lithium orotate

It has been some time since a chemical story has come to my attention. When a colleague suggested that lithium orotate is "better" than lithium carbonate, I felt compelled to investigate.

Lithium in its drug form comes in many names.
(lithium or lithium carbonate or calith or camcolit* or carbolit* or ceglution or duralith or durolith or eskalith or hypnorex or hynorex or hyponrex or lentolith or licab or licarb or licarbium or lidin or lilipin or li?liquid or li-liquid or lilitin or limas or liskonum or litarex or lithan or lithane or litheum or lithicarb or lithionate or lithizine or lithobid or lithocarb or lithocap or lithonate or lithosun or lithotabs or litheril or litilent or manialit* or maniprex or phanate or phasal or plenur or priadel or quilonium or quilonorm or quilonum or teralithe or theralite)

Oral doses of lithium in the soda 7 Up, originally named "Bib-Label Lithiated Lemon-Lime Soda," were available from 1929 to 1940 in the form of lithium citrate.

Within the review by Fairweather-Tait and Hurrell, it was reported that Schlebusch, et al. found magnesium orotate to have a higher bioavailability than magnesium hydroxycarbonate.  Other studies reported magnesium oxide with a lower bioavailability than magnesium citrate or magnesium aspartate, and magnesium from foods is as bioavailable as magnesium acetate, but the bioavailability of magnesium chloride is much lower than food or the acetate salt.  The study by Schlebusch was based on 14 healthy male volunteers with 5 samples collected over a 12 hour period. Hardly a large-scale clinical trial.

Andermann and Dietz compared three forms of zinc in rabbits.  They found zinc pantothenate and zinc sulfate were not significantly different (bioequivalent) whereas the plasma concentration after injection with zinc orotate had a faster distribution and elimination.  With oral administration, zinc orotate had a slower absorption phase, compared with that of the other two salts.  Magnesium and zinc are not the same ion as lithium, neither in size nor charge.

Balon wrote a letter to the editor of Annals of Clinical Psychiatry to share his opinion that lithium orotate, for self-diagnosed bipolar disorder is dangerous because this preparation is unregulated by the FDA and has not been fully investigated for toxicity in acute overdose and the long-term effects to the thyroid and kidney.  Lithium orotate is readily available online or over the counter.

Smith, A. J. et al. reported in 2014 the investigation of lithium salicylate and lithium lactate, which have markedly different pharmacokinetics than the more common FDA-approved salt, lithium carbonate.  Lithium salicylate produced elevated plasma and brain levels of lithium beyond 48 hours post-dose without a sharp peak, which is currrently observed with lithium carbonate.

Sartori reported in the journal Alcohol in 1986 with a group of 42 alcholic patients (33 males and 9 females) that treatment with lithium orotate proved useful as the main pharmacologic agent for the treatment of alcoholism.  The conclusion of the study was that a daily dose (150mg) given 4-5 times weekly was sufficient to for side-effects to subside, which included muscle weakness, loss of appetite or mild apathy.  Further advantages to lithium therapy included improved liver and cardiovascular function, reduction of migraine headaches, amelioration of seizures, improved white blood cell counts in leukopenia, reduction of edema in liver cirrhosis, suppression of manic episodes, and reversal of hyperthyroidism.  Does lithium orotate sound like a wonder drug to you?

In the review by O'Donnell and Gould, the mode of action of lithium is explored, shown in the above diagram (Fig.1).  This review focuses on the action of lithium carbonate in rodents (rat, mouse).  It is easier to investigate drug action in small mammals because they fit easily in laboratory shelves and can be sacrificed when it is time to harvest organs for analysis.  Rodents are easier to control in terms of diet and exercise, to isolate the variable of interest.  Transgenic mice or pharmacological

probes can be used to investigate how the factors associated with clinical disorders are reflected in the behavior of laboratory animals, which is where our current understanding of genetics, cell and molecular biology are advancing the field.  However since it is impossible to ask a mouse how it is feeling, it is difficult to use rodents to measure the efficacy of a mood disorder treatment.

Lastly, I wanted to discuss a meta-analysis conducted by Andrea Cipriana, et al. which aims to include studies on human subjects (sample size ranging between 4 patients to 418 patients).  This study found that lithium was associated with a reduced risk of suicide (by more than 60%) and a reduced risk of self-harm.  The side-effects of lithium included reduced renal (kidney) function, hypothyroidism, hyperparathyroidism, and weight gain.  Although this study does not address the bioavailability of lithium carbonate versus lithium orotate, it does show that lithium has its uses in the treatment of affective disorders.

After all this scientific research, I consulted the resource most people turn to nowadays, Wikipedia. The page connected some dots for me, since I am not an expert in clinical psychiatry or pharmacokinetics.  "Major medical research has not been conducted on lithium orotate since the 1980s due to...the abundant availability of lithium carbonate."  Through the Wikipedia page, I found the article by D. F. Smith, which showed no differences between three forms of lithium (orotate, carbonate, and chloride) but only studied 4-9 rats at a time.  This small sample size is not too convincing.  A nice story of the history of lithium carbonate is told by the RSC in a podcast you can download here originally posted on 25 April 2012.

References:

Andermann, G. and Dietz, M. "The bioavailability and pharmokinetics of three zinc salts: zinc pantothenate, zinc sulfate, and zinc orotate." European Journal of Drug Metabolism and Pharmacokinetics (1982) Vol. 7, Iss. 3, p. 233-239.

Balon, R. "Possible dangers of a 'nutritional supplement' lithium orotate" Annals of Clinical Psychiatry (2013) Vol. 25, No. 1, p. 71.

Cipriana, A.; Hawton, K.; Stockton, S.; Geddes, J. R. "Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis" British Medical Journal (2013) Vol. 346, doi: http://dx.doi.org/10.1136/bmj.f3646

Digital Deli, The. Golden Age Radio Spotlight on Advertising. http://www.digitaldeliftp.com/LookAround/advertspot_7-up.htm (accessed March 3, 2015)

Fairweather-Tait, S. and Hurrell, R. F. "Bioavailability of minerals and trace elements" Nutrition Research Reviews (1996) Vol. 9, p. 295-324.

O'Donnell, K. C. and Gould, T. D. "The behavioral actions of lithium in rodent models: leads to develop novel therapeutics" Neuroscience and Behavoiral Reviews (2007) Vol. 31, p. 932-962.

Royal Society of Chemistry. "Chemistry in its element: compounds" by Chemistry World. http://www.rsc.org/chemistryworld/podcast/CIIEcompounds/transcripts/lithium_carbonate.asp (accessed March 3, 2015)

Sartori, H. E. "Lithium orotate in the treatment of alcoholism and related conditions" Alcohol (1986) Vol. 3, Iss. 2, p. 97-100.

Schlebusch, H; Pietrzik, K; Gillesschmogner, G; Zein, A. "Bioavailability of magnesium from magnesiumorotate and magnesiumhydroxycarbonate" Medizinische Welt (1992) Vol. 43, Iss. 6, p.523-528

Smith, A. J.; Kim, S.-H.; Tan, J.; Sneed, K. B.; Sanberg, P. R.; Borlongan, C. V.; Shytle, R. D. "Plasma and brain pharmacokinetics of previously unexplored lithium salts" RSC Advances (2014) Vol. 4, p. 12362-12365.

Smith, D. F. "Lithium orotate, carbonate and chloride: pharmacokinetics, polydipsia and polyuria in rats" British Journal of Pharmacology (1976) Vol. 56, p. 399-402.