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. (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, 23 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.
Osteo Forte orotate
The benefits of calcium orotate for healthy bone metabolism can be amplified by adding a variety of other minerals. Magnesium, manganese, zinc, and boron are all known to act in concert with vitamin D and calcium. Osteo Forte Orotate combines calcium, zinc, and magnesium orotates with other nutrients in a synergistic formulation optimal for maintaining bone health.
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Hans Nieper was born in Germany in 1928 and died in 1998. He did his premedical studies at Johann Gutenberg University in Mainz, his medical studies at the University of Freiburg, and he received an M.D. degree from the University of Hamburg.
As an undergraduate, Nieper developed a fascination for theoretical physics – especially for the theories of gravitation, electromagnetism, and quantum mechanics. Once he realized that all biological phenomena (including medical phenomena) are manifestations of the behavior of the elementary constituents (molecules, atoms, electrons, etc.) that organisms are composed of, he began to weave theories of medicine in which health and disease are defined and explained in terms of the physics of elementary particles. Unfortunately, Nieper’s exposure to physics seems to have consisted of taking just one undergraduate physics course and then doing a great deal of reading over the years – an approach that seldom leads to excellence in such an intellectually demanding field. Thus, despite being very intelligent and having a fine memory, Nieper did not reach a deep or correct understanding of theoretical physics. In fact, his views on physics were superficial and naive, and the medical theories he tried to derive from them were rightly considered by physicists, biologists, and medical researchers to be errant nonsense.
On the other hand, Nieper’s true accomplishments were the outcome of his clinical experiments, not of his musings about theoretical physics, even if his fascination with physics did influence his choice of medical problems to investigate clinically. Nieper is remembered chiefly for his work with mineral supplements as treatments for cancer, multiple sclerosis, diabetes, and cardiovascular problems. With the help of various colleagues, Nieper developed a series of ‘mineral transporters’ – substances that he believed would increase the bioavailability of minerals in tissues and cells. The principal transporters he used were AEP (2-aminoethylphosphonic acid), aspartic acid, arginine, and orotic acid. Each of these transporters can be combined with certain minerals to form organic salts – such as magnesium AEP, magnesium aspartate, magnesium arginate, or magnesium orotate. Of these, Nieper favored the orotates for most applications.
Nieper had fairly definite opinions on how the orotates and other artificial transporters are able to deliver minerals to cells. He stated that when an AEP transporter reaches the outer membrane of a cell, the organic part of the transporter becomes trapped in the membrane, and the mineral ion that it carries is released when the transporter eventually gets metabolized. The aspartic acid transporter, Nieper said, gets past the outer cell membrane but becomes trapped in the inner cell membrane (which is located just inside the outer membrane), and releases its mineral ion when the aspartic acid molecule gets metabolized. The orotates, however, according to Nieper, pass through both cell membranes into the interior of the cell, and only get metabolized once they reach the membranes of structures within the cell, thus leaving the mineral ion in or near these structures.
Were these explanations of Nieper’s – of the molecular mechanics of these transporters – based on any real evidence, or were they just speculation on his part? While they sound plausible, there is essentially no published research that confirms or refutes them. Unfortunately Nieper developed a reputation for failing to distinguish between speculation and hard evidence. Consequently his ideas were shunned by mainstream medicine and have largely gone uninvestigated to this very day. That being the case, Nieper’s explanations, being the only ones we have, must serve as conceptual models. Even if they turn out to be wrong, what counts most for patients is the clinical results of using these transporters – not the explanations of their molecular behavior.
So! what about Nieper’s clinical observations? These are the ultimate source of people’s enthusiasm about mineral orotates and other mineral transport supplements. How believable are Nieper’s glowing reports of the effects of these supplements on his patients? Nieper seldom published in scientific journals; instead, most of his reports took the form of anecdotes about specific patients or selected groups of patients. He usually presented these observations in talks, books, or informal papers. Here are several examples:
“The [multiple sclerosis] patient receives 2-3 vials (10 ml/400 mg) of Ca-AEP in a carrier solution like Ringer, combined with K-Mg-aspartate and Ouabain in order to enhance the retaining of the Ca-EAP on membranes. – If this therapy be started within the first months of the onset of the disease the disease will apparently be wiped out for a foreseeable future.”
“The rate of new cancerous diseases with long-term magnesium orotate therapy is perhaps less than 20% of the frequency otherwise expected, at least for the first 10 years of the observation period.”
“We found that calcium orotate has no side effects at all. It is more successful than sodium fluoride in the calcification of bone metastases and we had excellent and reliable success in about 40% of all metastatic disease in the bone system.” 3
Given Nieper’s propensity to substitute speculation for evidence, and intuition for rigor, it is hard to give much credence to his claims of remarkable cures and benefits. That is not to say that he falsely reported his patients’ improvement – just that he cannot justifiably claim that the improvements he saw were due to specific causes. Since Nieper did not perform controlled studies of his treatments, his clinical observations cannot be used to prove or disprove efficacy.
The best we can do is to judge Nieper’s work on the basis of independent studies that have been performed on orotates and other transporters. When we search the medical literature for such studies, however, we find many studies of mineral aspartates, but only a handful of orotate studies, and virtually no studies of AEP or arginates. The aspartates have been used effectively for a variety of purposes, including tissue protection during radiotherapy, treatment of lung damage, Alzheimer’s, zinc deficiency, and mushroom poisoning, to name only a few.
As for the orotates: Magnesium Orotate has been shown to have significant benefits for patients with coronary heart disease and in competitive endurance athletes. Lithium Orotate showed benefit in treating alcoholism. Some Russian studies of Potassium Orotate found benefits in wound healing and in treating mood disorders. Zinc Orotate showed protective affects against alcohol damage to the liver and against radiation damage to the blood.
Nieper’s work has been widely denounced, especially by the U.S. government and by medical groups such as the AMA and the National Cancer Institute, all of which conducted vigorous campaigns to discredit his ideas and to discourage patients from going to Germany to be treated at his clinic. On orders from the FDA and other governmental bodies, physicians who prescribed the treatments advocated by Nieper were arrested and fined, and had their medical licenses canceled. U.S. manufacturers and retailers of similar supplements were raided by Federal agents, their assets were confiscated and the owners of the companies arrested. The U.S. Customs Service routinely seized the prescribed medications and supplements brought back from Germany by Nieper’s patients for their own use. In Nieper’s own words:
“…many critically ill cancer patients returning home from my clinic in Germany were detained by U.S. Customs agents on FDA orders. Their prescribed nontoxic medications, minerals, and nutritional supplements were seized, and my patients were made to feel like criminals. Thus, they were stripped of their essential medical supplies, stripped of their dignity and freedom of choice, and most importantly, stripped of their chances for survival. This was how the FDA ‘protected’ American citizens from my therapeutic treatments.”
Police-state actions like these eventually prompted Congress to strip the FDA of its authority to regulate nutritional supplements. The Dietary Supplement Health and Education Act of 1994 was enacted, and Nieper himself had a significant influence upon its content. Nevertheless, FDA harrassment of Nieper and his patients did not end – the agency continued to update its “import alerts” directed against all substances associated with Nieper’s clinic, the most recent update occurring on November 29, 2000. It is amusing to find Vitamin C (ascorbic acid) listed in this import alert as one of the ‘Unapproved New Drugs Promoted By Dr. Hans Nieper’.
Ultimately the value of Nieper’s work on mineral transporters does not depend upon whether his theories and explanations were valid, or upon whether his observations were biased, or upon the rulings of the government or the medical cartel. It depends only upon whether the transporters work when you use them. Many users are quite convinced that their lives or health have been rescued by these supplements, and this alone justifies their existence in the marketplace.
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This article addresses two biochemical puzzles about the mineral orotates: how they get into cells and what they do once they’re in.
We begin with the fact that the orotate salts are electrically neutral and relatively stable against dissociation, properties that seem to be crucial for the ability of orotates to participate in intracellular mineral uptake and transport. Dissociation is the process that takes place when a salt is dissolved in a solvent such as water and breaks up into its component ions. Table salt dissolved in water, for example, dissociates into sodium and chloride ions. At physiological pH the orotate salts are much more stable than table salt and will not readily dissociate into free orotic acid plus a mineral ion.
Free orotic acid (OA) itself is known to get into cells by simply leaking (diffusing) through cell membranes, rather than by being actively transported. But diffusion is a relatively inefficient process, which limits the amount of OA that can enter a cell. By contrast, uracil – a compound almost identical to OA, only minus the carboxylic acid group – is taken up efficiently by a transporter protein that binds to uracil molecules and drags them into the cell. This transporter appears to be specific for uracil or similar molecules which are uncharged, but not for uracil’s close cousin OA (which is negatively charged at body pH).
Bind the orotic acid with a mineral, however, and you end up with a stable electrically neutral salt. This property is just what is needed for OA along with its bound mineral to be taken up directly by the uracil transporter. At the same time, neutralizing the charge on OA makes the resulting complex more lipophilic or “fat-loving” than free OA; as a result, the stable orotate complex would be expected to diffuse more easily through the lipid membranes of cells. Essentially just such a mechanism was proposed by Nieper for enhancing the diffusion of mineral ions across cell membranes. Either way – via enhanced diffusion or active transport – complexing a mineral with orotate results in increased uptake of both components of the complex by cells.
That’s still not the whole story of orotate, however. Here and there in his papers, Nieper gives tantalizing clues about the role of the “pentose phosphate pathway” or PPP in mediating the effects of his mineral orotates. The PPP is a well-known biochemical cycle which, among other vital functions, is responsible for synthesizing D-ribose 5-phosphate. D-ribose is of course the sugar which gets incorporated into nucleotides (a process known as ribosylation) and ultimately into RNA/DNA. Was Nieper attempting to signal a deep connection between the ribosylation of orotate and its activity as a mineral transporter?
The answer is yes. To see what Dr. Nieper was hinting at, we need some additional background information on OA, also known as vitamin B13.
Although orotic acid isn’t officially considered a vitamin these days, over 40 years ago it was found to have growth-promoting, vitamin-like properties when added to the diets of laboratory animals. Subsequent nutritional studies in humans and animals revealed that OA has a “sparing” effect on vitamin B12, meaning that supplemental OA can partially compensate for B12 deficiency. OA also appears to have a direct effect on folate metabolism.
Many of the vitamin-like effects of OA are undoubtedly due to its role in RNA and DNA synthesis. (B12 and folate are also involved in DNA synthesis, but at a point downstream from where OA comes in.) Our bodies produce OA as an intermediate in the manufacture of the pyrimidine bases uracil, cytosine, and thymine. Together, these pyrimidines constitute half of the bases needed for RNA/DNA, the other half coming from the purine bases adenine and guanine which are synthesized independently of OA.
The enzyme orotate phosphoribosyltransferase (OPRTase), which is found in organisms ranging from yeast to humans, is responsible for catalyzing the first step in the conversion of orotic acid into uridine. It does so by facilitating the attachment of a ribose plus phosphate group to OA. The net result is the formation of a molecule named OMP (orotidine 5′-monophosphate), which in turn is the immediate precursor to UMP (uridine 5′-monophosphate).
Because the enzyme OPRTase requires magnesium ions for its activity, some researchers wondered whether a magnesium complex of orotic acid might be involved in binding orotate to the enzyme. They found that the true substrate for OPRTase is not orotate itself but rather a magnesium orotate complex. The fact that the complex is electrically neutral compared to the negatively charged orotate ion means that the complex is more easily transportable to the active site of the enzyme. These researchers suggested that the magnesium complex helps position orotate within the enzyme in the proper orientation for conversion to OMP. In the process the magnesium ion in the complex gets exchanged with the magnesium ion bound to the active site of the enzyme, the net result being that one magnesium ion is released.
So far, so good. Following up on Nieper’s hint, we see that orotate-and specifically magnesium orotate-can interact with the pentose phosphate pathway (PPP) to generate OMP and ultimately uridine. But Nieper also pointed out that the mineral-transport activity of the orotates does not necessarily have anything to do with the formation of RNA or DNA. To resolve this apparent contradiction, we must seek out an additional metabolic role for orotate independent of RNA/DNA synthesis
In fact, not all the uridine formed from orotic acid does wind up in RNA or DNA. There are other vital roles for orotic acid and uridine in the body-for example, OA gets taken up by red blood cells where it is rapidly converted to UDP-glucose by way of OPRTase and other enzymes. Here UDP is the nucleotide uridine diphosphate. The red blood cells can then act as a storage and distribution pool for delivering glucose and uridine to tissues such as brain, heart, and skeletal muscle. Because UDP-glucose is a precursor for glycogen (a storage form of glucose), the delivery of UDP-glucose to heart muscle and its conversion there to glycogen might account for some of the cardioprotective effects of orotic acid.
Which brings us right back to Dr. Nieper’s work.
Based on the available scientific evidence, it seems clear that magnesium orotate can get channeled directly into OMP synthesis and ultimately into UDP-glucose, which can then resupply a heart under stress with carbohydrates and nucleotides. Thus a mechanism exists for explaining why magnesium orotate works even better than orotic acid for heart conditions. In contrast, some of the mineral orotates such as copper and nickel either inhibit OPRTase or, in the case of calcium orotate, neither activate nor inhibit the enzyme. This suggests that the body preferentially uses magnesium orotate for promoting uridine synthesis. In a sense, complexing OA with magnesium magnifies the “vitamin-like” properties of vitamin B13.
Another effect of magnesium orotate is to inhibit the development of atherosclerosis when administered orally to humans or experimental animals. The animal study in particular tells us that magnesium orotate performs better than orotic acid, which in turn outperforms magnesium chloride, in inhibiting atherosclerotic changes caused by high levels of cholesterol in the diet. In other words, a synergy exists between magnesium and orotic acid such that the complex they form – magnesium orotate – is more potent than either one alone. Dr. Nieper explained this effect by suggesting that when OA in the magnesium orotate complex is coupled with ribose (ribosylated) in the walls of blood vessels, the magnesium ion is liberated during this process and becomes locally available for activating cholesterol-metabolizing enzymes.
The increase in potency of magnesium in going from a chloride salt to an orotate salt is notable and certainly consistent with Nieper’s ideas about orotate as a mineral transporter. But notice that orotic acid also increases in potency in going from free OA to its magnesium complex, an enhancement consistent with the idea that magnesium orotate gets preferentially directed toward uridine synthesis by OPRTase. It is just this combination of properties – enhanced transport of magnesium, itself known for its anti-atherosclerotic and anti-cholesterol effects, and enhanced synthesis of uridine from orotic acid - that makes magnesium orotate so helpful for treating cardiovascular disorders.
By contrast, the very similar compound calcium orotate has none of the effectiveness of magnesium orotate in lowering serum cholesterol, although it does have other characteristics beneficial for treating arterial disease. The difference in activity between magnesium and calcium orotate can best be explained by the specific effects of magnesium in activating cholesterol turnover as well as by the specificity of magnesium orotate-but not calcium orotate-for activating OPRTase.
As the preceding example shows, the various mineral orotates are likely to be targeted to distinct metabolic pathways in specific tissues. Another example is provided by an experiment involving lithium metabolism in the brain. Lithium is well known for its ability to moderate manic-depressive illness. In an experiment to evaluate lithium-induced changes in brain metabolism, rats were injected with a solution of lithium chloride daily for two weeks. One hour after the last lithium treatment all rats received an injection of radiolabeled orotic acid into the cerebral ventricles. At various intervals thereafter RNA was extracted from rat brains, separated into fractions, and analyzed for radioactivity. The results showed that lithium increases RNA turnover markedly in brain (but not in other tissues such as liver). The authors suggested that lithium acts at the membrane level and that the effects on RNA metabolism are due to changes in the transport of radiolabeled orotic acid-an explanation entirely consistent with Nieper’s idea that lithium combines with OA to yield a transportable complex.
In summary, 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.
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Elsewhere on this blog you will read that one of the many benefits of calcium orotate is its effectiveness for suppressing appetite among chronic overeaters, a phenomenon that Dr. Nieper mentions almost casually in one of his research papers. Although Nieper was more concerned at the time with treating serious medical conditions such as multiple sclerosis, chronic hepatitis, and severe psoriasis, his comment about appetite suppression really caught my attention. If calcium orotate is so effective in general, I wondered, why isn’t it better known as a treatment for weight loss, an issue to which so many of us can relate?
I decided to try out calcium orotate for myself and was astonished with the results. For me the effects were dramatic and almost immediate. Over a period of months I lost over 25 pounds without dieting in any way. During this time I ate all the food I wanted without counting calories. I was able to do so and still lose weight simply because I wasn’t as hungry as before. I found that small meals quickly filled me up; eating anything larger would leave me feeling uncomfortably full.
At the same time I became aware that calcium orotate was causing other effects as well. One 745 mg tablet was enough to wake me up, elevate my mood, and give me a pleasant buzz in the head. Of course, appetite suppressing drugs such as amphetamines can also act as cognitive stimulants, but there’s a world of difference between such drugs and calcium orotate. For one thing, calcium orotate is a natural product, the calcium salt of a component of whey. More important for me is that calcium orotate does not increase either my heart rate or blood pressure, two parameters I’m careful to monitor every day. Both heart rate and blood pressure would shoot up if I were taking amphetamines because this class of drugs releases norepinephrine, a powerful cardiovascular stimulant. The evident inability of calcium orotate to release norepinephrine means that calcium orotate utilizes a different metabolic pathway to achieve its cognitive and weight-loss effects. Precisely what that pathway is remains unknown.
After some experimentation I found that what works best for me is to take a single tablet on an empty stomach in the morning and then eat a modest, protein-rich breakfast about a half hour later (but not earlier). The appetite suppressing and cognitive enhancing effects of calcium orotate typically show up a half hour to an hour after ingestion and last for a total of about 8 hours. If the effects start to flag a bit, I’ll occasionally take a second tablet around noon. I don’t recommend taking two tablets at the same time, however, since a dose of that size leaves me feeling lightheaded and a bit queasy.
Delighted with my initial success, I decided to confirm my results by running an informal trial of calcium orotate among friends. I handed out bottles to Donna, Tom, Mark, and Jeanne, with the following results: Donna and Jeanne both lost weight, an average of 6 pounds per month, by taking one to two tablets per day. Both noticed the cognitive stimulation as well and Donna in particular reported that it had lifted her depression. By contrast Tom and Mark did not notice any effects, but since both are large men they may have needed a bigger dose than a single tablet per day. Tom had some difficulty in sticking with the program, so his lack of consistency in taking calcium orotate on a daily basis may have sabotaged any possibility of his seeing results. After dropping out of the “trial” he did, however, give his remaining supply of tablets to his wife Tess, with dramatic results. Tess is not someone I’d consider overweight, but the calcium orotate still worked its magic on her and she was able to drop a few pounds as well. Ultimately, Tess discontinued its use since she found that even one tablet per day was becoming too stimulating for her.
After calling the supplement company LifeLink, and talking with Troy and from his friend Ken, I’ve come up with a series of suggestions for maximizing the benefits of calcium orotate:
- Although it may not work for everyone, there’s a 60 to 80 percent chance it will work for any given person. Some people don’t feel anything after consuming several tablets while others can’t stand the effects of even a single tablet. Most people, however, will find that a single tablet per day is an effortless path to losing weight.
- You’ve got to give it a chance to work. If one tablet per day doesn’t have an immediate effect, keep trying for several days or try increasing the dose.
- Consistency is important. Take the specified dose every day to make it work.
- Take the first dose of the day on an empty stomach. Eating food too soon after can diminish the beneficial effects. On the other hand, eating no food at all after can make the stimulating effect too intense for some people.
- For those who can stand the extra stimulation, I’ve found that a more effective way of losing weight might be to wash down a calcium orotate tablet with a caffeinated beverage (e.g., green tea or coffee).
And in answer to the rhetorical question I posed in the opening paragraph of this article, I still have no idea why calcium orotate isn’t better known as a treatment for weight loss. Hopefully this situation is about to change. So let’s say you heard it here first.
With regard to the other orotates, I have previously mentioned that magnesium orotate increases endurance in exercising athletes and that potassium orotate has been shown to increase blood levels of reduced glutathione, the body’s natural antioxidant. Since endurance depends critically on the levels of oxidative stress in exercising muscle, I guessed that adding some potassium orotate to the magnesium orotate I was already taking might yield even better results. In general I take one tablet of each of the orotates every morning; on exercise days, I increase the dose by taking an extra tablet each of potassium and magnesium orotate an hour or two before heading for the gym. It didn’t take long for the results to become obvious. I’m now pushing heavier weights on the Nautilus machine than I’ve ever done previously.
I might as well add that since I’ve started taking one tablet each of zinc and lithium orotate each morning, I haven’t been sick once although the rest of my family has come down with an assortment of colds, flu, and intestinal viruses. So I’m sold on the immune-boosting effects of the orotates as well.