 meq/L in 48 hours. In the case of severe hyponatremia where severe neurologic symptoms are present, a faster infusion rate to correct serum sodium concentration may be needed. Patients rapidly treated or with serum sodium <120mEq/L are more at risk of developing osmotic demyelination syndrome (previously called central pontine myelinolysis). Occurrence is more common among patients with alcoholism, undernutrition, or other chronic debilitating illness. Common signs include flaccid paralysis, dysarthria. In severe cases with extended lesions patients may develop a locked-in syndrome (generalized motor paralysis). Damage often is permanent. If neurologic symptoms start to develop during treatment of hyponatremia, serum sodium correction should be suspended to mitigate the development of permanent neurologic damage.

Lithium-Induced Chronic Kidney Disease

The predominant form of chronic renal disease associated with long-term Lithium treatment is a chronic tubulointerstitial nephropathy. The biopsy findings in patients with Lithium induced chronic tubulointerstitial nephropathy include tubular atrophy, interstitial fibrosis, sclerotic glomeruli, tubular dilation, and nephron atrophy with cyst formation. The relationship between renal function and morphologic changes and their association with Lithium treatment has not been established. Chronic tubulointerstitial nephropathy patients might present with nephrotic proteinuria (>3.0g/dL), worsening renal insufficiency and/or nephrogenic diabetes insipidus. Postmarketing cases consistent with nephrotic syndrome in patients with or without chronic tubulointerstitial nephropathy have also been reported. The biopsy findings in patients with nephrotic syndrome include minimal change disease and focal segmental glomerulosclerosis. The discontinuation of Lithium in patients with nephrotic syndrome has resulted in remission of nephrotic syndrome.

Kidney function should be assessed prior to and during Lithium treatment. Routine urinalysis and other tests may be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine, creatinine clearance, or proteinuria). During Lithium treatment, progressive or sudden changes in renal function, even within the normal range, indicate the need for re­ evaluation of treatment.

Encephalopathic Syndrome

An encephalopathic syndrome, characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN (blood urea nitrogen) and fasting blood glucose, has occurred in patients treated with Lithium and an antipsychotic. In some instances, the syndrome was followed by irreversible brain damage. Because of a possible causal relationship between these events and the concomitant administration of Lithium and antipsychotics, patients receiving such combined treatment should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. This encephalopathic syndrome may be similar to or the same as neuroleptic malignant syndrome.

Serotonin Syndrome

Lithium can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs (monoamine oxidase inhibitors).

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Monitor all patients taking Lithium for the emergence of serotonin syndrome. Discontinue treatment with Lithium and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Lithium with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Hypothyroidism or Hyperthyroidism

Lithium is concentrated within the thyroid and can inhibit thyroid synthesis and release which can lead to hypothyroidism. Where hypothyroidism exists, careful monitoring of thyroid function during Lithium stabilization and maintenance allows for correction of changing thyroid parameters, if any. Where hypothyroidism occurs during Lithium stabilization and maintenance supplemental thyroid treatment may be used. Paradoxically, some cases of hyperthyroidism have been reported including Grave’s disease, toxic multinodular goiter and silent thyroiditis.

Monitor thyroid function before the initiation of treatment, at three months and every six to twelve months while treatment is ongoing. If serum thyroid tests warrant concern, monitoring should occur more frequently.

Hypercalcemia and Hyperparathyroidism

Long-term Lithium treatment is associated with persistent hyperparathyroidism and hypercalcemia. When clinical manifestations of hypercalcemia are present, Lithium withdrawal and change to another mood stabilizer may be necessary. Hypercalcemia may not resolve upon discontinuation of Lithium, and may require surgical intervention. Lithium-induced cases of hyperparathyroidism are more often multiglandular compared to standard cases. False hypercalcemia due to plasma volume depletion resulting from nephrogenic diabetes insipidus should be excluded in individuals with mildly increased serum calcium. Monitor serum calcium concentrations regularly.

Unmasking of Brugada Syndrome

There have been postmarketing reports of a possible association between treatment with Lithium and the unmasking of Brugada Syndrome. Brugada Syndrome is a disorder characterized by abnormal electrocardiographic (ECG) findings and a risk of sudden death. Lithium should be avoided in patients with Brugada Syndrome or those suspected of having Brugada Syndrome. Consultation with a cardiologist is recommended if: (1) treatment with Lithium is under consideration for patients suspected of having Brugada Syndrome or patients who have risk factors for Brugada Syndrome, e.g., unexplained syncope, a family history of Brugada Syndrome, or a family history of sudden unexplained death before the age of 45 years, (2) patients who develop unexplained syncope or palpitations after starting Lithium treatment.

Pseudotumor Cerebri

Cases of pseudotumor cerebri (increased intracranial pressure and papilledema) have been reported with Lithium use. If undetected, this condition may result in enlargement of the blind spot, constriction of visual fields and eventual blindness due to optic atrophy. Consider discontinuing Lithium if this syndrome occurs.

Symptoms of lithium overdose

The toxic concentrations for Lithium (≥1.5 mEq/L) are close to the therapeutic range (0.8 to 1.2mEq/L). Some patients abnormally sensitive to Lithium may exhibit toxic signs at serum concentrations that are considered within the therapeutic range.

To reduce the risk of acute Lithium toxicity during treatment initiation, facilities for prompt and accurate serum Lithium determinations should be available before initiating treatment.

Lithium may take up to 24 hours to distribute into brain tissue, so occurrence of acute toxicity symptoms may be delayed.

Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination may be early signs of Lithium toxicity, and can occur at Lithium concentrations below 2.0 mEq/L. At higher concentrations, giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine may be seen. Serum Lithium concentrations above 3.0 mEq/L may produce a complex clinical picture involving multiple organs and organ systems, coma, and eventually death. Serum Lithium concentrations should not be permitted to exceed 2.0 mEq/L.

Neurological signs of Lithium toxicity range from mild neurological adverse reactions such as fine tremor, lightheadedness, and weakness; to moderate manifestations like apathy, drowsiness, hyperreflexia, muscle twitching, and slurred speech; and severe manifestations such as clonus, confusion, seizure, coma and death. Cardiac manifestations involve electrocardiographic changes, such as prolonged QT interval, ST and T-wave changes and myocarditis. Renal manifestations include urine concentrating defect, nephrogenic diabetes insipidus, and renal failure. Respiratory manifestations include dyspnea, aspiration pneumonia, and respiratory failure. Gastrointestinal manifestations include nausea, vomiting, and bloating.

No specific antidote for Lithium poisoning is known. Early symptoms of Lithium toxicity can usually be treated by reduction or cessation of Lithium, before restarting treatment at a lower dose 24 to 48 hours later.

• blurred vision
• clumsiness or unsteadiness
• convulsions (seizures)
• diarrhea
• drowsiness
• increase in the amount of urine
• lack of coordination
• loss of appetite
• muscle weakness
• nausea or vomiting
• ringing in the ears
• slurred speech
• trembling (severe)

The risk of acute toxicity is increased with a recent onset of concurrent illness or with the concomitant administration of drugs which increase Lithium serum concentrations by pharmacokinetic interactions. Additional risk factors for acute Lithium toxicity include acute ingestion, age-related decline in renal function, volume depletion and/or changes in electrolyte concentrations, especially sodium and potassium. Dose requirements during the acute manic phase are higher to maintain therapeutic serum concentrations and decrease when manic symptoms subside. The risk of Lithium toxicity is very high in patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, and for patients receiving prescribed medications that may affect kidney function, such as angiotensin converting enzyme inhibitors (ACE inhibitors), diuretics (loops and thiazides) and NSAIDs. For these patients, consider starting with lower doses and titrating slowly while frequently monitoring serum Lithium concentrations and signs of Lithium toxicity.

In severe cases of Lithium poisoning, the first and foremost goal of treatment consists of elimination of this ion from the patient. Administration of gastric lavage should be performed, but use of activated charcoal is not recommended as it does not significantly absorb Lithium ions. Hemodialysis is the treatment of choice as it is an effective and rapid means of removing Lithium in patients with severe toxicity. As an alternative option, urea, mannitol and aminophylline can induce a significant increase in Lithium excretion. Appropriate supportive care for the patient should be undertaken. In particular, patients with impaired consciousness should have their oral airway protected and it is critical to correct any volume depletion or electrolyte imbalance. Specifically, patients should be monitored to prevent hypernatremia while receiving normal saline and careful regulation of kidney function is of utmost importance.

Serum Lithium concentrations should be closely monitored as there may be a rebound in serum Lithium concentrations as a result of delayed diffusion from the body tissues. Likewise, during the late recovery phase, Lithium should be re- administered with caution taking into account the possible release of significant Lithium stores in body tissues.

References

1. Lithium orotate in the treatment of alcoholism and related conditions. Alcohol. 1986 Mar-Apr;3(2):97-100. https://www.ncbi.nlm.nih.gov/pubmed/3718672
2. Smith DF, Schou M. Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate. J Pharm Pharmacol. 1979;31(3):61–63.
3. Kling MA, Manowitz P, Pollack IW. Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate. J Pharm Pharmacol. 1978;30(6):368–370.
4. The clinical applications of lithium orotate. A two years study. Agressologie. 1973;14(6):407-11. https://www.ncbi.nlm.nih.gov/pubmed/4607169
5. Smith DF. Lithium orotate, carbonate and chloride: pharmacokinetics, polyuria in rats. British Journal of Pharmacology. 1976;56(4):399-402. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1666891/pdf/brjpharm00512-0006.pdf
6. Low dosage lithium augmentation in venlafaxine resistant depression: an open-label study. Psychiatriki. 2012 Apr-Jun;23(2):143-8. https://www.ncbi.nlm.nih.gov/pubmed/22796912
7. Pauzé DK, Brooks DE. Lithium toxicity from an internet dietary supplement. Journal of Medical Toxicology. 2007;3(2):61-62. doi:10.1007/BF03160910. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550087/pdf/13181_2009_Article_BF03160910.pdf
8. Possible dangers of a “nutritional supplement” lithium orotate. Ann Clin Psychiatry. 2013 Feb;25(1):71. https://www.ncbi.nlm.nih.gov/pubmed/23376874
9. Kwan, D.; Beyene, J.; Shah, P. S. (1 November 2009). “Adverse Consequences of Internet Purchase of Pharmacologic Agents or Dietary Supplements”. Journal of Pharmacy Technology. 25 (6): 355–360.  https://doi.org/10.1177/875512250902500602
10. Orotic Acid, anhydrous MSDS. http://www.sciencelab.com/msds.php?msdsId=9926339
11. Chen KP, Shen W, Lu ML. Implication of serum concentration monitoring in patients with lithium intoxication. Psychiatry and Clinical Neurosciences. 2004;58:25–29.
12. Oakley P, Whyte I, Carter G. Lithium toxicity: An iatrogenic problem in susceptible individuals. Australian and New Zealand J of Psychiatry. 2001;35:833.
13. Okusa MD, Crystal LJT. Clinical manifestations and management of acute lithium intoxication. American J of Med. 1994;97:383–388.
14. Astruc B, Petit P, Abbar M. Overdose with sustainedrelease lithium preparations. EUR Psychiatry. 1999;14:172–174.
15. Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978., p. 140

What is methylene blue

Methylene blue (C₁₆H₁₈ClN₃S), also known as methylthioninium chloride, is a medication and is a synthetic basic dye consisting of dark green crystals or crystalline powder, having a bronze-like luster. Methylene blue in water or alcohol have a deep blue color. Methylene blue is used as a bacteriologic stain and as an indicator. Methylene blue stains to negatively charged cell components like nucleic acids; when administered in the lymphatic bed of a tumor during oncologic surgery, methylene blue may stain lymph nodes draining from the tumor, thereby aiding in the visual localization of tumor sentinel lymph nodes. As a medication, when administered intravenously in low doses, methylene blue may convert methemoglobin to hemoglobin and it is mainly used to treat methemoglobinemia ¹. Specifically, methylene blue is used to treat methemoglobin levels that are greater than 30% or in which there are symptoms despite oxygen therapy. Methylene blue is typically given by injection into a vein. Methylene blue inhibits guanylate cyclase and has been used to treat cyanide poisoning, but this use is no longer recommended.

Methylene blue is a diaminophenothiazine drug that at low doses (0.5 – 4 mg/kg body weight) has neurometabolic-enhancing properties ². Preclinical research with rodents has shown that at low doses, methylene blue is a metabolic and cognitive enhancer that improves brain oxygen consumption, brain glucose uptake, cerebral blood flow, fMRI responses and memory consolidation by induction of cytochrome oxidase, the respiratory enzyme found within nerve cells ². By enhancing cytochrome oxidase activity, methylene blue increases oxygen consumption and amount of ATP available in neurons during memory consolidation. Although methylene blue has the potential to enter any nerve cell, it preferentially accumulates in neurons with higher energy demand, such as those involved in memory consolidation after extinction training ³. Hence, by acting as a mitochondrial electron cycler and antioxidant, low-dose methylene blue increases cellular energy production and support enhanced memory consolidation in key brain regions associated with memory processing ². Based on the findings of this study ⁴, patients who continue to show moderate to high levels of fear at the conclusion of an exposure therapy session may have their fear inadvertently strengthened by methylene blue administration, thus leading to a less favorable therapeutic outcome.

Methylene blue common side effects include headache, vomiting, confusion, shortness of breath, and high blood pressure. Other side effects include serotonin syndrome, red blood cell breakdown, and allergic reactions. Use often turns the urine, sweat, and stool blue to green in color. Methylene blue is a thiazine dye. It works by converting the ferric iron (Fe+++) in hemoglobin to ferrous iron (Fe++). While use during pregnancy may harm the baby, not using it in methemoglobinemia is likely more dangerous.

Methylene blue is a monoamine oxidase (MAO) inhibitor and therefore can interact with selective serotonin reuptake inhibitor (SSRI) and monoamine oxidase (MAO) inhibitors to cause serious serotonin toxicity ⁵.

Methylene blue also interacts with dapsone and forms hydroxylamine which oxidizes hemoglobin causing hemolysis ⁶.

A few very rare case reports regarding methylene blue‐induced anaphylactic reactions upon injection in surgery patients were identified in the scientific literature ⁷. These reactions were IgE mediated and probably caused by a conjugation of methylene blue as hapten to a protein.

As no food or respiratory allergy nor skin allergy was identified in the literature search for methylene blue, and concern for anaphylactic reactions upon oral exposure is low, there are no safety concerns with respect to allergenicity of methylene blue ⁸.

Methylene blue contraindications

Methylene blue is contraindicated in patients who have developed hypersensitivity reactions to it and in severe renal insufficiency. It is relatively contraindicated in G6PD deficient patients as it can cause severe hemolysis and also in patients with Heinz body anemia ⁹.

What is methylene blue used for

Methylene blue, an inhibitor of nitric oxide synthase and guanylate cyclase has many uses in medicine. It has been found to improve the hypotension associated with various clinical states ¹⁰. It also improves hypoxia and hyper dynamic circulation in cirrhosis of liver and severe hepatopulmonary syndrome ¹¹. It also results in transient and reproducible improvement in blood pressure and cardiac function in septic shock ¹².

Methemoglobinemia

Causes of methemoglobinemia

Methemoglobinemia condition can be:

1. Passed down through families (inherited or congenital)
2. Caused by exposure to certain drugs, chemicals, or foods (acquired)

There are two forms of inherited methemoglobinemia. The first form is passed on by both parents. The parents usually do not have the condition themselves. They carry the gene that causes the condition. It occurs when there is a problem with an enzyme called cytochrome b5 reductase.

There are two types of inherited methemoglobinemia:

• Type 1 (also called erythrocyte reductase deficiency) occurs when red blood cells lack the enzyme.
• Type 2 (also called generalized reductase deficiency) occurs when the enzyme doesn’t work in the body.

The second form of inherited methemoglobinemia is called hemoglobin M disease. It is caused by defects in the hemoglobin protein itself. Only one parent needs to pass on the abnormal gene for the child to inherit the disease.

Acquired methemoglobinemia is more common than the inherited forms. Acquired methemoglobinemia occurs in some people after they are exposed to certain chemicals and drugs, including:

• Anesthetics such as benzocaine
• Nitrobenzene
• Certain antibiotics (including dapsone and chloroquine)
• Nitrites (used as additives to prevent meat from spoiling)

Certain foods, such as spinach, beets or carrots contain natural nitrates in large amounts. These foods should not be given to children younger than 6 months of age.

Methemoglobinemia symptoms

Symptoms of type 1 methemoglobinemia include:

• Bluish coloring of the skin

Symptoms of type 2 methemoglobinemia include:

• Developmental delay
• Failure to thrive
• Intellectual disability
• Seizures

Symptoms of hemoglobin M disease include:

• Bluish coloring of the skin

Symptoms of acquired methemoglobinemia include:

• Bluish coloring of the skin
• Headache
• Fatigue
• Shortness of breath
• Lack of energy

Methemoglobinemia prognosis

People with type 1 methemoglobinemia and hemoglobin M disease often do well. Type 2 methemoglobinemia is more serious. It often causes death within the first few years of life.

People with acquired methemoglobinemia often do very well once the drug, food, or chemical that caused the problem is identified and avoided.

Methemoglobinemia possible complications

Complications of methemoglobinemia include:

• Shock
• Seizures
• Death

Methemoglobinemia diagnosis and test

A baby with this condition will have a bluish skin color (cyanosis) at birth or shortly afterward. The health care provider will perform blood tests to diagnose the condition. Tests may include:

• Checking the oxygen level in the blood (pulse oximetry)
• Blood test to check levels of gases in the blood (arterial blood gas analysis)

Methemoglobinemia treatment

People with hemoglobin M disease don’t have symptoms. So, they may not need treatment.

Methylene blue is used to treat severe methemoglobinemia.

Methylene blue acts by reacting within red blood cell to form leukomethylene blue, which is a reducing agent of oxidized hemoglobin converting the ferric ion (Fe+++) back to its oxygen carrying ferrous state (Fe++) ¹³.

Ascorbic acid may also be used to reduce the level of methemoglobin.

Alternative treatments include hyperbaric oxygen therapy, red blood cell transfusion and exchange transfusions.

In most cases of mild acquired methemoglobinemia, no treatment is needed. But you should avoid the medicine or chemical that caused the problem. Severe cases may need a blood transfusion.

How is methylene blue given?

Methylene blue is injected into a vein through an IV. A healthcare provider will give you this injection. The IV infusion can take up to 30 minutes to complete.

Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving methylene blue. Your blood will also need to be tested to help your doctor determine that the medicine is working.

You may only need to receive one dose of methylene blue. If you do need a second dose, it can be given 1 hour after your first dose.

Methylene blue will most likely cause your urine or stools to appear blue or green in color. This is a normal side effect of the medication and will not cause any harm. However, this effect may cause unusual results with certain urine tests.

Vasoplegic syndrome

Vasoplegic syndrome is generally defined as an arterial pressure <50 mm Hg, cardiac index >2.5 L /min/m², right atrial pressure <5 mm Hg, left atrial pressure <10 mm Hg and low systemic vascular resistance <800 dyne/sec/cm ¹⁴.

Risk factors for vasoplegia

Recent studies have established various risk factors for postoperative vasoplegia. These include preoperative use of heparin, ACE inhibitors, congestive heart failure, poor left ventricular function, duration of cardiopulmonary bypass, re-operation, age of the patient and opiod anesthesia ¹⁵.

Mechanism of action of methylene blue in vasoplegia

It has been suggested that refractory vasoplegia may reflect a dysregulation of nitric oxide synthesis and vascular smooth cell guanylate cyclase activation. Based on recent pathophysiologic findings it appears that the soluble intracellular enzyme guanylate cyclase is activated to produce cyclic guanosine monophosphate (C-GMP) presumably under the influence of several mediators including nitric oxide ¹⁶.

Methylene blue acts by inhibiting guanylate cyclase, thus decreasing C-GMP and vascular smooth muscle relaxation ¹⁷.

Preoperative use in cardiac surgery

Methylene blue (1%) has been used IV over 30 min in ICU 1hour before surgery and found decreased incidence and severity of vasoplegic syndrome in high risk patients ¹⁴.

Intraoperative use in cardiac surgery

It has also been successfully added to cardiopulmonary bypass prime (2 mg/ kg) and continued as infusion (.25- 2mg/kg/hr) during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis ¹⁸.

Postoperative use in cardiac surgery

It can also be used to treat severe vasoplegia in post operative transplant patient ¹⁹. Hence studies have concluded decreased mortality in vasoplegic patients after cardiac surgery with methylene blue as compared to placebo ²⁰.

Methylene blue in septic shock

A release of nitric oxide has been incriminated in the cardiovascular alterations of septic shock. Since guanylate cyclase is the target enzyme in the endothelium dependent relaxation mediated by nitric oxide, Methylene blue- a potent inhibitor of guanylate cyclase has been found very effective in improving the arterial pressure and cardiac function in septic shock ¹².

Studies have found improvement in mean arterial pressure and systemic vascular resistance while decreasing vasopressor requirements in septic shock ²¹.

Methylene blue and hepatopulmonary syndrome

The hypoxemia in hepatopulmonary syndrome results from widespread pulmonary vasodilatation due to increased C-GMP. Methylene blue is found to ↑PaO2 and ↓alveolar-arterial difference for partial pressure of oxygen in all pts with hepatopulmonary syndrome. This was due to ↓C-GMP levels by Methylene Blue-a potent inhibitor of guanylate cyclase ²².

Methylene blue as antimalarial

Methylene blue has already been used some 100 years ago against malaria, but it disappeared when chloroquine and other drugs entered the market. However recent studies has shown the efficacy of Methylene blue as an effective and cheap antimalarial agent especially in countries with increasing resistance of P. falciparum to existing 1st line antimalarial agents-chloroquine and pyrimethamine-sulfadoxine.

Methylene blue, a specific inhibitor of P.falciparum glutathione reductase has the potential to reverse chloroquine resistance and it prevents the polymerization of haem into haemozoin similar to 4-amino-quinoline antimalarials.

A dose of 36-72mg/kg over 3 days is the most effective schedule ²³.

Apart from the intrinsic antimalarial activity and chloroquine sensitizing action it was also considered to prevent methemoglobinemia- a serious complication of malarial anemia ²⁴.

Methylene blue and cancer

Recent research suggests that Methylene Blue and other redox cyclers induce selective cancer cell apoptosis by NAD (P) H: quinine oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Hence methylene blue is being investigated for the photodynamic treatment of cancer ²⁵.

Methylene blue and ifosfamide neurotoxicity

Another, less well known use of methylene blue is its utility for treating ifosfamide neurotoxicity. A toxic metabolite of ifosfamide, chloroacetaldehyde, disrupts the mitochondrial respiratory chain, leading to accumulation of nicotinamide adenine dinucleotide hydrogen (NADH).

Methylene blue acts as an alternative electron acceptor, and reverses the NADH inhibition of hepatic gluconeogenesis while also inhibiting the transformation of chloroethylamine into Chloroacetaldehyde, and also inhibits multiple amine oxidase activities, preventing the formation of Chloroacetaldehyde ²⁶.

Hence it has prophylactic and therapeutic role in ifosfamide – induced encephalopathy ²⁷.

Methylene blue as dye and stain

Methylene blue infusion was found as a safe and effective method of localizing abnormal parathyroid glands ²⁸.

Methylene blue has also been used for intraoperative endoscopic marking of intestinal lumen for location of lesions ²⁹.

Methylene blue was also found as an effective and cheap alternative to isosulfan blue dye for sentinel lymph node localization in pt with breast cancer ³⁰.

Methylene blue also has been used in diagnostic microbiology as a stain. It is an inexpensive and rapid method for detection of Helicobacter pylori (H.pylori) ³¹.

Methylene blue neutralization of heparin

Methylene blue effectively neutralizes heparin especially in pts with protamine allergy. However work still needs to be done to determine the safety of the drug at the higher doses necessary to neutralize heparin levels achieved in bypass patients ³².

Methylene blue and priapism

Methylene blue has been used to treat high flow priapism by intra-cavernous injection which is known to antagonize endothelial derived relaxation factor ³³.

Methylene blue and Alzheimer’s disease

The relationship between Methylene blue and Alzheimer’s disease has recently attracted increasing scientific attention. It has been shown to attenuate the formations of amyloid plaques and neurofibrillary tangles and partial repair of impairments in mitochondrial function and cellular metabolism ³⁴.

Methylene blue photodynamic therapy

Photodynamic therapy using the light activated anti-microbial agent, Methylene blue kills methicillin resistant staphylococcus aureus (MRSA) in superficial and deep excisional wounds ³⁵. Methylene blue in combination with light also inactivates viral nucleic acid of hepatitis-C and human immunodeficiency virus (HIV-1) and treats cases of resistant plaque psoriasis ³⁶.

Methylene blue dose

Methemoglobinemia: Dose commonly used is 1-2mg/kg of 1% Methylene blue solution ¹³.

Vasoplegic syndrome: Methylene blue is used as a single dose of 1.5 -2 mg /kg IV over 20 min to 1 hour for rescue treatment ¹⁴.

Antimalarial: A methylene blue dose of 36-72 mg/kg over 3 days is the most effective schedule ²³.

Methylene blue side effects

Methylene blue turns urine greenish blue and bluish discoloration of skin and mucosa which is self limiting ³⁷. Methylene blue may also cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

For at least 24 hours after treatment with methylene blue, avoid exposure to sunlight or tanning beds. This medicine can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Methylene blue also interferes with the pulse oximeter’s light emission resulting in falsely depressed oxygen saturation reading ⁶.

Check with your doctor or nurse immediately if any of the following side effects occur:

Incidence not known

• agitation
• bluish-colored lips, fingernails, or palms
• confusion
• cough
• dark urine
• diarrhea
• difficulty breathing
• difficulty swallowing
• dizziness or lightheadedness
• fast heartbeat
• fever
• headache
• hives or welts, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• overactive reflexes
• pale skin
• poor coordination
• rapid heart rate
• redness of the skin
• restlessness
• shivering
• sore throat
• sweating
• talking or acting with excitement you cannot control
• tightness in the chest
• trembling or shaking
• twitching
• unusual bleeding or bruising
• unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of methylene blue overdose

• abdominal or stomach pain
• bigger, dilated, or enlarged pupils (black part of the eye)
• blue staining of the urine, skin, and mucous membranes
• bluish-colored lips, fingernails, or palms
• blurred vision
• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
• confusion
• dark urine
• difficulty breathing
• dizziness or lightheadedness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fear
• fever
• headache
• increased sensitivity of the eyes to light
• nausea
• pale skin
• rapid heart rate
• rapid shallow breathing
• shakiness in the legs, arms, hands, or feet
• sore throat
• tightness in the chest
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• change in taste
• changes in skin color
• feeling hot or cold
• increased sweating
• loss of taste
• muscle or joint pain
• pain at the infusion site
• pain in the arms or legs

Less common

• back pain
• bruising
• chills
• general feeling of discomfort or illness
• large, flat, blue or purplish patches in the skin
• loss of appetite
• muscle aches and pains
• muscle spasm
• runny nose
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects.

Methylene blue toxicity

Methylene blue is a safe drug when used in therapeutic doses (<2mg/kg) ³⁸. But methylene blue can cause toxicity in high doses. The features of toxicity being cardiac arrhythmias, coronary vasoconstriction, decreased cardiac output, renal blood flow and mesenteric blood flow; increased pulmonary vascular pressure and pulmonary vascular resistance and gas exchange deterioration ³⁸.

Due to methylene blue tissue reactive properties, a case of skin and fat necrosis followed by a dry gangrene of the skin in a female patient with breast cancer who underwent sentinel lymph node biopsy localization using peri-tumoral injection of methylene blue dye has been reported ³⁹.

Methylene blue can also cause hemolytic anemia characterized by Heinz body formation especially in people with severe renal insufficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency ⁶.

Neonates are particularly prone to adverse effects of methylene blue. It causes hyperbilirubinemia, meth-Hemoglobin formation, hemolytic anemia, respiratory distress, pulmonary edema, photo toxicity and bluish discoloration of tracheal secretions and urine ⁴⁰.

Methylene blue due to its monoamine oxidase (MAO) inhibiting property may precipitate potentially fatal serotonin toxicity at doses >5mg/kg ⁴¹ and rarely can cause severe anaphylactic shock ⁴².

You can develop serotonin syndrome if you take methylene blue together with antidepressants called selective serotonin reuptake inhibitors (SSRIs), selective serotonin/norepinephrine reuptake inhibitors (SSNRIs) and monoamine oxidase inhibitors.

Common selective serotonin reuptake inhibitors (SSRIs) include citalopram (Celexa), sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and escitalopram (Lexapro). Selective serotonin/norepinephrine reuptake inhibitors (SSNRIs) include duloxetine (Cymbalta) and venlafaxine (Effexor). Common monoamine oxidase inhibitors include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam) and tranylcypromine (Parnate).

If you take these medicines, be sure to read the warning on the packaging. It tells you about the potential risk of serotonin syndrome. However, do not stop taking your medicine. Talk to your doctor about your concerns first.

People with serotonin syndrome will likely stay in the hospital for at least 24 hours for close observation.

Serotonin syndrome treatment may include:

• Benzodiazepine medicines, such as diazepam (Valium) or lorazepam (Ativan) to decrease agitation, seizure-like movements, and muscle stiffness
• Cyproheptadine (Periactin), a drug that blocks serotonin production
• Intravenous (through the vein) fluids
• Withdrawal of medicines that caused the syndrome

In life-threatening cases, medicines that keep the muscles still (paralyze them), and a temporary breathing tube and breathing machine will be needed to prevent further muscle damage.

Serotonin syndrome prognosis

People may get slowly worse and can become severely ill if not quickly treated. Untreated, serotonin syndrome can be deadly. With treatment, symptoms usually go away in less than 24 hours.

Uncontrolled muscle spasms can cause severe muscle breakdown. The products produced when the muscles break down are released into the blood and eventually go through the kidneys. This can cause severe kidney damage if serotonin syndrome isn’t recognized and treated properly.

Serotonin syndrome symptoms occur within minutes to hours, and may include ⁴³:

• Agitation or restlessness
• Diarrhea
• Fast heartbeat and high blood pressure
• Hallucinations
• Increased body temperature
• Loss of coordination
• Nausea and vomiting
• Overactive reflexes
• Rapid changes in blood pressure.

References

1. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 34. ISBN 9780857111562.
2. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Progress in Neurobiology. 2012;96(1):32-45. doi:10.1016/j.pneurobio.2011.10.007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265679/
3. Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004;11:633–640 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC523083/
4. Telch MJ, Bruchey AK, Rosenfield D, et al. Post-Session Administration of USP Methylene Blue Facilitates the Retention of Pathological Fear Extinction and Contextual Memory in Phobic Adults. The American journal of psychiatry. 2014;171(10):1091-1098. doi:10.1176/appi.ajp.2014.13101407. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467026/
5. Gillman P K. Methylene blue implicated in potentially fatal serotonin toxicity. Anaesthesia. 2006;61:1013–4 https://www.ncbi.nlm.nih.gov/pubmed/16978328
6. Clifton, Jack II, Leikin, Jerrold Methylene blue. American Journal of Therapeutics. 2003;10:289–91.
7. Dewachter P, Castro S, Nicaise‐Roland P, Chollet‐Martin S, Le Beller C, Lillo‐le‐Louet A and Mouton‐Faivre C, 2011. Anaphylactic reaction after methylene blue‐treated plasma transfusion. British Journal of Anaesthesia, 106, 687–689. https://doi.org/10.1093/bja/aer009
8. Dyes in aquaculture and reference points for action. EFSA Journal 29 June 2017. https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2017.4920
9. Clifton, Jack II, Leikin, Jerrold Methylene blue. American Journal of Therapeutics. 2003;10:289–91. https://www.ncbi.nlm.nih.gov/pubmed/12845393
10. Bosoy , Dimitry , Axelband , et al. Utilization of methylene blue in the setting of hypotension associated with concurrent renal and hepatic failure: a concise review. OPUS 12 Scientist. 2008;2:21–9.
11. Peter schenk, Christian Madl, Shahrzad Rezaie-Majd, Stephen Lehr, Christian Muller. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med. 2000;133:701–6.
12. Preiser, Jean-Charles, Lejeune, et al. Methylene blue administration in septic shock: A Clinical Trial. Critical Care Medicine. 1995;23:259–64.
13. Methemoglobinemia: a case study. Boylston M, Beer D. Crit Care Nurse. 2002 Aug; 22(4):50-5. http://ccn.aacnjournals.org/content/22/4/50.long
14. Ertugrul Ozal, Erkan Kuralay, Vedat Yildirim, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg. 2005;79:1615–9. https://www.ncbi.nlm.nih.gov/pubmed/15854942
15. Armand Mekontso-Dessap, Remi Houel, Celine Soustelle, Matthias Kirsch, Dominique Thebert, Daniel Y. Loisance.Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg. 2001;71:1428–32. https://www.ncbi.nlm.nih.gov/pubmed/11383777
16. Levin Ricardo L, Degrange Marcela A, Bruno Gustavo F, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77:496–9. https://www.ncbi.nlm.nih.gov/pubmed/14759425
17. Gachot B, Bedos J.P, Veber B, Wolff M, Regnier B. Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. Intensive Care Medicine. 1995;21:1027–31 https://www.ncbi.nlm.nih.gov/pubmed/8750129
18. Grayling M, Deakin C D. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc Surg. 2003;125:426–7.
19. Kofidis T, Struber M, Wilhelmi M, et al. Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thoracic Cardiovasc Surg. 2001;122:823–4.
20. Levin Ricardo L, Degrange Marcela A, Bruno Gustavo F, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77:496–9.
21. Edmund S, Kwok H, Howers Daniel. Use of methylene blue in sepsis: A Systematic Review. Journal of Intensive Care Medicine. 2006;21:359–63.
22. Peter schenk, Christian Madl, Shahrzad Rezaie-Majd, Stephen Lehr, Christian Muller. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med. 2000;133:701–6
23. Meissner Peter E, Germain Mandi, Boubacar Coulibaly, et al. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malaria Journal. 2006;5:84. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617109/
24. Schirmer R.H, Coulibaly B, Stich A, et al. Methylene blue as an antimalarial agent. Redox rep. 2003;8:272–5. https://www.ncbi.nlm.nih.gov/pubmed/14962363
25. Wondrak GT. NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis. Free Radic Biol Med. 2007;43:178–90 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705808/
26. Alici-Evcimen Y, Breitbart WS. Ifosfamide neuropsychiatric toxicity in patients with cancer. Psychooncology. 2007;16:956–60.
27. Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové, Vermorken JB. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. British Journal of Cancer. 2000;82:291–4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363270/pdf/82-6690917a.pdf
28. Gordan Donald L, Airan Mohan C, Thomas William, Seidman Leon H. Parathyroid identification by methylene blue infusion. British Journal of Surgery. 2005;62:747–9.
29. Beretvas RI, Ponsky J. Endoscopic marking: an adjunct to laparoscopic gastrointestinal surgery. Surgical endoscopy. 2001;15:1202–3.
30. Simmons RM, Smith SM, Osborne MP. Methylene blue dye as an alternative to isosulfan blue dye for sentinel lymph node localization. Breast J. 2001;7:181–3.
31. Misra V, Misra SP, Dwivedi M, Gupta SC. The Loeffler’s methylene blue stain: An inexpensive and rapid method for detection of helicobacter pylori. Journal of Gastroenterology and Hepatology. 2008;9:512–3.
32. Sloand EM, Kessler CM, Mcintosh CL, Klein HG. Methylene blue for neutralization of heparin. Thromb Res. 1989;54:677–86
33. Steers WD, Selby JB. Use of methylene blue and selective embolization of the pudendal artery for high flow priapism refractory to medical and surgical treatments. J Urol. 1991;146:1361–3.
34. Murat Oz, Lorke Dietrich E, Petroianu George A. Methylene blue and Alzheimer’s disease. Biochemical pharmacology. 2009;78:927–32
35. Zolfaghari Parjam S, Samantha Packer, Mervyn Singer, et al. In vivo killing of Staphylococcus aureus using light-activated antimicrobial agent. BMC Microbiology. 2009;9:27.
36. Salah M, Samy N, Fadel M. Methylene blue mediated photodynamic therapy for resistant plaque psoriasis. J Drugs Dermatol. 2009;8:42–9
37. Ertugrul Ozal, Erkan Kuralay, Vedat Yildirim, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg. 2005;79:1615–9.
38. Ginimuge PR, Jyothi SD. Methylene Blue: Revisited. Journal of Anaesthesiology, Clinical Pharmacology. 2010;26(4):517-520. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087269/
39. Salhab M, Al sarakbi W, Mokbel K. Skin and fat necrosis of the breast following methylene blue dye injection for sentinel node biopsy in a patient with breast cancer. Int Semin Surg Oncol. 2005;2:26.
40. Cowett RM, Hakanson DO, Kocon RW, Oh W. Untoward neonatal effect of intraamniotic administration of methylene blue. Obstet Gynecol. 1976;48:74–5.
41. Gillman P K. Methylene blue implicated in potentially fatal serotonin toxicity. Anaesthesia. 2006;61:1013–4. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2044.2006.04808.x
42. Pascale Dewachter, Claudie Moutan-Faivre, Philippe Trechot, Jean-Claude Lleu, Paul Michel Mertes. Severe anaphylactic shock with methylene blue instillation. Anesth Analg. 2005;101:149–50. https://www.ncbi.nlm.nih.gov/pubmed/15976222
43. Serotonin syndrome. https://medlineplus.gov/ency/article/007272.htm