Editing Lithium orotate

{{short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 450705490
| image = Lithium-orotate-2D-skeletal.png
| image_class = skin-invert-image
| image2 = Lithium-orotate-from-xtal-3D-balls.png

<!--Clinical data-->
| tradename =  
| Drugs.com = {{drugs.com|monograph|lithium-salts}}
| legal_status = OTC
| routes_of_administration = Oral
| pregnancy_US      = X

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = L2N7Z24B30
| CAS_number = 5266-20-6
| PubChem = 23686432
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID      = 71254
| smiles            = [Li+].O=C([O-])\C1=C\C(=O)NC(=O)N1
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI          = 1S/C5H4N2O4.Li/c8-3-1-2(4(9)10)6-5(11)7-3;/h1H,(H,9,10)(H2,6,7,8,11);/q;+1/p-1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey       = IZJGDPULXXNWJP-UHFFFAOYSA-M

<!--Chemical data-->
| C=5 | H=3 | Li=1 | N=2 | O=4
}}

'''Lithium orotate''' (C<sub>5</sub>H<sub>3</sub>LiN<sub>2</sub>O<sub>4</sub>) is a [[salt (chemistry)|salt]] of [[orotic acid]] and [[lithium]]. It is available as the monohydrate, LiC<sub>5</sub>H<sub>3</sub>N<sub>2</sub>O<sub>4</sub>·H<sub>2</sub>O.<ref>{{cite journal | vauthors = Bach I, Kumberger O, Schmidbaur H | title = Orotate complexes. Synthesis and crystal structure of lithium orotate( - I) monohydrate and magnesium bis[ orotate( - I)] octahydrate | journal = [[Chemische Berichte]] | year = 1990 | volume = 123 | issue = 12 | pages = 2267–2271 | doi = 10.1002/cber.19901231207 }}</ref>  In this compound, lithium is non-covalently bound to an [[Orotic acid|orotate]] [[ion]], rather than to a [[carbonate]] or other ion, and like other salts, dissolves in solution to produce free lithium ions. It is marketed as a [[dietary supplement]], though it has been researched minimally between 1973–1986 to treat certain medical conditions, such as [[alcoholism]]<ref name="sartori">{{cite journal | vauthors = Sartori HE | title = Lithium orotate in the treatment of alcoholism and related conditions | journal = Alcohol | volume = 3 | issue = 2 | pages = 97–100 | year = 1986 | pmid = 3718672 | doi = 10.1016/0741-8329(86)90018-2 }}</ref> and [[Alzheimer's disease]].

While lithium orotate is capable of providing lithium to the body,<ref>{{cite journal | vauthors = Pacholko AG, Bekar LK | title = Lithium orotate: A superior option for lithium therapy? | journal = Brain and Behavior | volume = 11 | issue = 4 | year = 2021 | pages = e2262 | doi = 10.1002/brb3.2262 | pmid = 34196467| pmc = 8413749 }}</ref> like lithium carbonate and other lithium salts, there are no [[systematic reviews]] supporting the efficacy of lithium orotate and it is not approved by the U.S. [[Food and Drug Administration]] (FDA) for the treatment of any medical condition.

==Effectiveness==
In 1973, [[Hans Alfred Nieper|Hans Nieper]] reported that lithium orotate contained 3.83&nbsp;mg of elemental lithium per 100&nbsp;mg and lithium carbonate contained 18.8&nbsp;mg of elemental lithium per 100&nbsp;mg.<ref name="Nieper">{{cite journal | vauthors = Nieper HA |authorlink=Hans Alfred Nieper|title=The clinical applications of lithium orotate. A two years study |url=https://books.google.com/books?id=iuNKAAAAYAAJ|journal=Agressologie |volume=14 |issue=6 |pages=407–11 |year=1973 |pmid= 4607169}}</ref> Nieper went on to claim that lithium did not dissolve from the orotate carrier until it passed through the [[blood–brain barrier]]; 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.<ref name="smith">{{cite journal | vauthors = Smith DF | title = Lithium orotate, carbonate and chloride: pharmacokinetics, polyuria in rats | journal = British Journal of Pharmacology | volume = 56 | issue = 4 | pages = 399–402 | date = April 1976 | pmid = 1260219 | pmc = 1666891 | doi = 10.1111/j.1476-5381.1976.tb07449.x }}</ref> However, another study in 1978 study showed that eight hours after intraperitoneal injections brain lithium concentrations of rats were significantly greater after lithium orotate than after lithium carbonate. While little serum lithium remained at 24 h after injection of 2·0 m equiv kg−1 lithium carbonate, two‐thirds of the 2 h serum lithium concentration was present 24 h after lithium orotate. Furthermore, the 24 h brain concentration of lithium after lithium orotate was approximately three times greater than that after lithium carbonate. These data suggest the possibility that lower doses of lithium orotate than lithium carbonate may achieve therapeutic brain lithium concentrations and relatively stable serum concentrations.<ref>{{cite journal | vauthors = Kling MA, Manowitz P, Pollack IW | title = Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate | journal = The Journal of Pharmacy and Pharmacology | volume = 30 | issue = 6 | pages = 368–370 | date = June 1978 | pmid = 26768 | doi = 10.1111/j.2042-7158.1978.tb13258.x | s2cid = 28459663 }}</ref> A year later, Smith and Schou repeated the experiment at a higher dose (2 mM Li+) and found that the higher concentrations in the brain could be possibly accounted for by decreased renal function in rats treated with lithium orotate.<ref>{{cite journal | vauthors = Smith DF, Schou M | title = Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate | journal = The Journal of Pharmacy and Pharmacology | volume = 31 | issue = 3 | pages = 161–163 | date = March 1979 | pmid = 34690 | doi = 10.1111/j.2042-7158.1979.tb13461.x | s2cid = 8691638 }}</ref><ref name="Pacholko2021">{{cite journal | vauthors = Pacholko AG, Bekar LK | title = Lithium orotate: A superior option for lithium therapy? | journal = Brain and Behavior | volume = 11 | issue = 8 | pages = e2262 | date = August 2021 | pmid = 34196467 | pmc = 8413749 | doi = 10.1002/brb3.2262 | s2cid = 235697871 }}</ref> The proponents of lithium orotate have since criticized the results by citing the fact that the dose of lithium orotate used in the study was in the toxic range. In 2022, Pacholko redid the experiment and showed lithium orotate to have a safer kidney profile than lithium carbonate, it also showed that both had an increased [[Thyroid-stimulating hormone|TSH]] only in females, but the increase was lower in the orotate group.<ref name="Pacholko2022">{{Cite bioRxiv | vauthors = Pacholko AG, Bekar LK |date=2022-05-01 |title=Lithium orotate is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania |language=en |biorxiv=10.1101/2022.05.01.490227}}</ref>

The pharmacokinetics of lithium orotate in human brains is poorly documented, and there is no known mechanism by which orotate ions could alter the pharmacokinetics of dissociated lithium ions, however, lithium intake appears to be effective even at low doses, and this may account for lithium orotate's claimed effectiveness.<ref name="zervas">{{cite journal | vauthors = Alevizos B, Alevizos E, Leonardou A, Zervas I | title = Low dosage lithium augmentation in venlafaxine resistant depression: an open-label study | journal = Psychiatrike = Psychiatriki | volume = 23 | issue = 2 | pages = 143–148 | year = 2012 | pmid = 22796912 }}</ref><ref name="buck">{{cite journal | vauthors = Nunes MA, Viel TA, Buck HS | title = Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease | journal = Current Alzheimer Research | volume = 10 | issue = 1 | pages = 104–107 | date = January 2013 | pmid = 22746245 | doi = 10.2174/156720513804871354 }}</ref><ref name="mcgorry">{{cite journal | vauthors = Berger GE, Wood SJ, Ross M, Hamer CA, Wellard RM, Pell G, Phillips L, Nelson B, Amminger GP, Yung AR, Jackson G, Velakoulis D, Pantelis C, Manji H, McGorry PD | display-authors = 6 | title = Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study | journal = Current Pharmaceutical Design | volume = 18 | issue = 4 | pages = 570–575 | year = 2012 | pmid = 22239590 | doi = 10.2174/138161212799316163 }}</ref>

The reason why lithium orotate is poorly studied as a medication compared to lithium carbonate is concerns raised in 1979 regarding the potential amplified renal toxicity of lithium orotate in comparison to lithium carbonate.<ref name="pmid34196467"/> These concerns were likely based on the results of the use of excessively high concentrations of lithium orotate in the studies. As a result of these concerns, the clinical application and research of lithium orotate were halted for decades since the 1980s.<ref name="pmid34196467"/> Still, interest in lithium orotate has been rekindled, and research into its use as medication was resumed in the 2010s.<ref name="pmid34196467"/> The renewed interest is largely due to its purported ability to achieve higher serum and brain lithium-ion (Li+) concentrations than those observed from equivalent doses of lithium carbonate, a claim first made in 1978.<ref name="pmid34196467">{{cite journal |vauthors=Pacholko AG, Bekar LK |title=Lithium orotate: A superior option for lithium therapy? |journal=Brain Behav |volume=11 |issue=8 |pages=e2262 |date=August 2021 |pmid=34196467 |pmc=8413749 |doi=10.1002/brb3.2262}}</ref>

==Safety==
Preliminary studies seem to indicate that lithium orotate is safe if taken at lower dosages; a 6 month alcoholism cessation study led to only minor adverse effects in 8 out of 42 patients.<ref name="sartori" /> However, the lack of safety studies and the [[Over-the-counter drug|OTC]] status raises concerns.<ref name="Pacholko2021" /> Attention to it was specially raised in medical literature after a case report of an 18 year old woman with mild, acute lithium toxicity after taking an overdose (2.16 grams) of a lithium orotate supplement. She was discharged after treatment.<ref>{{cite journal | vauthors = Balon R | title = Possible dangers of a "nutritional supplement" lithium orotate | journal = Annals of Clinical Psychiatry | volume = 25 | issue = 1 | pages = 71 | date = February 2013 | pmid = 23376874 }}</ref><ref name=":0">{{cite journal | vauthors = Pauzé DK, Brooks DE | title = Lithium toxicity from an Internet dietary supplement | journal = Journal of Medical Toxicology | volume = 3 | issue = 2 | pages = 61–62 | date = June 2007 | pmid = 18072162 | pmc = 3550087 | doi = 10.1007/bf03160910 }}</ref><ref>{{cite journal| vauthors = Kwan D, Beyene J, Shah PS |title=Adverse Consequences of Internet Purchase of Pharmacologic Agents or Dietary Supplements|journal=Journal of Pharmacy Technology|date=1 November 2009|volume=25|issue=6|pages=355–360|doi=10.1177/875512250902500602|s2cid=70625804}}</ref> Lithium blood levels 90 minutes after ingestion reached 0.31 mEq/L, and an hour later after treatment, 0.40 mEq/L, levels below the serum toxicity level of 1.5 milliequivalents per liter (mEq/L).<ref name=":0" /><ref>{{cite book | vauthors = Hedya SA, Avula A, Swoboda HD | chapter = Lithium Toxicity |date=2023 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK499992/ |title = StatPearls |access-date=2023-04-13 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29763168 }}</ref> 

Orotic acid can be [[mutagen]]ic in very high doses of 50 mg/kg in mammalian somatic cells.<ref>{{Cite news|url=https://www.nutraingredients.com/Article/2009/07/30/Vitamin-B13-cannot-be-proven-safe-says-EFSA#|title=Vitamin B13 cannot be proven safe, says EFSA|work=nutraingredients.com|access-date=2018-10-08|language=en-GB}}</ref> It is also mutagenic for bacteria and yeast.<ref>{{Cite web |date=2013-05-21 |title=Material Safety Data Sheet - Orotic Acid, anhydrous MSDS |url=http://www.sciencelab.com/msds.php?msdsId=9926339 |url-status=dead |archive-url=https://web.archive.org/web/20180120182143/http://www.sciencelab.com/msds.php?msdsId=9926339 |archive-date=2018-01-20 |website=ScienceLab.com}}</ref> Although lithium orotate was not shown to be genotoxic,<ref name="Murbach2021">{{cite journal | vauthors = Murbach TS, Glávits R, Endres JR, Hirka G, Vértesi A, Béres E, Szakonyiné IP | title = A toxicological evaluation of lithium orotate | journal = Regulatory Toxicology and Pharmacology | volume = 124 | pages = 104973 | date = August 2021 | pmid = 34146638 | doi = 10.1016/j.yrtph.2021.104973 | s2cid = 235485928 | doi-access = free }}</ref> short and long term studies must be performed to guarantee public safety.<ref name="Pacholko2021" />

== See also ==
* [[Lithium (medication)]]
* [[Lithium carbonate]]
* [[Lithium citrate]]
* [[Lithium aspartate]]

== References ==
{{Reflist|2}}

== External links ==
* {{Cite web |title=Ask the Mental Health Expert |publisher=Ron Pies, M.D., clinical professor of psychiatry at Tufts University |date=December 2002 |url=http://www.healthieryou.com/mhexpert/exp1121602b.html |url-status=dead |archive-url=https://web.archive.org/web/20180724123607/http://www.healthieryou.com/mhexpert/exp1121602b.html |archive-date=2018-07-24}}

{{Mood stabilizers}}
{{Lithium compounds}}

{{DEFAULTSORT:Lithium Orotate}}

[[Category:Alternative medical treatments]]
[[Category:Lithium compounds]]
[[Category:Mood stabilizers]]