Lithium orotate??

Does anyone know anything about this drug?
I know it's not approved by the FDA, but anything other then that?
Anyone has any experiences with it?
Compared to lithium carbonate?

Lilly

Yes, yes I know a lot about this drug. What is it? It's elemental lithium attached to a nucleic acid. It's a very active compound, with doses as low as 9 mg/kg/day causing orotic aciduria, which is believed to be caused by competitive inhibition of uridine monophosphate (UMP) synthase, by blocking or otherwise impeding orotidine 5'-monophosphate decarboxylase (ODCase).

Lithium orotate (lithium orotate monohydrate) is a metal complex comprised of orotate and water ligands ionically bonded to lithium, it is a salt of orotic acid and an organic compound, with a formula Li+ · C5H3N2O4- · H2O. Crystal structure analysis shows that the lithium ligand is locked within a tetrahedral environment of four O atoms (Lutz 2001). Christensen established in 1983 that orotic acid was typically excreted from the kidneys presumably as sodium orotate, and never as a free acid. Given lithium's greater ionic strength than sodium, it is safe to conclude it doesn't dissolve or work the same way lithium carbonate does within the body. Kling stated, in 1978: "Lithium orotate was prepared by dissolving 20 m equiv LiOH · H2O (BDH Chemicals Ltd.) in distilled water and adding a stoichiometric amount of orotic acid (Sigma Chemical Co.). This mixture was heated with stirring until the orotic acid dissolved. From this upon cooling to 20°, a fine precipitate formed. The pH was adjusted to 7.4 with HCI, and the volume was adjusted to 100 ml. The resulting slurry was throughly and constantly stirred while portions were removed for injection with 25 gauge needles intraperitoneally into rats.". Smith also noted similar insolubility in his study.

It's unknown what lithium orotate is capable of, the medical community literally abandon it in the 1970s when they found it didn't behave like lithium carbonate, this was in large part to DF Smith's highly critical article involving renal impairment. He noted: "The kidneys weighed significantly more in rats given lithium orotate than in those in the three other groups. Inspection of the kidneys showed those from rats given lithium orotate to be larger and paler than the kidneys from the other rats." What Smith described in his report is hypochromic and megaloblastic anemia, which are symptoms of orotic aciduria, no one ever connected the two together, until just now.

It remains to be seen if lithium orotate is safe in small doses, in large doses it is toxic. Even more so than lithium carbonate. I believe it to be a very potent ODCase inhibitor. I think it works by one of three methods: a) lithium is decarboxylated inside the cell, b) it is recycled via pyrimidine savage pathways, or c) it is incorporated directly into proteins. Smith noted a renal lithium clearance 24 times less then lithium carbonate. Dewar noted in his 1971 study that lithium orotate promotes rapid RNA turnover in rats, wether this is a good or bad thing remains to be seen.

For those reasons, I would not recommend anyone take large doses of this stuff. I tested it personally, at 9 mg/kg/day, and by day 6 by kidneys felt like they were on fire. My urine pH had dropped below 4.5 as measured with a pH test strip... which is another symptom of orotic aciduria. I discontinued immediately, but urine pH did not return to normal levels until almost two full weeks had elapsed. I resumed experimenting with it at lower doses, 4 mg/kg/day produced meningitis like symptoms, later it was realized this was actually a continuous migraine with multiple auras per day, and was crippling all the way down to 1 mg/kg/day. 30 mg/day was the highest dose I had observed no adverse effects at, I would recommend this as the starting dosage for this compound. It is worth noting that during the time I was experimenting with lithium orotate I was also taking a lithium carbonate 300 mg/day.

Lithium carbonate is an inorganic soluble lithium salt, while lithium orotate is an organic insoluble salt. They are completely different, it's apples and oranges. In my option this compound should not be available without a prescription. People worry about lithium toxicity while on this compound, but the reality is you will die from protein inhibition well before you reach toxic lithium levels from this compound. If you feel sick, lethargic, have migraines, or feel a burning sensation emanating from your kidneys reduce the dosage or discontinue immediately.

It's highly active within the body, this is certain beyond any doubt. However, it's effectiveness and safety in treating disease is entirely unknown. It could be a miracle compound, or it could possible be a tumor promoting agent. The medical community stuck their noses up at it back in the 70s. The research I have just described, that lithium orotate is a UMP / ODCase inhibitor is my own, that I have just now revealed. I reached my conclusions after a systematic review of the chemistry and medical literature dating back to 1971, and empirical experimentation on myself.

Let me know if you have any questions, ideas, or suggestions? Half the reason I'm posting this here is to bounce the idea off of others... let me know what you guys think. If you've taken it, what dosage did you take and what effects did you notice?

I know only 2 things about Lithium- weight gain and more weight gain! I'd try to avoid Lithium like the plague! I'd focus on other mood stabilizing agents like Latuda and Lamictal that also help with depression and that are weight neutral! All the best!!

Some references:

ChemIDplus 5266-20-6: ChemIDplus - 5266-20-6 - Lithium orotate - Similar structures search, synonyms, formulas, resource links, and other chemical information.
Christensen 1983: Orotic Acid Sodium Salt in Kidney Stones and Urinary Deposits
Dewar 1971: Cambridge Journals Online - Psychological Medicine - Abstract - Effect of lithium administration on RNA metabolism in rat brain injected with radio labeled orotic acid
EFSA 2009: EFSA - Opinion of the Scientific Committee/Scientific Panel: Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements
Grosse 1980: The effect of orotic acid and sodium orotate on organ cultures of the hippocampus of embryonic rats
Hilal 2005: Electronic structure of orotic acid III geometric feature and thermal properties of some transition metal orotic acid complexes
Hur 2002: Molecular dynamic study of orotidine-5′-monophosphate decarboxylase in ground state and in intermediate state: A role of the 203–218 loop dynamics
Karkishchenko 1983: Anxiolytic effect of potassium orotate
Karkishchenko 1986: Quantitative evaluation of the anxiolytic and nootropic effects of potassium orotate in a wide range of doses
Kilomentor (Grey Literature): Possible Uses of the Pharmaceutically -Acceptable Orotic Acid
Kling 1978: Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate - KLING - 2011 - Journal of Pharmacy and Pharmacology - Wiley Online Library
Lutz 2001: Acta Crystallographica Structure Reports Online - Lithium Orotate Monohydrate
Musick 1981: Structural features of the phosphoribosyltransferases and their relationship to the human deficiency disorders of purine and pyrimidine metabolism.
Padmarao 2013: Coordination Chemistry of Orotic acid - International Journal of Engineering Science Invention
RTECS RM3180000: RTECS NUMBER RM3180000 Orotic Acid - Chemical Toxicity Database
Sartori 1986: Lithium orotate in the treatment of alcoholism and related conditions
Smith 1976: LITHIUM OROTATE, CARBONATE AND CHLORIDE: PHARMACOKINETICS, POLYDIPSIA AND POLYURIA IN RATS
Smith 1979: Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate - SMITH - 2011 - Journal of Pharmacy and Pharmacology - Wiley Online Library
Wenzel 1976: The effect of orotic acid and orotic acid derivatives on the in vitro differentiation of hippocampus neurons-morphometric and electron microscopic studies of ribosomes
Wu 2002: Crystal Structures of Inhibitor Complexes Reveal an Alternate Binding Mode in Orotidine-5′-monophosphate Decarboxylase

Lithiums been ood to me re weight gain. It was depakote that was terrible and zyprexa.

Weight gain is not a certainty with Lithium, is this the only reason you avoid it? As previously indicated, I take a combination of 300 mg of lithium carbonate and 30 mg of lithium orotate. I have no side effects, and appear to be doing just fine. Even trace amount of lithium have been shown to have positive effects on the body and mind...

Kapusta 2011: Lithium in drinking water and suicide mortality
Ren 2003: Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model.
Wada 2005: Lithium: Potential Therapeutics Against Acute Brain Injuries and Chronic Neurodegenerative Diseases
Zarse 2011: Low-dose lithium uptake promotes longevity in humans and metazoans

I know I took it for only a few weeks and started getting the shakey hands so I told my doctor I wanted something different.. Read the side affects they are horrible and the shaking can get worse and be around for forever.

I presume you're referring to lithium carbonate. Shaking hands is a symptom of acute elemental lithium toxicity, why wasn't the doctor monitoring your levels? This often happens when lithium is started too high or ramped up too fast. It goes away on its own after your body adjusts. In your case it sounds like the doctor should have started you at a lower dose, it should never be so pronounced that it forces you to stop treatment.

Using free elemental lithium (i.g. lithium carbonate, lithium citrate) to control the acute phases of this illness is akin to the delicate balance of chemo therapy. In chemo, the dose has to be high enough to kill the cancer, but too high and it will also harm the patient. Elemental lithium does have a very narrow therapeutic range, and it's right up against its toxic threshold. However, you don't need that high a dose for maintenance, and for prophylactic use trace amounts have been show to be effective.

My hands shake but my levels are fine.

Wow. My mind is blown. Bravo nbritton.

I took 10 mg LI orotate (elemental 10 mg. which is two 120mg pills from Doctor's Best brand) for several months before taking Li carbonate. The carbonate just "feels" better in my body, but to be fair i am on a small, maintenance dose right now. I can't say that the Li orotate did anything adverse at all, in fact it made me feel a bit better for sure. I would take it again in a heart beat if I didn't have access to Li carbonate.

My stupid shrink took me off of lithium carbonate and put me on lithium orotate. I was manic and in the hospital within a couple of weeks. I have a different pdoc now.

Five more references:

Dumler 1979: Effects of Orotate Administration on the Normal Rat Kidney
Gotz 1982: Electron microscopic and morphometric studies on the in vitro differentiation of mitochondria in neurons of hippocampus explant cultures as affected by orotic acid and sodium orotate
Krug 1977: Effects of orotic acid and pirazetam on cortical bioelectrical activity in rabbit
Lindner 1980: The effect of active substances on nerve fiber regeneration in nerve tissue cultures
Motyl 1991: Urinary excretion of purines in sheep with experimental orotic aciduri

I've included references to potassium and sodium orotate, these are relevant because, along with lithium, they are all group 1 alkali metals on the periodic table of elements. Of critical importance is the fact that they all have +1 oxidation states. This means ions from these metals all have a electron charges of +1, this is important because it determines the molecular structure of the orotate coordination complex. Zinc for instance, has a electron charge of +2, so it actually forms an ionic bond with two orotate molecules. As a result of this double orotate zinc bond, the zinc orotate complex is hypothesized to not be able to dock with the uridine monophosphate synthetase (UMPS) enzyme.


Peer review:
The EFSA Journal (2009) 1187, 1-25: Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements.

The European Food Safety Authority was asked to provide a scientific opinion of the safety of orotic acid and several of its metal orotates. The panel conducted a diligent review on the safety of orotic acid. The panel establish a NOEL (No Observed Effect Level) at 50 mg orotic acid/kg bw/day. The panel further established a LOEL (Lowest Observed Effect Level) at 100 mg orotic acid/kg bw/day.

As expected, 500 mg orotic acid/kg was found to be carcinogenic. They additionally noted tumor-promoting effects down to 100 mg/kg (Sarma et. al., 1986). This carcinogenic effect is expected, orotic acid is essential for the synthesis of RNA and DNA, and it is reasonable to presume that a massive excess of orotic acid would influence cell growth. A parallel analogy would be akin to giving a plant so much fertilizer that it dies from hypotonicity. The panel referenced RTECS RM3180000 (Registry of Toxic Effects of Chemical Substances) for acute toxicity and LD50, which in mouse was 2 g/kg oral, 841 mg/kg intraperitoneal, and 770 mg/kg intravenous. The Hazardous Substances Data Bank has an extensive collection of data that was not referenced in this work, however their conclusions are consistent with available data and their opinion regarding safe upper limits should be considered authoritative.

With that said, a number of problems exist with the conclusions reached by this panel regarding the utility of metal orotates.

The panel asserts their opinion regarding bioavailability of all metal orotates on the basis of a single study conducted with zinc orotate (Andermann G and Dietz M, 1982). To put it bluntly, making this statement on the basis of one report that studied one element is absurd, however to the panels defense no documentation was supplied by the petitioners. Transitional metals, such as zinc, do not have the same properties as alkalis. Furthermore the zinc cation has a charge of +2 and orotate is -1, this means zinc forms an ionic bond with two orotate molecules; it may not be able to dock with the uridine monophosphate synthetase (UMPS) enzyme, assuming it doesn't dissolve into separate free elemental zinc and orotate molecules.


Assuming that orotic acid is not precipitated from the kidneys as a free acid, what basis is there to believe that oral, intraperitoneal, or intravenous intake of orotic acid remains in it's free acid state (Christensen, 1983)? Christensen suggested in this review that orotic acid most likely binds with sodium to form sodium orotate monohydrate. The ability of orotidine 5'-phosphate decarboxylase to bind with metal coordinations has not been fully established, let alone the ability of this enzyme to decarboxylate them. More research is needed, particularly with lithium orotate as it has a higher charge density than sodium. Nearly every study regarding lithium orotate has demonstrated findings that differ from lithium carbonate, however no effort has been put forward to explain these findings. The panels statement regarding bioavailability is conjecture.

Wenzel et. al., 1979, gave sodium orotate to rats and had this to say about the subject: "The total number of ribosomes increases following the application of orotic acid by 20%, of sodium-orotate by 48% and of methylglucamine-orotate by 23% compared to the controls (alpha = 0,1%). 4. Sodium-orotate shows with reference to the neuronal development the clearest stimulatory effect. After 20 days in vitro the total number of ribosomes is by 60% higher at the treated cultures than in the controls."

My Preliminary Research Notes:
Here are my preliminary notes on lithium orotate, I was planning to publish a paper, but do not have time to finish or publish it. These are my initial notes I typed up back in August 2013, I was planning to suggest the use of lithium orotate as a control to study the effects of elemental lithium in the drinking water, but it became apparent while writing these notes that lithium orotate did not have the same pharmacodynamics as the other forms of lithium. My posts in this forum thread, including the EFSA review, can be used freely by others, all I ask for is appropriate credit. Furthermore, any part may be incorporated into Wikipedia. I simply don't have time to dedicate towards furthering this subject.

lithium 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylate monohydrate:



Lithium orotate (lithium orotate monohydrate) is a metal complex comprised of orotate and water ligands non-covalently bonded to lithium, it is a salt of orotic acid and an organic compound, with a formula Li+ * C5H3N2O4- * H2O. It is synthesized exclusively as a monohydrate, for use as a dietary supplement.

While orotic acid can be supplied in anhydrous form, this form has no known applications.

Synthesis:

Orotic acid:
C5H4N2O4

Lithium orotate:
Li + C5H4N2O4 → LiC5H3N2O4 + H

Lithium orotate monohydrate:
LiC5H3N2O4(s) → Li+(aq) + C5H3N2O4-(aq)

For reference, lithium carbonate:
Li2CO3(s) + 2H+(aq) → 2Li+(aq) + H2O(l) + CO2(g)

Lithium is a highly reactive element from the alkali metal group that can only be ingested as a chemical compound, it is reacted as a cation (Li+) with orotic acid (C5H4N2O4-) to produce a salt compound that can be ingested. During synthesis, the carboxyl group in orotic acid is deprotonated and its conjugate base, orotate (C5H3N2O4-), forms a carboxylate anion (RCOO-) that bonds with the lithium cation. As a result of this RCOO-Li+ bond it is not actually an organometallic compound, however it is often categorized as one. Orotate is presumed to function as a biochemical ligand within the lithium complex.

Some have expressed that the RCOO-Li+ bond is quickly broken once it enters the body, one study concluded that orotic acid was precipitated from the kidneys as an alkali metal orotate, and almost never it is free acid state. Under normal conditions, they concluded it was most likely precipitated as sodium orotate. However, with lithium having a smaller atomic radius and greater charge density, this compound is unlikely to readily dissolve.

It is often categorized as an organometallic compound, although strictly speaking it is not due to its carboxylate anion bond (RCOO-Li+).

Orotate (orotic acid) was historically believed to be vitamin, however it was discovered that the body manufacturers this compound as a component of pyrimidine metabolism. Orotate is covalently linked with a phosphorylated ribosyl unit. The covalent linkage between the ribose and pyrimidine occurs at position C1[4] of the ribose unit, which contains a pyrophosphate, and N1 of the pyrimidine ring. Orotate phosphoribosyltransferase (a/k/a "PRPP transferase") catalyzes the net reaction yielding orotidine monophosphate (OMP): Orotate + 5-Phospho-α-D-ribose 1-diphosphate (a/k/a "PRPP") = Orotidine 5'-phosphate + Pyrophosphate

What happens to lithium when orotate binds with the ribosyl and is catalyzed into orotidine monophosphate has not been studied, however pyrimidine metabolism happens throughout the body. Historically it was assumed that lithium and orotate separated principally within the brain, however no human studies support this conclusion empirically. One study in rats measured brain plasma levels and found no statistical difference in lithium concentrations between equivalent doses of elemental lithium from lithium carbonate, lithium orotate, or lithium chloride. Another study in rats concluded that "the 24 h brain concentration of lithium after lithium orotate was approximately three times greater than that after lithium carbonate."

It is also worth noting that one study involving patients with kidney stones concluded that orotic acid is precipitated from the kidneys most likely as sodium orotate, due to it's chemical properties; lithium and sodium are both alkali metals, however lithium has greater electronegativity than sodium. If this is correct lithium may stay attached to the orotate molecule, or re-bond to orotic acid, due to its greater affinity. Whatever the case, the authors strongly asserted that orotic acid is not precipitated as a free acid and that orotate salts can be found in kidney stones. Furthermore the FDA literature for lithium carbonate states that “sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity.”, if it is the case that orotate is precipitated as a sodium bonded salt this statement may explain Smith DF's findings from 1979. Additionally if Kling did not account for reduced kidney function this would explain why he noted higher lithium concentrations within the brain during his 1978 study.

Continuing with the metabolic process of orotate, uridine monophosphate (UMP) is formed from Orotidine 5'-monophosphate in a decarboxylation reaction catalyzed by the enzyme orotidylate decarboxylase. Uncatalyzed, the decarboxylation reaction is extremely slow (estimated to occur on average one time per 78 million years). Adequately catalyzed, the reaction takes place in one second.[2] In humans, the orotidylate decarboxylase function is carried out by the protein UMP synthase.[3] Defective UMP synthase can result in orotic aciduria, a metabolic disorder.

As previously stated, lithium is, at least initially, non-covalently bonded to orotate via this carboxyl group. It is not known if it is still attached prior to decarboxylation, separates during decarboxylation, interacts with decarboxylation, or inhibits decarboxylation. Hypothetically if UMP synthase was inhibited by lithium orotate it should produce the same symptoms of orotic aciduria, no cases of this have been reported. Another hypothetical is that if the carboxyl group stayed attached to the metal complex you could be left with CO2- * Li+ * H2O, which maybe would convert itself into HCO3 + H2, which is lithium bicarbonate and dihydrogen respectively. All of this is speculation, lithium orotate may not even make it through the gastric track intact.

The ratio of elemental lithium to lithium orotate is 25.94, this number is derived by dividing the molar mass of lithium orotate monohydrate by the molar mass of elemental lithium. Likewise, 5.32 is the ratio of elemental lithium to lithium carbonate, 7.04 for lithium citrate, 7.92 for lithium sulfate, and 20.03 for lithium aspartate.

While it is well established that lithium can induce nephropathy in high doses, one study conducted with rats documented additional kidney function impairment with lithium orotate relative to an equivalent dose of elemental lithium from lithium carbonate (“2 mmol lithium kg-1”), which if derived correctly implies a lithium orotate dosage of 934 mg/kg. The LD50 of orotic acid in mouse is 2000 mg/kg[ref:Aldrich], indicating a possible error in the study. Another study in cats documented nephropathy after administration of orotic acid, and in this instance the average dose of orotic acid was 450 mg/kg. At first glance this appears damning, however orotic acid is an essential molecule produced by the body and these studies were conducted with extremely high dosages; using an average adult weight of 62 kg, dosing at 450 mg/kg would equate to 27900 mg of orotic acid. The point at which the combined effects of orotate and lithium impair kidney function is unknown, however dietary supplement labeling typically recommends a dosage of just 240 mg per day (9.25 mg elemental lithium, 24.02 mg water, 206.73 mg orotate) and no case report or study has indicated adverse events at a dose this low. Individuals with renal impairment should consult a physician before taking this, or any other, supplement.

Lithium orotate administered at a rate equivalent to lithium carbonate, derived from molecular weights, is 4.873 times that of lithium carbonate. For instance, lithium orotate administered at 4386 mg is equivalent to 900 mg of lithium carbonate in terms of elemental lithium. It is not known if this high a dosage is safe and this is one of the reasons why it is not used in the treatment of psychiatric disorders. Emerging research however is indicating that even trace amounts of lithium can have positive effects; at the labeled dose of 240 mg, lithium orotate is capable of delivering roughly 24 times the amount of elemental lithium that was measured in one study. Furthermore if lithium is somehow incorporated into DNA, RNA, or protein synthesis by way of the orotate bond it could in fact be more bioavilable than any other form of lithium. Little is known about the pharmacokinetics of lithium orotate, as the psychiatric community abandoned it when the FDA approved lithium carbonate and lithium citrate for the treatment of mania, circa 1970s.

Ideas, Tests, Hypos, Applications:

• Lithium salt serum test strips (orotate salts are precipitated through kidneys).
• 14C radiocarbon of orotate salts to study for incorporation into proteins.
• Lithium orotate as a medicine to correct conditions causing alkaline urine.
• Lithium orotate adjunct to lithium carbonate (compounding to two).
• Acute injections of lithium orotate for the rapid control of mania in emergency care settings.
• Orotate coordinations for the delivery of drugs in vitro via ODCase decarboxylation and pyrimidine salvage pathway recycling.