Posted by Dr. Bob on December 22, 2003, at 16:35:31
In reply to Re: Lithium Orotate « BarbaraCat, posted by Dr. Bob on September 13, 2003, at 15:58:58
[Posted by Michael Motter on December 21, 2003, at 19:30:23]
> I previously posted my abstract for this but had some requests to post the full article I wrote. I hope this can be helpful to others. Please email me if you have any questions. mottermx@jmu.edu
>
> What is Lithium Orotate?
> By Michael Motter
> Pre-Doc Psychology Student
> James Madison University
>
>
>
> About Lithium Orotate:
>
> Lithium orotate is a popular nutritional supplement that has been marketed in the United States under such names as “Serenity” (www.findserenitynow.com), “Advanced Research” (www.betterlife.com), and “Life Link” (www.nubrain-store.com) to name a few of the many brands that can be found via the internet. Many of these websites claim that lithium orotate is a natural alternative to mood stabilizer and antidepressant medication without any side effects. They claim that lithium orotate can benefit anyone who has migraine headaches, alcoholism, bipolar disorder, depression, or epilepsy.
>
> These claims are backed by the research of Dr. Hans A. Nieper, a German physician, who first studied the use of lithium orotate for migraine headaches, alcoholism, depression, and epilepsy. Dr. Nieper’s article The Clinical Applications of Lithium Orotate: A Two Years Study (1973) concluded that lithium orotate is an effective treatment for migraine headaches, alcoholism, depression, and epilepsy. However, caution should be exercised when interpreting these conclusions. His findings are based on correlational studies and the subjective reports of his patients. Dr. Nieper simply administered lithium orotate to 64 patients that had been diagnosed with the various disorders discussed and used their subjective accounts as evidence of its effectiveness. There is no control group in which he made a comparison to or mention of how he went about controlling for extraneous variables that could have also accounted for their improvement. Thus, we have no idea if it was the lithium orotate or some other factor that accounted for his patient’s improvement. Other research by Satori (1986) suffers from the same flaws. His work supports Nieper’s claim that lithium orotate is an effective treatment for alcoholism and migraine headaches. Again all evidence is based on subjective report and there is no control group in which he compares his findings.
>
> What is Lithium:
>
> Lithium is a mineral or more specifically an alkali metal that is present in the human diet in ultratrace quantities and is also found in some natural mineral waters (Physicians Desk Reference, 2003). The typical daily dietary intake of lithium is approximately 200 to 600 micrograms. Fish, processed meat, milk, milk products, eggs, potatoes and vegetables are rich sources of this mineral. In the United States lithium carbonate and lithium citrate are approved by the FDA for the clinical treatment of bipolar disorder (Food & Drug Administration, 2003). Carbonate (carbonic acid) and citrate (citric acid) are mineral carriers that transport lithium throughout the body. According to Yung (1984) many physicians have also begun to prescribe lithium carbonate and citrate for the “off label” treatment of migraine headaches, seizure disorders, and psychosis. It is important to note that “off label” usage is generally considered an option only after all traditional treatment methods have failed and it is not approved by the FDA.
>
> How it Works:
>
> Lithium is administered orally and is generally taken with food, although its absorption is not markedly affected by the presence of food (Physicians Desk Reference, 2003). According to McKim (2003) lithium carbonate, citrate, and orotate is administered orally and therefore it passes through the stomach into the gastrointestinal tract where it is absorbed by the capillaries into the blood stream. These minerals are then absorbed rapidly into the blood stream (80-100%). Peak levels in the blood occur between a half-hour and two hours with citrate and carbonate. Once in the blood it travels to the brain where it must cross the cell membrane or blood brain barrier. Lithium carbonate and citrate cross the blood brain barrier via active transport. Lithium levels in the blood need to be elevated so that there is enough of it to pass through the membrane in order to be therapeutic. Mckim (2003), reports that no one knows for certain but it is theorized that lithium ions concentrate outside of the membrane causing the potential to become less negative and causing depolarization. The voltage gated ion channels open which allow the sodium ions to rush in. It is hypothesized that the lithium ions replace sodium ions and cross through the blood brain barrier resulting in neutralization of the resting potential.
>
> According to McKim (2003) lithium carbonate and citrate therapy requires reaching serum concentrations of lithium that are close to the toxic concentration. Lithium Carbonate and Citrate therapy requires serum levels of 1.0-1.5 mEq/L for acute mania and 0.6 – 1.2mEq/L for maintenance. During treatment lithium serum concentrations should not usually exceed 1.5 mEq/L. Mild to moderate toxic reactions may occur at lithium concentrations from 1.5 to 2 mEq/L, and moderate to severe reactions at concentrations above 2 mEq/L. Serum lithium concentrations should usually be monitored 3 times weekly and blood studies and urinalysis weekly during the initial period of administration and periodically as required thereafter.
>
> Lithium orotate is administered orally and therefore it passes through the stomach into the gastrointestinal tract where it is absorbed by the capillaries into the blood stream. According to Nieper (1973) digestion breaks off the lithium mineral from the lithium compound when lithium is attached to carbonate and citrate which is then absorbed rapidly into the blood stream. Therefore, lithium orotate is coated with a special coating which supposedly protects the lithium orotate while it passes through the stomach acids. This coating protects the compound and allows it to be absorbed by the capillaries into the bloodstream with most of the lithium still bound to the orotate. According to Nieper (1973) the orotate carriers show a special affinity for tissues in which metabolism involves the blood brain barrier. Orotate supposedly uses passive transport to cross through the blood brain barrier. Because the lithium is still mostly attached to the orotate carrier, it diffuses across the membrane releasing the lithium to the other side and leaving little left in the blood stream.
>
> Nieper (1973) reports that a mineral analysis of his patients whole blood and blood serum found that lithium orotate does not cause the approximate level of 0.02 ppm lithium in normal blood or serum to be exceeded by more than 30% (0.026 ppm). Lithium carbonate contains 18.8mg of elemental lithium per 100mg per 100mg (57mg per 300mg, 113mg per 600mg). Most lithium orotate compounds contains 3.83mg of elemental lithium per 100mg (4.8mg per 120mg). Lithium carbonate can cause serum to rise an average of 0.2 to 0.4 mEq/L after intake of 300 mg and 0.3 to 0.6 mEql/L after intake of 600 mg of lithium carbonate. It appears that lithium orotate does not contain enough elemental lithium per recommended dosage to cause lithium serum concentrations to rise beyond toxic levels. This may explain why they claim that lithium blood serum monitoring is unnecessary. It also raises the questions whether there is even enough lithium to cause any type of therapeutic effect.
>
> Nieper (1973) claims that lower elemental doses of lithium can be administered when attached to orotate because most of the lithium doesn’t dissolve from the carrier until it passes through the blood brain barrier. Therefore, all of the lithium (theoretically enough to be therapeutic) goes to the brain and a minimal amount gets left behind in the blood. Thus the amount of lithium that enters into the bloodstream doesn’t reach toxic levels and doesn’t need to be monitored.
> Lithium is excreted via the kidneys (renally). It is excreted rapidly and several daily doses are needed to maintain the therapeutic level. It is not metabolized; approximately 95% is renally excreted (saliva, sweat, feces 5%). Lithium is excreted unchanged in the urine. Renal excretion is biphasic, with rapid clearance of up to two-thirds within 6-12 hours followed by a slower elimination over the next twelve hours. The overall half-life is between 12 and 24 hours. The excretion rate varies considerably among individuals and increases with age. Half-life in geriatric patients and patients with impaired renal function is increased to 36 to 50 hours.
> What Are The Side Effects:
>
> Nieper (1973) claims that because of the low amount of lithium in the blood serum, the common side effects of lithium carbonate and citrate which include: diarrhea, frequent urination, dehydration, lethargy, nausea, skin rashes, tremor, thyroid dysfunction, and weight gain supposedly do not occur. The low levels also claim to make it safe for use with antithyroid, asthma, bronchitis, cystic fibrosis, emphysema, non-steroidal anti-inflammatory drugs (NSAID’s), and sinusitis medication and diuretics which may cause interactions with lithium carbonate or citrate. It gives no mention of antipsychotic medication which can have interactions with lithium carbonate and citrate (McKim, 2003).
>
> Nieper (1973) claims that lithium orotate does not have renal side effects because of its low dose. However, research conducted by Smith and Schou (1979) found that kidney functioning and urine flow were markedly lower in rats given a intraperitoneal injection (2 mmol lithium kg-1) of orotate than rats given carbonate, sodium chloride, or a sham injection. Renal lithium clearance was significantly lower. Kidney weight and lithium concentrations in serum kidney and heart were significantly higher in the orotate group which may be caused by the lower kidney functioning. Smith and Schou concluded that lithium orotate was not recommended as safe for humans. Smith (1976) reports that the pharmacokinetics of the lithium ion given as lithium orotate do not differ from lithium chloride or lithium carbonate when administered in rats. Though excessive secretion of urine and excessive thirst developed more slowly in rats given lithium orotate than in those given lithium carbonate or lithium chloride. Lithium orotate is recommended to be unsafe during pregnancy and breast feeding. Lithium passes into milk and its use should be avoided during lactation as concentrations are 33 to 50% of those in the mother's serum (McKim, 2003). Several anecdotal accounts of lithium orotate were found on internet chat rooms claiming that lithium orotate caused depression.
>
>
> Comparison of the Different Forms of Lithium:
>
> An overall comparison of the differences in costs, research efficacy, and side effects between lithium orotate and lithium carbonate or citrate shows that there is considerable difference in these three areas. The cost of lithium orotate varies depending on the website where it is purchased. For ninety 120mg tablets of Serenity the monthly cost is $39.99 per month or approximately $0.44 per pill. Two-hundred 120mg tablets of Advanced Research costs $12.99 per month or approximately $0.06 per ill. One hundred 135mg tablets of Life Link totals $12.00 per months or approximately $0.12 per pill. One hundred and fifty 300mg tablets of lithium carbonate or citrate on the other costs approximately $25.00 per month or almost $0.17 per pill.
>
> Dr. Nieper and Dr. Sartori’s claims are based only on subjective case study reports. A search on the National Library of Medicine’s (2003) website indicate that there have been no double-blind controlled studies on the effects of lithium orotate for any medical or health related purposes. Thus the claims made by Dr. Nieper and Dr. Satori are based on weak scientific evidence. Smith (1976) reports that pharmacokinetics of the lithium orotate do not differ from lithium chloride or lithium carbonate when administered in rats. Furthermore, according to Garbutt, West, Carey, Lohr, & Crews (1999) suggestions that it might be useful in treating alcoholism are unfounded. Lithium is not useful for treating patients who have alcohol dependence without other psychiatric conditions. There is limited research on the effects of lithium in primary alcoholics without comorbid mood disorders. According to Picket & O’Dell (1992) there is no credible research to support the supplemental or medically unsupervised use of lithium for any purpose. There are no indications for the supplemental use of lithium. If lithium dosage is too low, you will derive no benefit. There is little research on the claims that lithium orotate is absent of the side effects that accompany lithium carbonate or citrate. What research has been done by Smith and Schou (1979) indicates that the renal side effects of lithium orotate may be more severe than carbonate or citrate in rats.
> Lithium orotate is not regulated by the FDA. It is marketed as a “dietary supplement”. According to Dietary Supplement Health and Education Act (DSHEA) of 1994 (Food & Drug Administration, 2003) a dietary supplement is
> a product taken by mouth that contains a dietary ingredient intended to supplement the diet. The dietary ingredients in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders (page 1).
> Because it is not regulated by the FDA the claims that the various companies make about it’s effectiveness are not regulated by the government but instead by the company. A company is responsible for determining that its products are safe and that claims they make about them are substantiated by adequate evidence to show that they are not false or misleading. This means that the supplements do not need approval from FDA before they are marketed. Companies do not have to provide the FDA with the evidence it relies on to substantiate safety or effectiveness before or after it markets its products. In addition it is also interesting to note that Dr. Nieper has a history with the federal government. The 1994 FDA Import Alert states that Dr. Nieper was accused of importing numerous drugs into the United States without FDA approval (FDA, 1994).
> Conclusion:
> In conclusion there is some of anecdotal evidence that lithium orotate is an effective treatment for the various health concerns it claims to help. However, there have been no controlled research studies that validate these claims. Why Dr. Nieper never followed up his patients claims with more rigorous research remains a mystery. Is it possible that he was merely a “snake-oil” salesman trying to make a quick buck or is there something we are missing? It appears that many in the complementary and alternative healing community believe that there is something missing in modern medicine that does not fully address our health concerns. But even if this is the case and lithium orotate is beneficial, then it would seem logical to pursue further research. This would not only validate their claims but also reduce the risk of harm. Harm that has all too often occurred in the absent minded world of nutritional supplements, see ephedra and phen/fen.
>
> References
> Food & Drug Administration (1994). Automatic Detention of New Drugs Promoted by
> Dr. Hans Nieper of West Germany. Retrieved June 26, 2003 from www.fda.gov/ora/fiars/ora import ia6628.html
>
> Food & Drug Administration (2003). Dietary Supplement Health and Education Act
> (DSHEA) of 1994. Retrieved June 26, 2003 from www.cfsan.fda.gov
>
> Garbutt, J.C., West, S.L., Carey, T.S., Lohr, K.N., & Crews, F.T. (1999).
> Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA, 281(14), 1318-25.
>
> McKim, W. A. (2003). Drugs & Behavior: An Introduction to Behavioral
> Pharmacology (5th ed.). Upper Saddle River, New Jersey: Prentice Hall.
>
> Nieper, H. A. (1973). The clinical applications of lithium orotate: A two year study.
> Agressologie, 14(6), 407-411.
>
> Physicians Desk Reference (2003). Lithium. Retrieved June 25, 2003 from
> www.pdrhealth.com
>
> Pickett, E.E., & O'Dell, B.L. (1992). Evidence for dietary essentiality of lithium in the
> rat. Biol Trace Elem Res, 34, 299-319.
>
> Satori, H.E. (1986). Lithium orotate in the treatment of alcoholism and related
> conditions. Alcohol, 3(2), 97-100.
>
> Smith, D. F. (1976). Lithium orotate, carbonate and chloride: pharmacokinetics,
> polyuria in rats. British Journal of Pharmacology, 56, 399-402.
>
> Smith, D. F., Schou, M. (1979). Kidney function and lithium concentrations of rats
> given an injection of lithium orotate or lithium carbonate. Journal of
> Pharmaceutical Pharmacology, 31(3), 161-163.
>
> Yung, C.Y. (1984). A review of clinical trials of lithium in neurology. Pharmacology,
> Biochemistry, & Behavior. 21, 1, 57-64.
>
>
> Further Readings
>
>
> Kling, M. A., Manowitz, P., Pollack, I.W. (1978). Rat brain and serum lithium
> concentrations after acute injections of lithium carbonate and orotate. Journal of
> Pharmaceutical Pharmacology, ;30(6), 368-70.
>
> Nieper, H. A. (1999). The Curious Man. Avery Publishing Group.
>
>
>
poster:Dr. Bob
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