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Tab       DiOne (Diacerein, Glucosamine, Chondroitin and MSM) Brand: DiOne Generic: Diacerein, Glucosamine, MSM and Chondroitin Class: Medical Food Supplement Route of administration: Oral Dosage form: Tablet Dose: 1 tablet twice a day Contraindications: Pregnancy: Cat. C Pack Size: 30 tabs. Price: Rs. 960/- Supplement facts: Supplement Amount per serving Diacerein 50mg Glucosamine 600mg Chondroitin 400mg MSM 168mg 1. Diacerein The use of diacerein for the treatment of osteoarthritis is still under sometimes controversial discussion. Its postulated modes of action, all indicating IL-1 antagonism, make the drug an interesting option for the treatment of osteoarthritis not only for symptom relief but also for structure modification. Studies in different animal models [1-8] showed that diacerein consistently moderated cartilage loss in osteoarthritis. In humans, the ECHODIAH trial [9] showed a reduction in the progression of hip osteoarthritis in the diacerein-treated patients compared with the placebo group. Overall, this meta-analysis provides evidence for statistically significant and clinically relevant efficacy of diacerein on improvement of pain and function in patients with hip and/or knee osteoarthritis. The large number of patients included in this meta-analysis gives the basis for well-founded conclusions to be drawn. Considering the pain relief results, one has to consider that complete withdrawal of analgesic co-medication was not possible during the studies analyzed. In most of the trials, acetaminophen, which is also considered an appropriate treatment modality for moderate osteoarthritis, [10,11] was allowed as an escape medication in both the diacerein and control groups, and the amount taken was recorded by the patient in a diary. However, although mean intake of acetaminophen was similar during the active treatment period, its consumption increased significantly in the NSAID-treated patients, but not in the diacerein group, during the treatment-free follow-up period. After the end of treatment, SYSADOAs are supposed to have a carryover effect [12] In this meta-analysis, we found evidence for this carryover effect with respect to pain and consumption of escape medication in all sub analyses performed, not only in the individual trials but also in the pooled population, and not only compared with placebo [13,14] but also with active treatment modalities comprising diclofenac sodium, [15,16] tenoxicam, [17] piroxicam,[18,19] and naproxen [20]. Given the fact that all selected studies had a randomized, controlled, parallel-group de-sign, these findings indicate a positive impact of diacerein on the clinical status of patients with osteoarthritis. The patient’s global tolerability ratings at the end of active treatment showed no statistically significant differences between other active treatments and diacerein. However, as expected, a significant inferiority of diacerein vs placebo was observed, also indicating reproducibility of the results obtained here. The risk-benefit ratio associated with long-term use of NSAIDs and analgesics is well documented in the literature, [20,21-23] but clinical studies on the use of NSAIDs for more than 6 weeks in patients with osteoarthritis are rare [20,24]. Nonsteroidal anti-inflammatory drugs, particularly the selective cyclooxygenase-2 inhibitors, are known to exert a higher risk for thromboembolic disorders such as myocardial infarction or stroke [25]. In this context, it is important to consider that most patients affected by osteoarthritis also experience disorders, or at least risk factors, of the cardiovascular system and that according to the European Agency for the Evaluation of Medicinal Products [26] and the Food and Drug Administration, [27] NSAIDs should be administered at the lowest possible dose for the shortest period. In contrast, cardiovascular adverse events in patients treated with diacerein can be considered very rare. In France, over a period of 11 years (from September 1994 to November 2005) and with more than 14 million prescriptions of diacerein, only 9 cases of cardiovascular adverse events with diacerein were spontaneously reported (information collected by the Drug Safety Department, Negma-Lerads, Toussus-Le-Noble, France). In particular, no acute coronary syndrome or myocardial infarction was reported. Thus, with respect to tolerability, diacerein may have some advantages compared with long-term application of NSAIDs. 2. Glucosamine and Chondroitin Currently, glucosamine (glucosamine sulfate (GS); glucosamine hydrochloride (GH)) and CS are the most commonly used supplements to ease the pain and discomfort of arthritis in humans and animals. Glucosamine and chondroitin are components of the ECM of articular cartilage. Glucosamine (2-amino-2-deoxy-d-glucose) is an amino sugar and a constituent of glycosaminoglycan (GAG), which plays a role in the normal growth and repair of articular cartilage. In fact, glucosamine is considered a building block of cartilage. Glucosamine is extracted from crab, lobster, and shrimp shells. Following oral administration of either GS or GH, these salts are ionized in the stomach, making glucosamine available for absorption in the small bowel. Ninety percent of GS is absorbed, but due to an extensive first-pass metabolism, bioavailability approaches only 25% [28] Its excretion is mainly through the kidneys, with only a small unmodified amount eliminated through the stool. CS is a sulfated GAG composed of a chain of alternating sugars, N-acetyl-d-galactosamine and d-glucuronic acid. CS is a normal constituent of aggrecan, the major proteoglycan of articular cartilage. It is extracted from animal cartilage, such as trachea and shark cartilage. Due to its larger size as compared to glucosamine, approximately 30% of CS is absorbed, with 12–13% bioavailability [29]. Studies suggest that glucosamine helps relieve pain by enhancing proteoglycan synthesis, which is impaired in osteoarthritic cartilage [30] . [31] investigated the effects of glucosamine on MMP production, MAPK phosphorylation, and activator protein (AP)-1 transcription factor activation in human chondrocytes. Findings revealed that glucosamine reduced the expression of MMPs (MMP-1, MMP-3, andMMP-13) and inhibited c-jun amino terminal kinase, p38 phosphorylation, and, consequently, c-jun binding activity. In essence, glucosamine inhibits IL-1β-stimulated MMP production in human chondrocytes by affecting MAPK phosphorylation. The glucosamine and CS combination suppresses IL-1-induced gene expression of iNOS, COX-2, mPGEs, and NF-κB in cartilage explants. This leads to reduced production of NO and PGE2, two mediators responsible for the cell death of chondrocytes and inflammatory reactions [32]. CS provides hydration, assists in cushioning impact stress, helps create osmotic pressure within the ECM to maintain the compressive resistance of cartilage, improves function/mobility of the joint, reduces the progression of OA, and reduces joint pain [33] CS has been shown to increase hyaluronan production by human synovial cells, which has a beneficial effect on maintaining viscosity in the SF. CS stimulates chondrocyte metabolism, leading to the synthesis of collagen and proteoglycan, the basic components of new cartilage [34]. CS also provides elasticity and assists in cushioning impact stress. It is suggested that CS may help the body to repair damaged cartilage and help restore joint integrity. It may also protect existing cartilage from premature breakdown. Because CS production by the body decreases with age, its supplementation may be especially helpful for older humans. Furthermore, CS inhibits the enzymes leukocyte elastase and hyaluronidase, which are found in high concentrations in SF of patients with rheumatic diseases. It has also been hypothesized to reduce inflammation, inhibit synthesis of degradative enzymes including MMPs, increase synthesis of ECM constituents, and reduce apoptosis of articular chondrocytes [35]. [36] reviewed details of the biochemical basis of the effect of CS on OA articular tissue. At molecular levels, CS inhibits NF-κB nuclear translocation and phosphorylation of p38 MAPK, ERK1/2, and JNK [37]. When given in combination, these two supplements: stimulate the synoviocyte and chondrocyte metabolism; inhibit the enzymatic degradation and reduce the fibrin thrombi in the periarticular microcirculation; and can regulate the genetic expression and the synthesis of NO and PGE2, thereby exerting anti-inflammatory properties. In addition to anti-inflammatory action, GS and CS exhibit an antioxidant expression that leads to a significant reduction in iNOS expression and activity [38], thereby reducing the otherwise NO-induced cell death of chondrocytes. In several studies, GS and CS have been evaluated as single agents and in combination for the treatment of OA. In fact, it is a common practice for glucosamine and chondroitin to be used together because they offer a greater beneficial effect than when given alone, although they work through different mechanisms of action. In a clinical trial, GS was found to be as effective or slightly more effective than analgesics [39,40,41,] or NSAIDs [42] for decreasing pain. A trial by [43] did not show a difference between GS and placebo. In another clinical trial,GS was found to be ineffective for reducing pain in patients with severe knee OA, but it was more effective when it was used in combination with CS due to a synergistic effect in patients with moderate to severe pain [44] found that the chondroprotective agents (GS and CS) were effective in improving the function of patients with OA, but the radiological modifications in the knee were statistically insignificant after 12 months of monitoring. However, the findings of Narvy and Vangsness (2010) supported a role of these nutraceuticals in reducing radiographic progression of knee OA. Recently, Kozakcioğlu (2012) revealed that GS and CS both have a suppressor effect on the structural deformities of OA. In a recent study, Erhan et al. (2012) showed that topical glucosamine treatment combined with physical therapy in patients with knee OA had no superiority over placebo, based on radiological findings (Kellgren– Lawrence score) and joint stiffness index (Western Ontario and McMaster Osteoarthritis, WOMAC score). In all clinical trials, GS, GH, and CS were found to be as safe as placebo [45]. The acute oral LD50 of glucosamine is >8 g/kg in rats and 15 g/kg in mice, which can be considered nontoxic. Oral administration of glucosamine at 2,700 mg/kg for 12 months in animals produced no adverse effects. Oral administration of large doses of glucosamine in animals has no documented effects on glucose metabolism. However, Lafontaine-Lacasse et al. (2011) reported that, at beyond recommended dosages, glucosamine may damage pancreatic cells, thereby possibly increasing the risk of developing diabetes. In a few patients, hepatotoxicity (hepatitis and/or cholestasis) developed following exposure to glucosamine [46] These authors established a temporal relationship between onset of liver injury and glucosamine ingestion. Clinical studies have not identified any significant side effects of CS, which suggests its long-term safety [47]. Recently, the Task Force of the European League against Rheumatism (EULAR) committee also granted CS a level of toxicity of 6 on a 0–100 scale, confirming that CS is one of the safest remedies for OA. Currently, glucosamine and chondroitin are not recommended by Osteoarthritis Research Society International (OARSI) and the American College of Rheumatology (ACR) [48]. In dogs with moderate OA, daily administration of GH (2,000 mg) and CS (1,600 mg) for a period of 120–150 days significantly reduced pain associated with OA [49]. Gupta et al. (2009) also reported significant reduction of pain in horses with moderate OA receiving GH (5.4 g) and CS (1.8 g) daily for a period of 150 days. In both dogs and horses, GH and CS produced no side effects and were well-tolerated. Previously, in a number of in vivo and in vitro studies, GS and CS have been found to be very effective against OA in animal models [50]. These studies suggested that the combination of GS and CS appears to be more effective in preventing or treating OA in animals than either product alone. A Golden Retriever developed polyuria and polydipsia when treated with 1,000 mg of glucosamine/day [51]. The polyuria and polydipsia resolved after the glucosamine dose was lowered to 500 mg/day. In an experimental study, glucosamine was reported to cause hyperglycemia, insulin resistance, and a diabetic-like state in rats [52]. Beriault et al. did not confirm hyperglycemia and insulin resistance with glucosamine, but it promoted endoplasmic reticulum stress, hepatic steatosis, and accelerated atherogenesis in mice. 3. Methylsylfonylmethane (MSM) Methylsylfonylmethane (MSM), also known as methyl sulfonate or dimethyl sulfone, is a naturally occurring organosulfur compound and a putative methyl donor. MSM is the first oxidized metabolite of dimethyl sulfoxide (DMSO). It occurs naturally in some plants and it is added in small amounts to many foods and beverages as a dietary supplement. Currently, MSM is sold via 52 different products as a single agent in capsule, caplet, lotion, and cream forms, and in more than 30 different products in combination with other dietary supplements. MSM is sold as a dietary supplement and marketed with a variety of claims often in combination with glucosamine and/or chondroitin for helping to treat or prevent OA. However, there is a paucity of scientific evidence to support the use of MSM. It has been suggested that the benefits claimed for MSM far exceed the number of scientific studies. In October 2000, the US Food and Drug Administration (FDA) warned one MSM promoter, Karl Loren, to cease and desist from making therapeutic claims for MSM. Due to its sulfur content, MSM is used by the body to maintain normal connective tissue. MSM may have anti-inflammatory activity, chemopreventive property, prostacyclin (PGI2) synthesis inhibition, antiatherosclerotic action, salutary effect on eicosanoid metabolism, and free radical scavenging activity [53,54]. MSM is an analgesic, anti-inflammatory, and blood vessel dilator. In OA, MSM works by reducing inflammation and blocking the pain response in nerve fibers. However, like any other nutraceutical, MSM does not cure OA. MSM serves the same purpose as the NSAIDs, but MSM has none of the negative outcomes associated with NSAIDs. In a randomized, double-blind, placebo-controlled trial,[54] reported that compared to placebo, 3 g of MSM twice per day (6 g/day total) for 12 weeks produced significant decreases in WOMAC pain and physical function impairment (P < 0.041 and P < 0.045, respectively). No notable changes were found in WOMAC stiffness and aggregated total symptoms scores. MSM ameliorated symptoms of pain and improved physical function during the intervention without major adverse events. In another clinical trial, patients with OA of the knee taking MSM daily (1.125 g three times) for 12 weeks showed a decrease in pain and improvement in physical function [55]. In a 12-week trial,[56] treated patients with knee OA with 1.5 g MSM (500 mg three times per day), 1.5 g glucosamine sulfate (GS), MSM plus GS, or placebo for 12 weeks. Significant decreases in the Lequesne Index were reported with MSM, GS, and their combination (P < 0.05). The authors reported a 33% decrease in pain in the MSM group; joint mobility, swelling, global evaluation, and walking time were also improved. The MSM dosage used by [56] was lower than the recommended dosage of MSM for clinical practice. In all of these studies, the improvements were small; therefore, further studies are warranted to establish their clinical significance. For further details on the effects of MSM and DMSO in OA, readers are referred to [57]. Acute and subchronic toxicity studies in rats using a single dose of 2 g/kg and a daily dose of 1.5 g/kg MSM for 90 days showed no adverse events, organ pathology, or mortality [58]. These doses of MSM are considered five times to seven times the maximum dose used in humans [54]. There are no clinical studies on adverse effects, changes in blood chemistry, safety monitoring data, or possible subclinical neurotoxicity symptoms. Side effects of MSM following its oral use are mild and may include digestive upset, headaches, increased blood pressure, increased hepatic enzymes, allergic reactions, and skin rashes. References: 1. Pavelka K, Trc T, Karpas K, et al. The efficacy and safety of diacerein in the treatment of painful knee osteoarthritis: a randomised, double-blind, placebo controlled multicentre study. Poster presented at: The Annual European Congress of Rheumatology, EULAR; June 8-11, 2005; Vienna, Austria. 2. Brandt KD, Smith G, Kang SY, et al. Effects of diacerhein in an accelerated canine model of osteoarthritis.Osteoarthritis Cartilage 1997;5:438-449 3. Smith GN Jr, Myers SL, Brandt KD, Mickler EA, Albrecht ME. Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis. Arthritis Rheum 1999;42:545-554. 4. Ghosh P, Xu A, Hwa SY, Burkhardt D, Little C. Evaluation of the effects of diacerhein in the sheep model of arthritis [in French]. Rev Prat. 1998;48(17) (suppl):S24-S30. 5. Bendele AM, Bendele RA, Hulman JF, Swann BP. The beneficial effects of diacerein treatment in a guinea pig model of osteoarthritis [in French]. Rev Prat.1996;46:S35-S39. 6. Bendele A, Bendele R, Hulman J, Swann B. A chronic study of the efficacy and toxicity of diacerhein treatment of guinea pigs with osteoarthritis. Abstract presented at: The 2nd OARS International Congress Symposium: Research and Therapeutics in Osteoarthritis: IL-1 Inhibitors; February 4-5, 1995; Nice, France. 7. Mazieres B, Berda L. Effect of diacerhein (art 50) on an experimental postcontusive model of OA [abstract]. Osteoarthr Cartil. 1993;1:47. 8. Douni E, Sfikakis PP, Haralambous S, Fernandes P, Kollias G. Attenuation of inflammatory polyarthritis in TNF transgenic mice by diacerein: comparative analysis with dexamethasone, methotrexate and anti-TNF protocols. Arthritis Res Ther. 2004;6:R65-R72. 9. Dougados M, Nguyen M, Berdah L, et al. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo controlled trial: Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539-2547. 10. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, II: osteoarthritis of the knee.Arthritis Rheum. 1995;38:1541-1546. 11. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, I: osteoarthritis of the hip.Arthritis Rheum. 1995;38:1535-1540. 12. Lequesne M, Brandt K, Bellamy N, et al. Guidelines for testing of slow acting drugs in osteoarthritis. J Rheumatol Suppl. 1994;41:65-73. 13. Pelletier JP, Yaron M, Haraoui B, et al; the Diacerein Study Group. Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo controlled trial. Arthritis Rheum. 2000;43:2339-2348. 14. Lequesne M, Berdah L, Gerentes I. Efficacy and tolerance of diacerhein in the treatment of gonarthrosis and coxarthrosis [in French]. Rev Prat. 1998;48(17) (suppl):S31-S35. 15. Tang FL, Wu DH, Lu ZG, Huang F, Zhou YX. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee. Poster presented at: The 11th Asia Pacific League of Associations for Rheumatology (APLAR) Congress, International Convention Center (ICC); September 11-15, 2004; Jeju, Korea 16. Mantia C. A controlled study of the efficacy and tolerability of diacetylrhein in the functional manifestations of osteoarthritis of the hip and the knee: a double blind study versus diclofenac. Unpublished clinical study report; Palermo Hospital, Palmero, Italy; 1987 17. Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein in the treatment of osteoarthritis of the hip. Arthritis Rheum. 1994;37:529-536 18. Louthrenoo W, Nilganuwong S, Aksaranugraha S, et al. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: a randomised, multicentre, double-blind, piroxicam-controlled, parallel-group, phase III study. Poster Presented at: The 11th Asia Pacific League of Associations for Rheumatology (APLAR) Congress, International Convention Center (ICC); September 11-15, 2004; Jeju, Korea 19. Pietrogrande V, Leonardi M, Pacchioni C. Results of a clinical trial with a new drug, diacerhein in arthrosic patients. Report presented at: The LXXXVI Congress of the Italian National Society of Internal Medicine; September 24, 1985; Sorrento, Italy. 20. Portioli IA. Naproxen-controlled study on the efficacy and tolerability of diacetylrhein in the functional manifestations of osteoarthritis of the knee and hip: a double- blind study versus naproxen. Unpublished clinical study report; Santa Maria Nuova Hospital, Reggio Emilia, Italy; 1987 21. Leeb BF, Bucsi L, Keszthelyi B, et al. Treatment of osteoarthritis of the knee joint. efficacy and tolerance to acemetacin slow release in comparison to celecoxib [in German].Orthopade. 2004;33:1032-1041. 22. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet.1994;343:769-772. 23. Brandt KD. Should osteoarthritis be treated with nonsteroidal anti-inflammatory drugs? Rheum Dis Clin North Am. 1993;19:697-712 24. Dieppe P, Cushnaghan J, Jasani MK, McCrae F, Watt IA. Two-year, placebo controlled trial of non-steroidal anti-inflammatory therapy in osteoarthritis of the knee joint. Br J Rheumatol. 1993;32:595-600 25. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364:2021-2029 26. The European Agency for the Evaluation of Medicinal Products. Questions and answers on non-selective NSAIDs: CHMP review of safety of non-selective NSAIDs. London, England: European Agency for the Evaluation of Medicinal Products; 2005. Publication EMEA/250423/2005 27. Food and Drug Administration. Public health advisory non-steroidal anti-inflammatory drug products (NSAIDs). 2006. http://www.fda.gov/cder/drug/advisory/nsaids.htm. Accessed February 1, 2006 28. Setnikar, J., Rovati, L.C., 2001. Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review. Arzneimittelforschung 51, 699–725. 29. Deal, C.L., Moskowitz, R.W., 1999. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum. Dis. Clin. North Am. Huskisson, E.C., 2008. Glucosamine and chondroitin for osteoarthritis. J. Int. Med. Res. 36, 1161–1179 25, 379–395. 30. Hooper, M., 2001. Is glucosamine an effective treatment for osteoarthritic pain? Cleve. Clin. J. Med. 68, 494–495. 31. D’Abusco, A.S., Calamia, V., Cicione, C., et al., 2007. Glucosamine affects intracellular signaling through inhibition of mitogen-activated protein kinase phosphorylation in human chondrocytes. Arthritis Res. Ther. 9, R104. 32. Chan, P.S., Caron, J.P., Rosa, G.J., Orth, M.W., 2005. Glucosamine andchondroitin sulfate regulate gene expression and synthesis of nitric oxide and prostaglandin E2 in articular cartilage explants. Osteoarthritis Cartilage 13, 387–394. 33. Frech, T.M., Clegg, D.O., 2007. The utility of nutraceuticals in the treatment of osteoarthritis. Curr. Rheumatol. Rep. 9, 25–30. Hochberg, M.C., Zhan, M., Langenberg, P., 2008. The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebocontrolled trials of chondroitin sulfate. Curr. Med. Res. Opin. 24, 3029–3035. 34. Jerosch, J., 2011. Effects of glucosamine and chondroitin sulfate on cartilage metabolism in OA: outlook on other nutrient partners especially omega-3 fatty acids. Int. J. Rheumatol. 2011, 1–17. 35. Vangness, C.T., Spiker, W., Erickson, J., 2009. A review of evidencebased medicine for glucosamine and chondroitin sulfate use in knee osteoarthritis. Arthroscopy 25, 86–94. 36. Monfort, J., Pelletier, J.P., Garcia-Giralt, N., Martel-Pelletier, J., 2008. Biochemical basis of the effect of chondroitin sulfate on osteoarthritis articular tissues. Ann. Rheum. Dis. 67, 735–740. 37. Jomphe, C.R., Gabriac, M., Hale, T.M., et al., 2008. Chondroitin sulfate inhibits the nuclear translocation of nuclear factor-kappa B ininterleukin-1beta-stimulated chondrocytes. Basic Clin. Pharmacol. Toxicol. 102, 59–65. 38. Valvason, C., Musacchio, E., Pozzuoli, A., et al., 2008. Influence ofglucosamine sulfate on oxidative stress in human osteoarthritic chondrocytes: effects of HO-I, p22(Phox) and iNOS expression. Rheumatology 47, 31–35. 39. Lopez, V.A., 1982. Double-blind clinical evaluation of the relative efficcacy of ibuprofen and glucosamine sulfate in the management of osteoarthritis of the knee in out-patients. Curr. Med. Res. Opin. 8, 145–149. 40. Muller-Fassbender, H., Bach, G.L., Haase, W., et al., 1994. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 2, 61–69 41. Qiu, G.X., Gao, S.N., Giacovelli, G., et al., 1998. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung 48, 469–474. 42. Towheed, T.E., Anastassiades, T.P., Shea, B., et al., 2001. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst. Rev. CD002946. 43. McAlindon, T., Formica, M., LaValley, M., et al., 2004. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based randomized double-blind controlled trial. Am. J. Med. 117, 643–649. 44. Sawitzke, A.D., Shi, H., Finco, M.F., et al., 2008. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 58, 3183–3191. 45. Anderson, J.W., Nicolosi, R.J., Borzelleca, J.F., et al., 2005. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem. Toxicol. 43, 187–201. 46. Smith, A., Dillon, J., 2009. Acute liver injury associated with the use of herbal preparations containing glucosamine: three case studies.BMJ Case Rep. 1603, 1–8. 47. Hathcock, J.N., Shao, A., 2007. Risk assessment for glucosamine and chondroitin sulfate. Regul. Toxicol. Pharmacol. 47, 78–83. 48. Singh, J.A., Furst, D.E., Bharat, A., et al., 2012. Update of the 2008 American College of Rheumatology recommendation for the use of disease modifying anti-rheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 64,625–639. 49. Gupta, R.C., Canerdy, T.D., Lindley, J., et al., 2011. Comparative therapeutic efficacy and safety of type-II collagen (UC-II), glucosamine and chondroitin in arthritic dogs: pain evaluation by ground force plate. J. Anim. Physiol. Anim. Nutr. 96, 770–777. 50. Dechant, J.E., Baxter, G.M., Frisble, D.D., et al., 2005. Effects of glucosamine hydrochloride and chondroitin sulfate, alone and in combination, on normal and interleukin-1 conditioned equine cartilage explants metabolism. Equine Vet. J. 37, 227–231. 51. Breese McCoy, S.J., Bryson, J.C., 2003. High-dose glucosamine associated with polyuria and polydipsia in a dog. J. Am. Vet. Med. Assoc. 222, 431–432. 52. Giaccari, A., Morviducci, L., Zorretta, D., et al., 1995. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycemia. Diabetologia 38, 518–524. 53. Ebisuzaki, K., 2003. Aspirin and methylsulfonylmethane (MSM): a search for common mechanisms, with implications for cancer prevention. Anticancer Res. 23, 453–458. 54. Kim, L.S., Axelrod, L.J., Howard, P., et al., 2006. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage 14, 286–294. 55. Debbi, E.M., Agar, G., Fichman, G., et al., 2011. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complement. Altern. Med. 11, 50. 56. Usha, P., Naidu, M., 2004. Randomized, double-blind, parallel, placebo- controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin. Drug Investig. 24, 353–363. 57. Brien, S., Prescott, P., Bashir, N., et al., 2008. Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) in the treatment of osteoarthritis. Osteoarthritis Cartilage 16, 1277–1288. 58. 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Cap    Valmar (Melatonin, 5-HTP, Pyridoxine & more) Brand: Valmar Generic: Melatonin, 5-HTP, Pyridoxine & more Class: Medical Food Supplement Route of administration: Oral Dosage form: Capsule / Syrup Dose: Capsule : Syrup Contraindications: Pregnancy: Cat. C Pack Size: 30 caps. Price: Capsule: Rs. 410/- | Syrup: Rs. 170/- Supplement facts: Supplement Amount per serving Melatonin 3mg 5-HTP 50mg Pyridoxine 2mg Valmar Blend (Valerian,GABA,L-Glycine,Passion flower, Lemon balm, L-theanine, English lavender) 519mg 1. Melatonin Melatonin is an indoleamine with the chemical name N-acetyl-5-methoxytryptamine and is found in animals, plants, and bacteria. It has endocrine and antioxidant properties in both animals and plants. It is biosynthesized from the neurotransmitter serotonin, which in turn is made from the essential amino acid tryptophan. Because its normally charged amino group is acetylated and a methoxy rather than a hydroxyl group is present in the 5 position, melatonin is a relatively nonpolar compound that readily crosses the blood–brain barrier (BBB) and easily enters cells of all types. In mammals, melatonin has several roles; it is involved in circadian regulation and modulation of reproductive and immune responses, mood, and aging. It is produced by the pineal gland and several peripheral tissues, notably the gut [1]. Because it is liberated into the bloodstream from the pineal and acts through receptors located in a wide variety of body tissues, it can be considered a systemic hormone. Levels of melatonin vary diurnally, seasonally in some mammals, and throughout the life cycle. They are highest during hours of darkness and are lowest among the elderly. This chapter focuses on two areas: (i) recent findings suggesting a variety of therapeutic applications—ranging from improvement of disturbed sleep patterns and mood disorders to adjuvant cancer treatment and surgery and fertility enhancement and (ii) support for the safety of exogenously supplied melatonin. The potential molecular mechanisms underlying these potentially clinically beneficial uses are also discussed. 1.2. Range Of Conditions Where Melatonin May Have Clinical Utility The evidence for the beneficial properties of melatonin in the derangements described is often derived from studies on animal models of disease, but any relevant human findings are also added to each section. 1.2.1. Disturbances of Sleep Patterns Melatonin is perhaps most well-known for its ability to induce sleep. Plasma levels are highest during hours of darkness and decline rapidly at the onset of light. Thus, melatonin is widely used to reset normal circadian sleep patterns after disruption by jet lag. Sleep quality can be defined by tiredness upon waking, feeling rested, and the number of awakenings experienced during the night. This can be partly correlated with objective polygraphic measures to determine the extent of fragmentation of sleep. Melatonin has been found to improve sleep quality in patients with a variety of diseases. A dosage of 3 mg/day taken at bedtime for 24 days in a group of 2,062 patients with chronic cerebral ischemia improved multiple types of subjective sleep characteristics [2]. An analysis was made combining results from four clinical trials studying the effects in 401 hypertensive patients aged 55 years or older. The analysis determined that 2 mg/ day of prolonged-release melatonin taken 2 h before bedtime for 3 weeks improved quality of sleep and morning alertness [3]. The improvements in sleep quality were maintained during a follow-up period of 6 months; moreover, the rate of adverse events was lower in the patients using melatonin. Although melatonin had no significant effect on blood pressure in this study, a meta-analysis of seven other clinical trials demonstrated that 2–3 mg/day of controlled-release (but not fast-release) melatonin over periods of 28–90 days significantly reduced nocturnal blood pressure in a variety of subjects, including those with hypertension [4]. In a study of 36 type 2 diabetic individuals, a regimen of 2 mg/day of prolonged-release melatonin taken 2 h before bedtime for 3 weeks resulted in significant improvement in sleep efficiency, wake time after sleep onset, and reduced number of awakenings [5]. The melatonin receptor agonist ramelteon has been used to treat chronic insomnia clinically with success [6]. Some studies demonstrate that melatonin improves sleep quality more modestly. In a recent review of 35 randomized clinical trials, use of melatonin by healthy adults was found to show limited promise for preventing phase shifts from jet lag and for improving insomnia; both healthy adults and insomniacs benefited. However, available data could not confirm a positive benefit for either the initiation of sleep or sleep efficacy [7]. Aging is associated with an altered sleep profile; sleep time is shortened and sleep is more disrupted. Sleeplessness is often found with cardiovascular disease, obesity, type 2 diabetes, cancer, and a range of inflammatory disease states. There is evidence that melatonin can be of use in amelioration of the disrupted sleep associated with Alzheimer’s disease (AD) [8], but this is disputed [9]. Melatonin has also found utility in hypertensive patients in the treatment of sleep disruption caused by depression of intrinsic melatonin production by beta-blockers [10]. Reports of the add-on utility of melatonin to the treatment of several disorders, including epilepsy [11], may primarily be attributable to the improved quality of the sleep–wake cycle [12], but melatonin has also been shown to directly potentiate the anticonvulsant efficacy of phenobarbital [13]. Melatonin is effective as an adjuvant for improving cognitive function and sleep quality impaired by a number of disorders. A study group of 73 outpatients with mild to moderate AD took 2 mg prolonged-release melatonin or placebo daily 1–2 h before bedtime for with myofascial temporomandibular disorder (TMD) and pain [14]. 1.2.2. Melatonin and Mood Disorders The clinical applicability of melatonin and pharmacological agents active at its receptors to depressive and anxiety mood disorders has been reported. The principal antidepressant drug used is agomelatine, which acts as a melatonin MT1 and MT2 receptor agonist. However, agomelatine also acts as a serotonergic 5-HT(2C) receptor antagonist, and this could also contribute its antidepressant activity [15]. Ramelteon, another MT1/MT2 agonist, has no serotonergic antagonistic activity but retains antidepressant properties [16]. The mechanism of action may involve both restoration of a normal sleep cycle and the intrinsic anxiolytic and analgesic properties of melatonin, which has opioid activity [17]. Ramelteon has also been reported to protect against delirium [18]. The biochemical and behavioral deficits found in animal models of several neurodegenerative diseases, including AD, Parkinson’s disease (PD), and cerebral stroke, are mitigated by melatonin treatment [19]. However, reports involving melatonin intervention in these diseases in human trials are very limited. Restoration of deranged sleep patterns may account for the majority of benefits seen in clinical testing of melatonin [20]. Melatonin has shown promise for managing some troublesome side effects of drugs used to treat mood disorders. In a study of schizophrenic patients, treatment with 3 mg/day of melatonin for 8 weeks reduced the metabolic side effects of weight gain, abdominal obesity, and hypertriglyceridemia induced by olanzapine [21]. However, 20 mg/day of controlled-release melatonin for 1 month was no more effective than placebo for reducing dependence on benzodiazepines in a group of 92 elderly outpatients [22]. 1.2.3. Slowing Of Common Age-Related Processes Aging is associated with an increasingly elevated level of inflammatory events [23]. Inappropriate and excessive immune responses characterize many diseases associated with aging, including a range of cardiovascular and neurodegenerative disorders. This heightened level of inflammation appears to be unprovoked by exogenous agents andmay reflect the inappropriate continuation of earlier and more relevant immune responses [24]. In the nervous system, many of the genes whose expression is elevated with age relate to immune function, and melatonin treatment has been shown in aged experimental animals to reverse this trend and restore a more youthful pattern of mRNA production [25]. This is also reflected by reversal of age-associated morphological and biochemical changes in brain [26]. Another important feature of brain aging where melatonin may be of value concerns adult neurogenesis, which has significance that is increasingly being acknowledged. Diminished neurogenesis precedes old age [27], and this decline can be delayed by supplementation with melatonin [28]. In addition, the maintenance of dendritic complexity is enhanced by melatonin [29]. Studies on melatonin in aging humans are relatively scarce, but several promising reports exist. Daily use of 3 mg melatonin protected the retina by delaying macular degeneration—a leading cause of severe visual loss in older people [30]. Even low doses of melatonin used during the evening increased daytime activity of healthy elderly people [31]. 1.2.4. Melatonin and Disease Related To Immune Function Melatonin has also been found to be of utility in the treatment of other diseases and adverse health states in which excess inflammation may not constitute a major element of pathogenesis but where immune function is likely a factor, including cancer [32]. Supplementation of the diet of aged mice with melatonin leads to a major reduction of tumor incidence [33]. Although melatonin is generally reported as supporting cell survival, it appears to promote apoptosis in malignant cells [34]. Several meta-analyses have shown that adjuvant treatment of cancer—particularly solid tumor cancers—with melatonin significantly improves outcomes [35]. Similarly, two recent case studies have reported encouraging results in patients with breast cancer [36] and hepatocellular carcinoma [37]. Encouraging but modest benefits were reported very recently in a clinical trial involving 151 advanced nonsmall cell lung cancer patients also receiving chemotherapy. In this study, 10 or 20 mg/day of melatonin taken at night for 6 months following initiation of chemotherapy decreased DNA damage and tended to improve quality of life; however, even though the longest-living survivors were among those patients receiving melatonin, supplementation did not lengthen survival time significantly overall [38]. Melatonin therapy can also speed the rate of healing of diverse types of wound [39]. In an experimental model of multiple sclerosis—which certainly reflects inappropriate immune responses—melatonin was able to reverse demyelination [40]. 1.2.5. Melatonin and Oxidative Stress There are several states that are predominantly characterized by excessive generation of reactive oxidant species. These include strenuous exercise and chronic pulmonary obstructive disease. Melatonin has been shown to be able to reduce indices of free radical damage in each of these in humans [41]. The relatively low tissue content of active unconjugated melatonin is approximately 1 pM [42] , which makes a direct antioxidant effect unlikely because several other potent antioxidants such as water-soluble glutathione and lipophilic α-tocopherol are present at much higher intracellular concentrations. Nonetheless, melatonin has been shown to reduce indices of oxidative stress in several clinical situations, including metabolic syndrome [43], Duchenne muscular dystrophy [44], and in severely ill children [45]. 1.2.6. Melatonin and Nociception Melatonin may be effective for reducing chronic pain associated with some diseases. Being antinociceptive, it can act to support conventional anesthetics [46]. In a randomized, placebo-controlled clinical trial involving 32 patients with myofascial TMD pain, pain levels evaluated by two different measurements were reduced in those using 5 mg/day at bedtime over a course of 4 weeks; moreover, these patients also reported requiring smaller and smaller amounts of other analgesics to cope with their pain as the trial progressed [47].. 1.2.7. Reduced toxicity of venoms and pharmacological agents after Melatonin administration Melatonin has been found to ameliorate the venominduced hemorrhage and myonecrosis incurred after a snake bite [48]. . It is also protective against the nephrotoxicity of tenofovir, a reversetranscriptase inhibitor used in the treatment of HIV infection [49]. The toxicity of several antineoplastics, such as neocarbazine and cyclophosphamide, is reduced in the presence of melatonin [50]. 1.2.8. Beneficial Effects of Melatonin Use During Surgical Procedures Melatonin improves survival of animals after heart transplantation both in the presence and absence of cyclosporine [51]. Prior administration of melatonin also improved survival rates after kidney transplantation [52]. . The persistence of ovaries following transplantation was also increased [53]. Clinical studies in these areas are very limited, but melatonin had only marginally beneficial effects in major liver resection surgery [54]. However, it has been shown to be nearly as effective as clonidine as an agent for sleep induction preceding surgical anesthesia in children aged 1–5 years [55]. Moreover, melatonin administration has been reported to lead to improved outcome following organ transplant procedures [56] and neonatal surgery [57]. The more successful reports used much higher doses of melatonin. Melatonin appears to have clinical utility in reducing the damage incurred by ischemia-reperfusion injury in the liver, which is very susceptible to such fluxes in vascular supply [58]. However, several trials on the potential of melatonin to mitigate the effects of reperfusion injury on the heart have not been proven to be successful [59]. 1.2.9. Migraine Amelioration by Melatonin Melatonin shows promise for reducing severity of migraine headaches in adults and children. In a recent study of 60 children (mean age, 10.3 years), monthly frequency of migraines was reduced by 55%, duration was reduced by 51%, and severity was reduced by 43%; the most frequent side effect was daytime sleepiness that occurred in seven subjects [60]. 1.2.10. Melatonin Supplementation and Fertility The quality of oocytes used for in vitro fertilization has been reported to be improved by treatment of the donors with melatonin [61]. The efficacy of oral melatonin supplementation on oocyte and embryo quality in patients in an assisted reproductive technologies program has been studied [62]. Patients were treated with 3 mg/day melatonin for at least 2 weeks. To evaluate the cumulative effect of melatonin supplementation, cycle outcomes between the first (no supplementation) and second cycles (melatonin supplementation) of patients who completed two treatment cycles were compared. There were no significant differences in maturation rates, blastocyst rates, and the rate of good-quality blastocysts between the first and second cycles. However, melatonin increased the fertilization rate from 35.1% to 68.2% and the proportion of good-quality embryos from 48.0% to 65.6%; these effects were ascribed to a reduction in oxidative damage. 1.3. Safety of Melatonin The term nutraceutical implies that a substance has little or no toxicity even when consumed for long periods of time. Although melatonin is considered to have little toxicity, much of the evidence for this comes from short-term studies [63]. In attempting to assess its safety as a nutraceutical, in addition to considering short-term toxicity data, a careful evaluation of any information pertaining to melatonin’s long-term consumption should be performed. The only adverse report of potential harmfulness of melatonin is a report indicating that, in an isolated system, its metabolite 6-hydroxymelatonin promoted metalion induced lesions to guanine and thymidine residues in DNA [64]. Most redox-capable antioxidants such as ascorbic acid and lipoic acid can also facilitate this cycling. Neither short-term treatment nor extended treatment of humans with melatonin has led to symptoms of dependence, tolerance, rebound insomnia, or withdrawal [65]. With respect to evaluating the safety of melatonin, it is important to distinguish two possible applications: its low-dose nutraceutical consumption by relatively healthy individuals and the acute administration of high dosages to patients with serious medical conditions. The former involves the oral, possibly chronic, intake of relatively low dosages (0.3–10 mg/day), anticipated to be taken at bedtime or when the induction of nocturnal physiological conditions is desired. Frequently, the goal is the restoration or modulation of normal homeostatic function to compensate for age-related changes or circadian cycle disruption, rather than as treatment of serious disease. Here, safety considerations need to focus on the presence or lack of association of low-dose, possibly chronic, consumption of melatonin with increased incidence of disease or pathology in humans. Although high-quality, long-term clinical studies would provide the best evidence for or against such an association, the lack of such studies means that one has to rely on shorterterm, less powerful ones. Nevertheless, the safety and toxicity of melatonin have been the focus of a number of studies, and this hormone is frequently characterized as being both safe and nontoxic [66]. The safety of melatonin used as a nutraceutical ingredient in food has been challenged on at least one occasion in a Food and Drug Administration (FDA) warning letter [67]. Rather than restate evidence for melatonin’s safety, insight from a different perspective may be gained by scrutinizing—at least as an illustrative case—the opposing evidence provided in this document in which it may be presumed that the strongest available references would be selected for characterizing melatonin as being toxic and/or unsafe. The warning letter cited 23 reports that “have raised safety concerns” about melatonin. Of these, the entire text of 21 could be accessed. Surprisingly, terms such as “safe,” “safety,” “toxic,” “toxicity,” or “adverse” did not occur at all in these 21 or they occurred in statements actually supporting the safety and/or nontoxicity of melatonin. Most of these references provide poor or no support for safety concerns either in humans or in the experimental models studied in rodents or in vitro. Among the references cited as raising concerns over melatonin’s effects on blood glucose homeostasis, two of the studies [68] performed no glucose measurements and mentioned no concerns; a third study in rats [69] found that melatonin induced no change in blood glucose. A fourth study [70] reported decreased glucose tolerance and insulin sensitivity in older women treated with 1 mg of melatonin in the morning. Typically, longterm supplementation of melatonin is recommended to be used only at bedtime, and not in the morning. As noted by the study’s authors, the effects measured may merely represent the induction during the daytime of the reduced nocturnal glucose sensitivity observed in normal, healthy humans. In contrast to the results of this study, beneficial improvements in HbA1c and no such possibly deleterious effects on glucose metabolism were found in a more recent study of diabetic patients [71]. There were two adverse reports among studies cited to support reproductive concerns [72] observed strain-specific mortality in rat pups when dams received a 250-times higher dose (on a weight basis, for a 75-kg human) than the 3 mg/day frequently recommended for humans. The strain-specificity and high dosage suggest these results may not be relevant to typical human nutraceutical usage. A second study reporting reduced semen quality in men receiving 3 mg/day of melatonin for 3 months [73] is of more concern. However, this reduction occurred in only two of eight subjects, suggesting that only a minority of males may be affected; in any case, a much larger study is required for confirmation. With regard to females, an in vitro study merely exposed cultured human granulosa cells to melatonin without expressing any safety implications [74]. Additional human studies in which no safety concerns were mentioned included those of [75] and [76], but only the abstracts could be checked. Rodents were used in seven of the reports cited in the FDA warning letter. In rodents, adverse effects were observed only at melatonin concentrations much higher than the 0.5–10 mg typically suggested for long-term nutraceutical consumption in humans. Moreover, all but one of the rodent experiments were performed on animals that modeled human disease, and thus they may have questionable applicability to healthy humans. For example, [77] studied castrated rats without adverse effects, whereas [78] reported that under normal conditions, increased retinal cell death and thinned outer nuclear layer in retinas of non-pigmented rats were associated with administration of 100 times the melatonin dosage typical of human intake. Because melatonin may have greatly different effects in humans compared to rodents in certain circumstances [79] , caution needs to be used in applying the results of animal studies when evaluating the safety of melatonin consumption by humans [80] showed that large amounts of melatonin fed to mice in an atherogenic diet exacerbate plaque formation, but they state that “melatonin had no toxicity on animal health even at this high dose” and express caution by noting that one cannot infer “that high melatonin doses (in mice) would have any deleterious effect on atherosclerosis development in humans.” In humans, other vascular studies—those of [81],—expressed no safety concerns. Similarly, authors of a vision-related study in humans [82] expressed no concerns about melatonin’s safety. Safety concerns of melatonin may apply when treating patients with specific medical conditions, but not in healthy humans using melatonin at bedtime. [83] .reported that a single 15 mg dose of melatonin administered during the daytime lowered input to subjects’ retinal cones; no safety concerns were raised other than cautioning that melatonin should not be taken during the daytime, and the authors concluded that this effect “may serve to promote (normal) night vision.” Further suggesting that undesirable effects may not be a concern in healthy individuals, serious adverse events were reported only in studies of small numbers of human subjects with medical conditions. In this regard, [84] reported that exogenous melatonin, in conjunction with late-night bright light, exacerbated symptoms in eight patients with restless legs syndrome, and [85] observed an increased incidence of seizures among six children with neurological disabilities who had undergone multiple medical procedures. In summary, this examination of references supporting the “safety concerns” raised against melatonin supports the notion that there is little evidence engendering significant generalized concerns about melatonin’s safety, particularly with regard to typically recommended dosages of melatonin consumption in healthy humans. There is no doubt that the toxicity of melatonin is extremely low. Thus, even 800 mg/kg body weight has not been proven lethal in experimental animals [86]. Few nutraceutical vitamins or cofactors have such a large margin of safety. 2. l-Theanine Tea is often used as a relaxing beverage. l-Theanine is an amino acid extracted from green or black tea. In the brain, l-theanine increases dopamine, serotonin, and the inhibitory neurotransmitter glycine [87], [88] have reported inhibitory effects of higher doses of theanine on caffeine stimulation evaluated by electroencephalogram (EEG) in the rat. However, when given by itself, lower doses of theanine resulted in excitatory effects, suggesting a dual activity of theanine depending on the dose [89] have reported that even lower doses of l-theanine can induce alpha-wave production as observed in EEG tracings from 54 healthy participants at baseline and at 45, 60, 75, 90, and 105 min after 50 mg l-theanine or placebo. Statistical analysis of data showed a significantly greater increase in alpha-wave production in the theanine group than in the placebo group [90] have reported that the acute stress response elicited by a math test was attenuated by 200 mg theanine, as assessed by heart rate and salivary IgA. 3. Gamma Aminobutyric Acid GABA is an inhibitory neurotransmitter widely distributed throughout the CNS. Too much excitation can lead to irritability, restlessness, insomnia, seizures, and movement disorders, so it must be balanced with inhibition that is provided by GABA acting like a “brake” during times of stress. Medications for anxiety, such as benzodiazepines, stimulate GABA receptors and induce relaxation. Either low GABA levels or decreased GABA function in the brain is associated with several psychiatric and neurological disorders, including anxiety, depression, insomnia, and epilepsy. Studies indicate GABA can improve relaxation and enhance sleep. Because of the association between low GABA levels and these conditions, many antianxiety and sleepenhancing drugs have been developed that interact primarily with GABA receptors. These include the benzodiazepine drugs—alprazolam, diazepam, flurazepam, quazepam, temazepam, and triazolam—and zolpidem tartrate and baclofen. GABA mediates presynaptic inhibition of primary afferent fibers in the motor system. It regulates brain excitability via GABAA receptors, which are classified into three major groups (alpha, beta, and gamma) with subunits that determine its pharmacological activity. GABAA receptors are highly expressed in the thalamus, a region of the brain involved with sleep processes [91] have reported that gabapentin (structurally similar to GABA; increases brain GABA levels) has been found to be effective for panic disorder and improves sleep disturbances associated with alcohol consumption [92] showed GABA-agonist drugs are sedatives used to treat insomnia. Natural therapies that produce relaxation also act, at least in part, by enhancing GABA levels [93] have reported that valerenic acid potentiates and inhibits GABAA receptors [94] have reported reduced GABAA receptor binding in veterans with posttraumatic stress disorder as demonstrated by positron emission tomography scan. On EEG, alpha waves are generated in a relaxed state, whereas beta waves are seen in stressful situations that make mental concentration difficult. Therefore, the ratio of alpha to beta waves is used as an indication of relaxation and better concentration. In general, the greater the alphato- beta ratio, the more relaxed and alert the person is. [95] have reported relaxation and immunity enhancement effects of GABA administration in humans, and it was seen that GABA produced significant effects on increasing alpha waves and on decreasing beta waves, resulting in a significant increase in the alpha-to-beta wave ratio. Due to its relaxation effects, GABA may be considered to be a sleep aid. 4. l-Tryptophan/5-Hydroxytryptophan (5-HTP) l-Tryptophan, a large neutral amino acid essential to human metabolism, is the metabolic precursor of serotonin (a neurotransmitter), melatonin (a neurohormone), and niacin (vitamin B3). Tryptophan hydroxylase is the rate-limiting enzyme for serotonin production and involves the conversion of tryptophan to 5-HTP. This enzyme can be inhibited by stress, insulin resistance, magnesium or vitamin B6 deficiency, or increasing age [96] have demonstrated the inhibitory effect of 5-HTP on cholecystokinin-4-induced panic attacks in healthy volunteers. Another study conducted by [97] examined that acute l-5-HTP administration inhibits panic attacks induced by carbon dioxide in panic disorder patients, as displayed by reduced panic symptom scores and number of panic attacks in comparison to placebo [98] have reported that l-5-HT treatment helps in reduction of sleep terrors in children because of its enhancement of serotonin and melatonin as compared to the untreated group. 5. Pyridoxal 5′-Phosphate (Active Vitamin B6) Pyridoxal 5-phosphate (the active form of vitamin B6) is a necessary cofactor for the formation of several important neurotransmitters associated with stress. 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In: Wurtman, R.J., Wurtman, J.J. (Eds.), Nutrition and the Brain Raven Press, New York, NY, pp. 89–139