OROTATES AND THE MINERAL TRANSPORTERS OF DR. HANS NIEPER
By Ed Sharpe
What's the best way to take mineral supplements? Picolinates? Amino acid chelates? Chelates involving other organic acids such as citrates? Whenever anyone asks my opinion on such matters, I find myself giving an answer they often don't expect: "Try orotates!" The blank looks I usually get in response tell me that most people need some educating on the subject, hence this article.
Orotates are the mineral salts of orotic acid, a natural substance found in our bodies and also in various foods including dairy products. As theorized many years ago by the pioneering German physician Hans Nieper, orotates are a component of a natural system of electrolyte carriers for distributing minerals throughout the body. 1 (A different compartment of this same system uses amino acid complexes such as aspartates and arginates to deliver minerals.) Based on his observations of cells in culture, Nieper concluded that molecules of calcium orotate and magnesium orotate can pass through cell membranes intact without "dissociating" or breaking apart into their component ions, and thereafter release their respective ions only at specific membrane sites within the cell.  Subsequently he extended this principle to include other orotates such as lithium and zinc.
Working at his clinic in Hannover, Germany, Nieper applied his unique discoveries to the treatment of diseases such as cancer, heart disease, multiple sclerosis, and rheumatoid arthritis as well as other autoimmune conditions. Over the course of more than four decades Dr. Nieper treated thousands of patients with his innovative mineral transporters, many apparently with great success. However, in later years he published relatively little in medical journals, preferring instead to reserve his time for treating patients and for presenting occasional seminars about his work to medical professionals and consumers. As a result, his discoveries have been considered controversial by mainstream medicine or simply ignored, at least until recently.
Hans Nieper died in October, 1998 at the age of 70-ironically just at a time when many of his ideas had finally begun gaining wider acceptance. Only a few weeks before his death, in fact, the collected papers from a symposium on the medical uses of magnesium orotate were published in the journal Cardiovascular Drugs and Therapy. Overall, the symposium lent credence to Nieper's claims for the cardiovascular benefits of magnesium orotate while calling for additional human trials. 
How do the orotates work?
That's a complex question necessitating a somewhat detailed discussion of biochemistry and for this reason my explanation has been relegated to an article of its own. See How Orotates Work. For now I'll just state my summary conclusions: There is independent scientific evidence corroborating Nieper's theory of orotates as mineral transporters. In my judgment, the evidence tends to support Nieper's criteria for orotate as an electrolyte carrier, namely, (1) a low dissociation constant, (2) an affinity for specific cellular systems or organs, and (3) a metabolic pathway which liberates the transported mineral within the targeted organ or system. 
Perhaps the recent wave of interest in Dr. Nieper's compounds will inspire further research on the mechanism of transport. Until then there's plenty of evidence for the validity of Dr. Nieper's ideas in previous publications by Nieper and other researchers. The following sections summarize these results on the medical and biological effects of the various mineral orotates, together with a brief discussion of other potential uses. Beyond that, there is direct and compelling evidence from personal experience-see my article Orotates for Weight Loss, Cognitive Enhancement, and Athletic Performance for details. To give but one example, there can be little doubt about the effectiveness of Nieper's products when the majority of people trying calcium orotate as an appetite suppressant can tell almost immediately that it works, just as Nieper said it would.
Of all the macronutrient minerals in the human body, magnesium is the one most likely to be deficient. Magnesium deficiency has been linked to a large number of disorders, including diabetes , hypertension , dementia , and osteoporosis.  Magnesium compounds are medically accepted as helpful for treating migraines, asthma, chronic lung disease, and cardiac conditions such as heart attack and arrhythmias.  Magnesium orotate should be even more effective than other magnesium supplements for such conditions, in view of its enhancement of magnesium transport and its documented benefits    in cardiovascular disorders.
In addition to its cholesterol-lowering and heart-energizing effects, magnesium orotate has also been reported to improve the elasticity of blood vessels.  Using capillarographic recordings Dr. Nieper was able to show that a daily dose of 380 mg magnesium orotate over 15 months was sufficient to normalize or greatly improve the elasticity of peripheral blood vessels in 60 of 64 patients. Such an effect on vessel elasticity suggests the use of magnesium orotate for lowering blood pressure as well as for inhibiting arteriosclerosis.
Dr. Nieper generally combined magnesium orotate with other nutrients for optimal effect. For example, it's known that potassium deficiency is closely linked with magnesium deficiency because magnesium ions are needed to activate an important cellular pump which regulates sodium and potassium levels.   In addition, potassium orotate itself is thought to be beneficial for conditions such as cardiomyopathy and congestive heart failure (see section below on Potassium orotate). So it's not surprising to find that Nieper recommended a combination of magnesium orotate (1.5 to 2.5 grams per day) plus potassium orotate (138 to 300 mg daily) for treating angina and coronary heart disease.  He also suggested adding the pineapple enzyme bromelain (120 to 140 mg per day) to inhibit platelet aggregation and dissolve fibrin clots. The 2- and 4-year mortality rates for patients on this regimen were reportedly reduced by 90% or more compared to patients in other studies who received conventional medications. 
A similar Nieper combination designed for unclogging arteries involved magnesium orotate (1 to 1.5 grams per day) together with carnitine (4 grams per day), selenium (Se-enriched yeast, 300 to 400 mcg per day), bromelain (240 mg daily), and the enzyme serrapeptase 10 to 15 mg per day). See my article on CardioPeptase for additional information.
Finally, it's worth pointing out that magnesium orotate isn't just for heart patients-it's also for healthy athletes. In a double-blind, randomized study,  competitive triathletes were studied after 4 weeks of supplementation with placebo or magnesium orotate.  Blood was collected before and after a test consisting of a 380-meter swim, a 20-km bicycle race, and a 5-km run. Compared to placebo, magnesium orotate caused a greater increase during the test in serum glucose and venous partial pressure of oxygen, and a greater decrease in serum insulin, blood acidity, and serum cortisol. The changes in glucose use and reduction in stress responses occurred without affecting the athletes' competitive potential-quite the reverse, in fact. The exercising athletes had greater endurance as a result of the magnesium orotate supplements. By contrast, a different study in which athletes were supplemented with magnesium oxide (which is relatively poorly absorbed) reported no improvement in exercise performance, attesting to the superior uptake of magnesium in the orotate form compared to the oxide. 
Potassium deficiency is not considered to be common in view of the availability of adequate amounts of this mineral in most diets. Nevertheless, potassium deficiency is known to arise as a secondary consequence of magnesium deficiency.  Another cause of deficiency is the use of potassium-wasting diuretics to control high blood pressure.  Disease states known to be associated with low serum or tissue potassium include diabetes , insulin resistance , and high blood pressure   as well as rheumatoid arthritis  and heart disease. 
Dr. Nieper's original motivation to develop orotic acid as an electrolyte carrier was inspired by results due to E. Bajusz showing that potassium orotate can prevent idiopathic myocardial necrosis in hamsters, while potassium chloride is ineffective.   Nieper subsequently found that potassium orotate was highly effective for alleviating human cardiovascular diseases when combined with magnesium orotate (see discussion in the section below on Magnesium orotate). Even when administered by itself to heart attack patients, potassium orotate has been reported to result in faster recovery of myocardial contractibility than in placebo-treated controls. 
Other reported applications for potassium orotate include acceleration of wound healing  and enhancement of recovery and immune function following surgery.  Although not an antioxidant itself, potassium orotate facilitates the tissue uptake of vitamin C from serum and increases blood levels of reduced glutathione.  Finally, studies in animals have revealed antidepressant, psychostimulant, and anxiety-reducing effects associated with chronic potassium orotate administration.  
Although no absolute need for lithium has yet been established in human nutrition, lithium intake can affect many different systems in the body in a positive way. Lithium is most famous for treatment of manic-depressive disorders. At high doses lithium can depress dopamine release  (which tends to flatten elevated moods), while at lower doses it can stimulate serotonin synthesis  (which gives an antidepressant effect). Although most people don't need treatment for manic-depressive illness, a very large number with mild depression could benefit from low-dose lithium supplements. Recently it's been discovered that lithium has potent neuroprotective effects as well (see the article Lithium increases gray matter in the brain). The hope now is that lithium supplements will prove capable of halting the progress of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, among others.
Lithium is also known for its immune-enhancing and antiviral effects, especially against herpes simplex virus.  It may be equally effective against measles, judging by results obtained in vitro.  The downside to lithium's immune-stimulating activity is that it can also set off autoimmune reactions in susceptible individuals.  For this reason, if you suffer from an existing autoimmune disease such as rheumatoid arthritis or lupus, don't take lithium supplements without first consulting your health care professional.
Another benefit of supplementing with lithium is its insulin-sensitizing effect.  Lithium has been found to decrease blood glucose levels, especially when used in conjunction with insulin or oral glucose-lowering drugs.  Results such as these have led to suggestions that lithium might be useful in treating diabetes.  
As expected in view of the neurological activity of lithium compounds, Dr. Nieper found that lithium orotate in doses of 138 mg 4 to 6 times per week was effective in treating cases of depression, headaches and migraine, epilepsy, and even alcoholism.  The amount of lithium contained in the doses was only a small fraction of the amount conventionally given as therapy for manic-depressive illness, thus avoiding the risk of kidney toxicity typically associated with high-dose lithium. Elsewhere Dr. Nieper reported that 5 mg of lithium in the form of orotate was roughly as effective as 100 mg of lithium in the form of carbonate, giving a 20-fold enhancement of potency thanks to efficient transport of the lithium by its orotate carrier. 
Nieper's results were subsequently confirmed in a group of 42 alcoholic patients who were followed for between 6 months and 10 years.  Treatment with 138 mg of lithium orotate per day resulted not only in a marked decline in alcoholic relapses, but also in improvements in liver, cardiovascular, thyroid, and immune function. Migraines, cluster headaches, manic behavior, and seizure disorders were also reduced among this group. Eight patients reportedly developed muscle weakness, loss of appetite, and mild apathy as a result of treatment, but symptoms disappeared after the dose was reduced to 138 mg 4 to 5 times per week. The improvements in liver function appeared to be due to a synergy between lithium orotate and calcium orotate, both of which were administered to the alcoholic patients with liver disease. For more information on the treatment of liver disorders with a combination of lithium and calcium orotate, see the section below on Calcium orotate.
Note on lithium safety
As mentioned above, lithium in large doses can be toxic, especially to the kidneys. The therapeutic dose of lithium when administered as lithium carbonate is close to the toxic dose (i.e., there is a narrow therapeutic window), and for this reason blood levels and organ function need to be monitored continually. This is true only for lithium carbonate and not for lithium orotate. For example, according to the Physicians' Desk Reference, the recommended dose of lithium carbonate administered for treatment of psychiatric disorders is 300 mg three to four times per day. Since each 300 mg tablet of lithium carbonate provides 56.8 mg of elemental lithium, the total amount of lithium delivered would range from 170.4 mg to 225.6 mg per day. By contrast one lithium orotate tablet delivers 5.8 mg elemental lithium, which is roughly 1/30 to 1/40 the amount delivered by the recommended daily dose of lithium carbonate. Even taking several lithium orotate tablets per day would amount to a dose well below the toxic level for lithium.
Similarly, consumers of lithium carbonate are often warned of possible toxic effects if other medications such as ACE inhibitors or diuretics are taken concurrently. Although these warnings appear to be true for pharmaceutical lithium compounds only and not for modest doses of lithium orotate, it would nevertheless be wise to consult with a health care professional for anyone contemplating taking lithium orotate concurrently with either of these medications.
Zinc deficiency has been implicated in age-related osteoporosis  and, conversely, zinc supplements can speed the healing of fractures in animal models.  Zinc also plays a vital role in immune function, where deficiency is associated with atrophy of the thymus, reduction in white blood cell counts, and increased susceptibility to infection.   Another important role for zinc is in maintaining male reproductive function. Deficiency of zinc is associated with hypogonadism and low levels of serum testosterone, reversible upon supplementation.  Zinc also appears to be important for the activity of growth hormone (GH) since GH loses effectiveness under conditions of zinc deficiency. 
As is well known, one of the major roles for zinc in human nutrition is its antioxidant activity.  Increasing zinc intake may protect against conditions associated with both oxidant stress and zinc deficiency, such as diabetes.  Zinc deficiency is known to be associated with an increased prevalence of coronary artery disease as well as diabetes, and with several associated risk factors including hypertension, hypertriglyceridemia, and insulin resistance (syndrome X).  
In view of the association of zinc deficiency with diabetes, it's not surprising to learn that zinc orotate stabilizes blood glucose and reduces the need for insulin in diabetics, according to Dr. Nieper.  In addition, zinc orotate and other zinc compounds synergize with sulfur-containing antioxidants (sulfhydryls) to protect against free radical-induced tissue injury,   a result which may have relevance to the treatment of diabetes as well as other diseases of increased oxidative stress. 
Treatment or prevention of osteoporosis is one of the main applications for calcium supplements generally and for calcium orotate in particular. Dr. Nieper specifically cited its effectiveness in treating both inflammatory and osteoporotic decalcification and in relieving pain resulting from osteoporosis of the spine.  In another paper Nieper reported successful recalcification of malignant bone tumors (thereby preventing further metastases) with calcium orotate in 10 out of 13 subjects.  He also found that a daily oral dose of about 600 mg was sufficient to reverse bone loss caused by radiological therapy in cancer patients, an effect documented by X-ray photos of several subjects before and after treatment with calcium orotate.   A further paper reported on the benefits of calcium orotate in treating joint diseases such as arthritis and spondylitis.  On the basis of results such as these, it seems likely that calcium orotate can also have a beneficial impact on the degenerative bone changes characteristic of osteoarthritis. (For information on an orotate formulation optimized for bone health, see description below of Osteo Forte Orotate.)
But calcium orotate has many other uses as well. In his remarkable paper of 1969 Dr. Nieper reported his observations after dispensing more than 38,000 doses of calcium orotate to a large number of patients over the course of a year.  Nieper found that low-dose calcium orotate was effective in treating severe refractory psoriasis, lowering blood pressure in cases of arteritis and arteriosclerosis, relieving angina pectoris, and ameliorating cases of multiple sclerosis, disseminated encephalitis, retinitis, chronic hepatitis, and colitis. The dosages employed varied from about 300 to 1000 mg calcium orotate per day. No side effects were noted except for a loss of appetite among obese chronic overeaters, some of whom were able to lose a substantial amount of excess weight.
In subsequent research Nieper reported achieving complete remissions of chronic, aggressive hepatitis in 14 patients treated with 3 grams of calcium orotate per day for 2 years; 4 of these patients also required cortisone therapy, although at a decreased dosage.  Nieper found that an optimal therapeutic effect was achieved after a period of 9 to 18 months of daily supplementation, but not earlier. However, with a regimen of 2 grams calcium orotate plus 138 mg lithium orotate per day, the same beneficial results could be achieved in cases of hepatitis and cirrhosis in only 2 to 3 months. This research should be re-investigated in view of the emerging global health crisis of hepatitis C.
Around 1975 Dr. Nieper began treating lupus erythematosus patients with calcium orotate.  He found that a dose of 1 to 2.5 grams was surprisingly effective when administered over a period of at least one year, even in advanced cases with pulmonary constriction, pleural effusions, or cardiomyopathy.   Therapy also involved low-dose prednisone and a variety of nutrients to promote adrenal steroid synthesis, such as selenium and vitamins C and D2, as well as other calcium and magnesium salts. An account of one patient's successful response to therapy with calcium orotate and other Nieper compounds can be found in an article available from the Brewer Science Library.  In addition Nieper found that multiple sclerosis sometimes accompanies lupus, so it's not surprising that his protocol for treating MS is strikingly similar to that for treating lupus.   He recommended a dose of 1 gram calcium orotate per day for MS patients, with a higher dose given to those patients with a tendency toward migraine-like headaches.
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