5 NAD Therapy: the Biochemical Basis
NAD is a co-enzyme that is mainly absorbed from food or produced naturally in the body from certain nutritional elements, by means of various biochemical processes105, 259 . "Most niacin in food is in the form of NAD or NADP. Niacin is absorbed in the small intestine, mostly in the form of NAD or NADP"369.
Various researchers emphasise the central and vital role of NAD in most processes of life136, 191. Dr Davis stresses the importance of NAD, as follows: "NAD is important for energy. If you have too little NAD, many of your enzymatic reactions fail to function and then you cannot produce the energy. You cannot produce ATP. NAD supplements must also be added to the minimum maintenance. NAD is a very specific component, an essential component of your body. If you do not have it, none of your systems functions, and this includes your brain. If you don't have NAD, you die; it's as simple as that. You will never have no NAD. You will always have a little NAD, because your electron-transfer chain possesses areas in which energy is generated, the electrons take in NAD and release it. In this way, it causes the functioning of the electron-transfer chain. This is why I say, that NAD is not a nutritional supplement. NAD is an essential and highly specialised component of the body, which requires it to function"65. Despite the fact that most of us have learned about NAD at school while studying biology, it remains relatively unknown as a nutriceutical energy metabolic supplement especially for EMD.
5.1 BIOSYNTHESIS OF NAD
NAD is a co-enzyme that is mainly absorbed from food or produced naturally in the body from certain nutritional elements, by means of various biochemical processes105, 259 . "Most niacin in food is in the form of NAD or NADP. Niacin is absorbed in the small intestine, mostly in the form of NAD or NADP"369. NAD is mainly obtained from the NAD that is present in food38. NAD can be produced in the liver, in particular, under the control of the hormones that are secreted by the adrenal glands259. Nicotinamide is an important precursor of NAD, under physiological conditions151. Tryptophan is another important precursor of NAD and the body obtains a large proportion of NAD from this source. In the case of human nutrition, 60 mg tryptophan is the equivalent of 1 mg niacin64.
“NAD is synthesized in red cell from nicotinic acid and PRPP through the formation of nicotinate mononucleotide and desamido-NAD. Synthesis of one mole of NAD requires two moles of ATP. NADP comes from NAD phosphorylation by NAD-kinase (EC.18.104.22.168). NAD and NADP analysis on a population with ATP level ranging from 800 to 2500 nmoles/ml red cells showed a close correlation between ATP and pyridine cofactors. Moreover, NADP level appeared to be dependent of the redox-state of NADP/NADPH couple. Subjects with low NADPH (G-6-PD) deficient red cells, (Hb Koln) showed lower NADtot/NADP tot ratio, suggesting a NAD-kinase equilibrium shift toward NADP related to lower levels of the negative effector NADPH.”796 “Nicotinamide mononucleotide adenylyl transferase (NMNAT) is an essential enzyme in all organisms, because it catalyzes a key step of NAD synthesis. However, little is known about the structure and regulation of this enzyme... NMNAT appears to be a substrate of nuclear kinases and contains at least three potential phosphorylation sites”.786
5.2 BIOCHEMICAL FUNCTIONS OF NAD
NAD was the first co-enzyme to be identified in 1904 by Harden and Young138. NAD has more than 100 functions in the human metabolism. Even the activity of the citric-acid cycle, which is found in most cells, becomes restricted in the lack of NAD and NADP154. The body constantly requires NAD and if the NAD level becomes too low, the need for it is activated in the primitive part of the brain. This biochemical action cannot be controlled by the mind or changed by willpower. Alcohol and the metabolites, which it creates, suppress this need for NAD. Excessive exercising and the associated secretion of endorphins also suppress the need for NAD51.
5.2.1 Metabolic Detoxification of Chemical Substances
NAD has already been used successfully since 1939, for the short-term treatment of alcoholism51. O'Halleren was however the acknowledged leader in treating various types of substance dependencies with the aid of NAD supplements. He used NAD to treat alcohol-, heroin-, cocaine-, morphine-, meperidine-, codeine-, amphetamine-, barbiturate- and sedative dependents166. NAD does not have the same side-effects as nicotinic acid at high dosages, like serious flushing and the release of histamine211.
The intracellular metabolism of alcohol, and possibly also of other chemical substances, requires NAD or derivatives thereof, in order to take place. Ninety per cent of alcohol is absorbed almost immediately in the body's cells; the remaining 10% is discharged mainly in the urine. Acetaldehyde is the first metabolite of various chemical substances, including alcohol, that is produced26, 133, 166, 173, 176, 227, 249. Acetaldehyde is also formed during stress. Acetaldehyde is used as a preservative in certain dairy products214. The last step in the metabolic detoxification process occurs in the citric-acid cycle, where three NADs are involved in the process. This cycle is also responsible for the conversion of proteins, carbohydrates and fats into ATP. This is a purely biochemical autonomic reaction, and neither the person's will or any other form of control can be exercised over it. The biochemical reactions can be simplified as follows:
Chemical Substance + NAD -> Acetaldehyde + NAD -> Acetate + CoA -> Acetyl-CoA +3NAD(H) -> ATP + H2O + CO2 + Heat
Ethanol toxicity is closely related to its metabolism in the liver. The elevated NADH/NAD ratio (ie NAD deficiency) results in alterations of the intermediary metabolism of lipids, carbohydrates, proteins, purines, hormones and porphyrins. This shift in metabolic pathways results in hyperlactacidaemia, lactacidosis, ketosis and hyperuricaemia. Furthermore, excess NADH can results in free radical production491, 492, 493.
The NADH that builds up, eg during eg alcohol metabolism, will drive pyruvate to lactate which can lead to acidosis. The pyruvate is now not available for gluconeogenesis and if, as is common in serious alcoholism, the patient is not eating properly, hypoglycemia can result. The high NADH/NAD ratio will affect other processes such as b-oxidation. One clinical manifestation is liver disorders associated with alcoholism: fatty liver, alcoholic hepatitis and, sometimes, cirrhosis. The burden on oxidizing systems also leads to increased use of the P450 or microsomal oxidizing system which can have important effects on steroid metabolism and other processes involving this system491, 492, 493.
5.2.2 Repairing DNA
NAD and niacin (a precursor of NAD), play an important role in defending cells against DNA damage by genotoxic particles. Research shows that niacin supplementation, particularly for persons who initially have lower levels, improves the level of NAD in blood and lymphocytes99. NAD plays a major role in repairing DNA44, 156, 196. Research shows that damage to DNA can possibly stimulate the biosynthesis of NAD and that the repair of DNA can be increased and accelerated in cells with increased levels of NAD112. Cytotoxic substances reduce the intracellular levels of NAD and can lead to the death of cells. DNA strand breakage decreased proportionately to NAD concentrations over time in lymphocytes exposed to oxygen radicals367. The results suggest a general correlation between DNA damage and acute lowering of cellular NAD pools377, 564.
“Rejoining of DNA single-strand breaks generated by treatment of plasmids with gamma-rays, neocarzinostatin, or bleomycin was catalyzed inefficiently by human cell extracts. The reaction was strongly promoted by the addition of NAD+, which was employed for rapid and transient synthesis of poly(ADP-ribose)... NAD(+)-promoted DNA repair by soluble cell extracts also occurred with alkylated DNA as substrate and was suppressed by 3-aminobenzamide. A similar stimulatory effect by NAD+ was observed for repair of ultraviolet-irradiated DNA, and this could be ascribed to the presence of pyrimidine hydrates as minor radiation-induced DNA lesions”.788
5.2.3 Generating Energy
During one of our dietitian's lectures in Nutritional Biochemistry at Pretoria University, an individual's theoretical daily need for NAD, assuming that none is recycled, was calculated. The calculation showed, that the average person's body contains approximately 16 grammes of NAD and that it had to be recycled 2 160 times during every 24 hours through the body. Had the body lacked the ability to recycle NAD successfully, 35,91 kg of NAD (approximately 72 000 containers of NutriNAD, or 7,2 million MultiNAD or MalaikaNAD capsules) would have to be taken every day, in order to supplement it. NAD plays an important role in the production of ATP (the basic energy molecule) in the body.
NAD and NADP, which are pyridine nucleotides, are rated as being amongst the important high energy compounds in the biochemistry of organisms138. The reduction of NAD plays an important part in the citric-acid cycle and contributes to the production of 22 molecules of ATP from one molecule of glucose38. NAD and its derivatives NADH, NADP and NADPH have regulatory functions in the generation of triose phosphates and pyruvate from glucose607. NAD is reduced to NADH in the metabolism of glucose. The hydrogen molecule is obtained from the metabolism of fats, carbohydrates and proteins. The activated NADH plays a part in several critical bodily functions, amongst others, in the continued production of ATP, which is the basic energy compound in the body45. NAD plays an important role in the release of energy from carbohydrates, fats and proteins137. In the absence of oxygen, pyruvate must be converted to lactate to regenerate NAD from NADH in the cytoplasm. In the presence of oxygen, the mitochondria can reoxidize cytosolic NADH by an indirect process, involving the mitochondrial "shuttle systems"348.
5.2.4 Improving Immunity
Phagocytes use NADPH as a source of energy, to destroy pathogens. The NAD(P)H, that is available, is also used to protect the body against free radicals and to, in this way, prevent illnesses and damage. High dosages of ascorbic acid can supplement the activity of the NAD(P)H, which is only available to a limited extent45. Research on the effect of the Epstein-Barr virus on lymphocytes, indicates that the cultivated cells' levels of NAD were lower. The addition of NAD restored the levels within two hours. The study also discusses the effect of NAD on the mitochondrial metabolism and the relationship between NAD and the activity of complex I in cultured human cells194.
5.2.5 Improving Brain Functions
The brain is metabolically speaking one of the most active organs in the body and consumes approximately 20% of allenergy generated21, 350. Its weight-to-energy ratio is ten times more than that of most other organs. The brain does not really have any reserves of energy, in the true sense of the word, and must therefore be supplied continuously with energy by the body. The brain, as a whole, consumes approximately 4 x 1021 molecules of ATP per minute and this increases during REM sleeping. During the first ten years of a child's life, the brain consumes up to twice as much energy as during adulthood212. When pyruvate oxidation is impaired, glycolysis will run faster than normal to try to make up for deficient ATP production. This will cause more production of lactate. The brain relies on oxidation of glucose as an energy source and has a limited ability to oxidize fatty acids. In cases of severe energy depletion mental retardation is not surprising348. NAD plays an important part in the production of ATP in cells38.
Derivatives of niacin, mainly in the form of NAD and NADP coenzymes, are found abundantly in brain tissue. In the case of niacin deficiency, the brain's supply of NAD declines sharply and the functioning of the brain is disturbed; malfunctioning of the brain (dementia) is indeed one of the primary characteristics of pellagra. If the NAD deficiency lasts for an extended period, permanent brain damage develops144.
Scientists have discussed the possible use of NAD for the treatment of neurodegeneration155 and the improvement of brain functions. NADH plays a role in the synthesis of the neurotransmitters, i.e. noradrenaline and dopamine, which are important for maintaining a positive state of mind42. South African research on NAD, that was conducted for the manufacturer, also confirms the normalising effect of NAD on the neurotransmitters, i.e. dopamine, adrenaline and noradrenaline. NAD probably plays a role in the production of serotonin and other neurotransmitters in the brain214.
5.2.6 Normalizing Cell Functions
“The corepressor CtBP (carboxyl-terminal binding protein) is involved in transcriptional pathways important for development, cell cycle regulation, and transformation. We demonstrate that CtBP binding to cellular and viral transcriptional repressors is regulated by the nicotinamide adenine dinucleotides NAD+ and NADH”.779
“NAD is the substrate of a novel chromatin-associated enzyme-ADP-ribosyl transferase (ADPRT). In this study, the cell-cycle dependent change in cellular NAD content was observed in a line of human amnion FL cells. It was found that the cellular NAD content of FL cells was highest in G1 and lowest in S/G2-G2. 3AB, a potent ADPRT inhibitor, can inhibit the cell cycle dependent change in cellular NAD content and also inhibit DNA synthesis in the S phase and extend the S phase. The results indicate that ADP-ribosylation may be involved in DNA replication and cell cycle progression. It was also found that the DNA-damaging agents, MNNG, MMS and 4NQO could lower cellular NAD content in a dose-dependent way”.780
“Hepatocytes were found to be remarkably resistant to suicidal NAD+ depletion due to consumption for chromatin-associated poly(ADP-ribose) biosynthesis, which normally follows infliction of DNA damage in mammalian cells... This differential behavior, demonstrable also with other carcinogens, can be attributed to the different NAD+ biosynthetic capacities of these cells”.781
“Marked depletion of intracellular NAD+ prior to toxicity and a protection against toxicity associated with maintenance of NAD+ suggest a possible role for the maintenance of intracellular NAD+ in cellular integrity.“ 782
“Many cellular enzymes use NAD+ as coenzyme or substrate, depending on the nature of the enzymatic reaction. Under certain conditions the cellular NAD+ concentration may become rate-limiting for such enzymes. For instance, when eucaryotic cells are exposed to high concentrations of DNA-damaging agents, the resulting DNA strand breaks may stimulate the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to such an extent that the cellular pool of NAD+, which is the substrate for this enzyme, is severely depleted, possibly leading to acute cell death”.783
“When mouse leukemia cells are treated with gamma-radiation or neocarzinostatin the intracellular NAD and ATP levels fall rapidly. We have shown that the ATP response is a consequence of the decreased NAD level. We suggest that this low NAD level results in decreased glycolytic activity and that there is a subsequent accumulation of phosphorylated sugars associated with the fall in ATP. Under these extreme conditions, therefore, the NAD level probably regulates the rate of glycolysis in cells which are utilising a rapidly metabolisable sugar as their energy source”.784
“Ionizing- and ultraviolet-radiation cause cell damage or death by directly altering DNA and protein structures and by production of reactive oxygen species (ROS) and reactive carbonyl species (RCS). These processes disrupt cellular energy metabolism at multiple levels. The formation of DNA strand breaks activates signaling pathways that consume NAD, which can lead to the depletion of cellular ATP. Poly(ADP)-ribose polymerase (PARP-1) is the enzyme responsible for much of the NAD degradation following DNA damage, although numerous other PARPs have been discovered recently that await functional characterization. Studies on mouse epidermis in vivo and on human cells in culture have shown that UV-B radiation provokes the transient degradation of NAD and the synthesis of ADP-ribose polymers by PARP-1... Identifying approaches to optimize these responses while maintaining the energy status of cells is likely to be very important in minimizing the deleterious effects of solar radiation on skin”.785
“Peroxynitrite and hydroxyl radicals are potent initiators of DNA single strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose)synthetase (PARS). Rapid activation of PARS depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. This process can result in acute cell dysfunction and cell necrosis. Accordingly, inhibitors of PARS protect against cell death under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARS activation, PARS also appears to modulate the course of inflammation by regulating the expression of a number of genes... In vivo data demonstrate that inhibition of PARS protects against various forms of inflammation, including zymosan or endotoxin induced multiple organ failure, arthritis, allergic encephalomyelitis, and diabetic islet cell destruction”.787
“Recent studies point to the naturally occurring molecules in expression of radiation damage and in protection. DNA repair was shown to be one of the parameters that can be modified to attain improved protection. The need for a natural compound that can enhance DNA repair in order to improve cellular protection focused our attention on nicotinamide (NA). The effects of addition of NA, a precursor for NAD+ synthesis, on the DNA repair capacity following gamma and ultraviolet irradiations were studied in several repair-proficient and repair-deficient cell lines. The addition of low concentrations of NA (less than 3 mM) resulted in increased repair synthesis in the repair-proficient cells. Addition to repair-deficient cells resulted in decreased repair synthesis. Cells which repair damage from one type of radiation, and not from another, responded accordingly to the presence of NA. However, addition of high concentrations of NA to repair-proficient cells resulted in decreased repair synthesis. Thus, nicotinamide can improve the repair capacity in a concentration-dependent manner, but it clearly requires the existence of functional repair processes.”789
“An intimate relationship exists between DNA single-strand breaks, NAD metabolism, and cell viability in quiescent human lymphocytes. Under steady-state conditions, resting lymphocytes continually break and rejoin DNA. The balanced DNA excision-repair process is accompanied by a proportional consumption of NAD for poly(ADP-ribose) synthesis. However, lymphocytes have a limited capacity to resynthesize NAD from nicotinamide. An increase in DNA strand break formation in lymphocytes, or a block in DNA repair, accelerates poly(ADP-ribose) formation and may induce lethal NAD and ATP depletion”.790
“These data indicate for the first time hormonal modulation of NADase resulting in two signals: (1) enhancement of NAD+ which may explain the increase in ADP ribosylation and activation of cholera-toxin
substrates leading to facilitation of protein secretion; (2) suppression of cell cADP-ribose and consequently intracellular Ca2+ which may explain the melatonin-induced inhibition of protein secretion”.791
“Extracellular NAD is degraded to pyridine and purine metabolites by different types of surface-located enzymes which are expressed differently on the plasmamembrane of various human cells and tissues... ATP was found to be the main labeled intracellular product of exogenous NAD catabolism; ADP, AMP, inosine and adenosine were also detected but in small quantities... These results confirm that adenosine is the NAD hydrolysis product incorporated by cells and further metabolized to ATP, and that adenosine transport is partially ATP dependent”.792
5.3 NADH IN FOOD
Free nicotinic acid (vit B3) and nicotinamide (active form) are present in nature in only small amounts. Nicotinic acid is mainly bound to macromolecules in plants, while nicotinamide is usually a component of NADP (coenzyme form) in the animal world. Nicotinic acid can be formed in humans from the metabolism of dietary tryptophan. Important sources of preformed niacin include beef, pork, wheat flour, maize (corn) flour, eggs and cows’ milk. Human milk contains a higher concentration of niacin than cows’ milk. In unprepared foods, niacin is present mainly in the form of the cellular pyridine nucleotides NAD (coenzyme 1)and NADP.
Raw food contains the amounts of NADH detailed in the following table. Cooked food contains much less NADH because some of the NADH is lost during the preparation23. The NAD co-enzyme continuously varies between the NAD or NADH compound in the body68, 83, 105. Other derivatives of NAD are NADP and NADPH138. For the sake of completeness, the figures have been converted to show the quantity of food required to be taken to match the NAD used per infusion and contained in one MultiNAD capsule.
5.4 STORAGE OF NAD IN CELLS
"Pyridine nucleotides are mostly stored within mitochondria where they are involved in different functions ranging from energy metabolism to cellular signalling. Here we discuss the mechanisms of mitochondrial NAD metabolism and release that may contribute to the crucial roles played by these organelles as triggers or amplifiers of physiological and pathological events".687 There are two pools of NAD in most cells. One is the inner mitochondrial pool and the other is the cytoplasmic pool. "Tissue levels of NAD appear to be regulated primarily by the concentration of extracellular nicotinamide, which in turn is controlled by the liver in a hormone-sensitive manner. Hepatic regulation involves the conversion of excess serum nicotinamide to 'Storage NAD' and inactive excretory products, and the replenishment of serum nicotinamide by the hydrolysis of 'Storage NAD.' Tryptophan and nicotinic acid contribute to 'Storage NAD,' and thus are additional sources of nicotinamide627."
5.5 POSSIBLE CAUSES OF NAD DEFICIENCY
It appears from literature that several factors can lead to NAD deficiencies. Genetics, nutrition, chemical substances and certain diseases possibly play a part51. Mitochondrial disorders could be a cause68. Nutrient dependency, ageing and nutrient deficiencies are possible causes105. Malfunctioning of the liver and adrenal glands might play a role259. NAD possibly cannot be recycled properly. The contributing potential of digestive problems can be added to this214. In the case of certain disorders, for example an overactive thyroid gland, too much energy is released as heat and it is stored inadequately68.
NAD deficiencies are probably also induced or aggravated by the following substances:
∙ biopsy-proven zidovudine myopathy resulted in a high lactate:pyruvate ratio538.
∙ patients on valproic acid had reduced lactate and lactate:pyruvate ratios539.
∙ elevated lactate in white matter and the possible response to antioxidants suggests mitochondrial dysfunction in progressive spongiform leukoencephalopathy following inhalation of heated heroin vapor540.
∙ lactic acidosis is induced by ingestion of sustained-release nicotinic acid542.
∙ the mean plasma lactate concentration was elevated in 42 patients poisoned with paracetamol543.
∙ parvovirus infection was accompanied by rapid depletion of intracellular NAD stores565.
∙ NAD synthesis is decreased significantly in thalassemic red blood cells566.
∙ The ratio of lactate to pyruvate was elevated in both sexes after a 40-day period of a 25% fat-calorie restricted diet. The lactate and pyruvate decreased significantly only in males (pyruvate greater than lactate) but not in females314.
∙ DNA-damaging agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methyl-methanesulphonate (MMS) and 4-nitroquinoline-N-oxide (4NQO) could stimulate ADP-ribosyl transferase (ADPRT) activity and reduce the cellular NAD content in a dose-dependent way564.
∙ Several tumor-therapeutic drugs reduce NAD and NADH levels, thereby inhibiting glycolytic energy production631.
5.6 THERAPEUTIC CHARACTERISTICS OF NAD
“Nicotinamide mononucleotide adenylyltransferase (NMNAT), a member of the nucleotidyltransferase alpha/beta-phosphodiesterases superfamily, catalyzes a universal step (NMN + ATP = NAD + PP(i)) in NAD biosynthesis. Localized within the nucleus, the activity of the human enzyme is greatly altered in tumor cells, rendering it a promising target for cancer chemotherapy.”778 NAD-deficiency disorders include conditions like anorexia nervosa, substance dependency, early diabetes, heart problems, hypertension and various behavioural disorders. NAD deficiencies can develop as a result of diets that lead to lower NAD levels. Approximately 10% of people suffer from a serious and possibly chronic lack of NAD, which can often also be of a genetic nature51. Therapy with NAD precursors like nicotinamide might have remedial effects on possible biochemical abnormalities, thereby retarding progression of diabetic microangiopathy607. "NAD and NADH are converted into each other in numerous different metabolic activities. In some metabolic reactions it is NAD which is the needed catalyst, with NADH a useful by-product, in other reactions the situation is reversed638".
5.6.1 Patents for NAD Therapy
NAD was patented in 1964, for the treatment of drug dependency. It was registered in 1966, for the treatment of alcoholism. The patent for the use of NAD supplementation in the treatment of ileus and shock was awarded in 1967. The patent for use in the treatment of schizophrenia was also approved during the same year. Shortly thereafter, the patent for the use of NAD in the treatment of arthritis was also approved. A patent is registered which generates NAD or nicotinamide adenine dinucleotide phosphate (NADP) in the body344.
5.6.2 Determining NAD Levels
NAD is present in all body cells and it is clinically not easy to measure it. Researchers found in their experiments, that the absolute conversion-speed of NAD is 78 000 molecules per second per cell and that it has a half-life of between 48 and 78 minutes186. NAD's half-life in the brain is approximately 3-4 days and in the liver approximately 10 hours64. High-pressure fluid-chromatography measurements can be used to measure levels of NAD. The measuring method can be replicated easily and is a reliable method for measuring levels of NAD in human blood195, 197. Standard blood-tests, which provide an indication of NAD levels, consist of the lactate and pyruvate, ß-hydroxybutyrate and acetoacetate measurements138. The latter two measurements indicate the mitochondrial levels of NAD/NADH and this is a useful measurement for determining possible defects in the citric-acid cycle. In the presence of NAD or NADP 15-18% of the cortisol was converted to cortisone: no other products could be detected443.
“A significant decline of cellular energy after aerobic performance was detected with both approaches to a similar extent (P<0.01). However, the extracellular NADH metabolisation assay (ENMA) is more convenient to perform than the determination of intracellular ATP/ADP. Due to its easy and versatile handling, a huge array of possible applications like monitoring the training efficiency of athletes, the fitness of senior citizens or the recovery from disease may be envisioned.”775
5.6.3 Duration and Effect of NAD Therapy
NAD is not a drug and it takes a while before its effect can be consciously experienced. Most people become aware of an increase in energy after four or six weeks' supplements. It is furthermore also important to bear in mind, that NAD Therapy only provides energy for dealing with problems and cannot solve problems on its own. It provides the energy that is necessary to be able to identify and deal with the psychological and mental problems, which contribute or are due to low levels of energy.
Clinicians found during their treatment of a patient with MELAS, that the supplements' effect could be observed in the level of erythrocytes, after 6 weeks' treatment. The blood level of lactate to pyruvate declined by 50% within 3 days and its urine level declined within two weeks. Clinical improvement and reduction of scarring in the brain, as determined by MRI scans, occurred within a month140.
“Alkylating agents cause a marked depletion of cellular NAD+ levels by activating nuclear ADP-ribosyl transferase (ADPRT), which utilizes NAD+ as a substrate in the synthesis of poly(ADP-ribose). As a consequence of NAD+ depletion, it is possible that cellular ATP pools could be depleted. Because of this, exogenously supplied NAD+ had been proposed as a way to counteract some of the effects of an alkylator. We found that exogenously supplied NAD+ significantly increased intracellular levels of NAD+.”777
5.6.4 Safety of NAD Therapy
NAD Therapy has been used intravenously in South Africa since 1974 and, according to the manufacturer, no side-effects have yet been reported by clinicians. More than 15 000 NAD supplements (500 mg per drip) have been administered intravenously at Alkogen since 1989, to more than 6 000 patients, who ranged in age from as young as 9 - 90. Furthermore, no race-, gender- or age-related contra-indications were encountered. Since 1995 many patients have used 50mg of NAD orally disolved in 340ml of carbonated sodawater. This has now become the norm because almost all of the 6 000 patients at Alkogen and those of the 120+ participating private practitioners have changed to the 50mg NutriNAD capsules specifically formulated for such use.
The following information is based on confidential results from research, that is in the possession of the manufacturer of the intravenous form of NAD. The same quality of NAD is also used in the MultiNAD capsules. The lethality dosage (LD50) of NAD is as follows:
Results of acute toxicity do not indicate any pathological changes in mice, rabbits, rats or dogs. Results of chronic toxicity after 52 weeks, during which NAD of up to 300 mg/kg was administered intramuscularly to rats every day, indicate no toxicity that can be attributed to NAD. Haematological evaluations, blood-chemical measurements and histopathological examinations of the heart, liver, kidneys, spleen, gonad, adrenal glands, thyroid and pituitary gland did not yield any significant changes. The same research indicates no significant changes during reproduction and gestation in rats. The NAD infusion is terminated on all patients during pregnancy, irrespective of these findings. During pregnancy only the capsules are continued with.
5.6.5 Stability of NAD Therapy
The NAD in the NutriNAD, MalaikaNAD and in the MultiNAD capsules consists of the same form of NAD. NAD is a powder, that ranges in colour from white to pale yellow. The NAD vials have an expiry date of two years after manufacturing, when stored in a refrigerator. If the NAD is in any solution, it will remain stable in a refrigerator for at least a week. All NAD preparations must therefore preferably be in powder form and must be stored in a refrigerator or cool place. A Canadian company recently changed thieir bottles to read NAD instead of NADH. NAD, known as Coenzyme 1, plays an important role in energy production. The company, felt that NADH was less stable as a supplement than NAD638.
5.6.6 Alternative Names for NAD
NAD is also referred to in literature as diphosphopyridine nucleotide (DPN), nadide, adenine-D-ribose-phosphate-phosphate, cozymase, coenzyme 1, D-ribose-nicotinamide, vitamin PP and enzopride.
5.6.7 NAD Therapy and Interaction with Other Medication
No contra-interaction with any other medication, like antidepressants, neuroleptics or other medications, was reported with the use of the NAD containing capsules. It was however found, that the dosages of some medications (antihypertensives, insulin, medication for cholesterol, antidepressants, anxioliticums etc) have to be decreased in time. What however does happen, are that side-effects similar to an overdose of other medications, which are used at the same time, often come to the fore. Medication for blood pressure is an example of this. NAD stabilises the person's blood pressure and therefore the dosages of the medication for blood pressure must be adjusted accordingly, to prevent side-effects such as a too high or low blood pressure. What also happens often, is that other symptoms and conditions, which were masked by the EMD, become apparent to the EMD sufferer, when the body becomes stabilised. It is then incorrectly referred to as side-effects of NAD Therapy.
5.6.8 Contra-indication for NAD Therapy
According to the manufacturer, no contra-indication has been reported since 1974 by any clinician, for the use of NAD. NAD must however be used with care in persons with Gilbert's disease, in whom it can cause serious abdominal pain65.
5.7 HOMEOPATHY AND NAD THERAPY
Many of the medications, that are utilised in the practising of homeopathy, in the form of tablets and injections, contain NAD. The use of NAD Therapy is in line with the natural order, that is adhered to by disciplines which use natural healing. These medications are used to treat a large variety of conditions and particularly in homotoxilogy. These medications have furthermore been used for many years.
5.8 POPULARITY OF NAD THERAPY
Although NAD Therapy were used in the treatment of alcoholism since 1939, patented in 1964 and the NAD vials officially registered in 1974 in South Africa it is still relatively unknown by treatment professionals. A possible explanation is that treatment professionals not working with substance dependency or those working with substance dependency from the moral treatment approach would probably be not aware of NAD Therapy and its energy related characteristics. NAD has been available as oral supplements in capsule form since 1997 in South Africa. An international researcher ascribes the relative unpopularity of NADH, also applicable to NAD therapy, to its high cost of around 10,000 dollars per kilogram346. Several laboratories around the world are currently involved in studies for the development of NAD analogues for therapeutical applications92. Although NAD is part of all nature and man since creation, NAD Therapy is relatively new. The chronological course of NAD reveals that it only picked up momentum since the ground breaking article of Prof Cleary in 1986.
∙ 1904 The coenzyme nicotinamide adenine dinucleotide (NAD) is identified
∙ 1939 NAD is first used for the treatment of alcoholism
∙ 1955 Dr Hoffer uses NAD for the treatment of scizophrenia
∙ 1961 Dr O’Halleren uses NAD-drips for the treatment of all chemical addictions
∙ 1970 The role of the mitochondria in various diseases are outlined
∙ 1974 The NAD-drips are registered and manufactured in South Africa for the treatment of acute and chronic alcoholism
∙ 1986 Prof Cleary writes the first article on NAD Deficiency Diseases
∙ 1989 Alkogen is founded for the outpatient treatment of all chemical addicts with NAD-drips
∙ 1993 Mitochondrial DNA are identified as mainly maternally inherited
∙ 1994 Patients with a variety of disorders are treated at Alkogen with NAD-drips
∙ 1997 Alkogen manufactures the capsule MultiNAD and other nutritional supplements containing the metabolic energy cofactors
∙ 2000 The Afrikaans edition of this NAD Therapy ebook was published
∙ 2002 The first edition of this NAD Therapy ebook is published in which more than 100 disorders relating to NAD Deficiency are discussed
∙ 2003 Alkogen manufactures the capsule NutriNAD with 50mg pure NAD replacing the NAD-drips in the Alkogen treatment program
∙ 2003 Prof Cleary published the first international article on Alkogen’s NAD Therapy
∙ 2003 Nutrimalaika, the nurses-led centres, is founded for the treatment of infants and children up to 12 years, old suffering from EMD with MalaikaNAD (especially formulated for children) and NutriNAD supplements.
5.9 SPORT AND NAD THERAPY
“We previously reported that the blood NAD levels are decreased by severe exercise. College female students exercised moderately with bike-ergometers. The blood NAD levels elevated after moderate exercise. However, the blood NAD levels decreased after all-out exercise. The changes in whole blood tryptophan (a precursor of pyridine nucleotides) levels were similar to that in NAD. The glucose levels in whole blood and the non-esterified fatty acid levels in serum decreased according to exercising time.” 774
The Cori Cycle operates during exercise, when aerobic metabolism in muscle cannot keep up with energy needs. Glucose synthesized in liver and transported to muscle and blood. A highly exercising muscle generates a lot of NADH from glycolysis but without oxygen there is no way to regenerate NAD from the NADH (need NAD!). Lactic acidosis can and would result from insufficient oxygen (an increase in lactic acid and decrease in blood pH). So, the NADH is reoxidized by reduction of pyruvate to lactate by enzyme lactate dehydrogenase. Results in replenishment of NAD for glycolysis. Then the lactate formed in skeletal muscles during exercise is transported to the liver where it is used for gluconeogenesis. Lactate is transported through the bloodstream to the liver. Lactate is oxidized to pyruvate in the liver. Liver lactate dehydrogenase reconverts lactate to pyruvate since has high NAD/NADH ratio. Pyruvate is used to remake glucose by gluconeogenesis. Glucose is transported back to the muscles via the bloodstream. 733