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Inositol, IP3 and IP6
28/07/2010 Print

Natural Sources:     

Major sources of inositol include beans, citrus fruit, nuts, rice, certain meats and wheat germ.     


Forms:     

Standardized inositol capsules and tablets; Multivitamin and Mineral tablets containing inositol.     


Therapeutic Uses:     

- Aging Disorders
- Alzheimer's Disease
- Antidepressant
- Autism
- Brain Functioning
- Calcium Metabolism (intracellular)
- Cancer
- Child Development
- Depression
- Diabetes mellitus
- Fetal Development
- Galactosemia
- Infant Health
- Kidney Health Maintenance
- Multiple Sclerosis
- Nerve Damage (diabetes-related)
- Numbness
- Obsessive-compulsive Disorder
- Pain Relief
- Panic Disorder
- Physical Performance
- Post-traumatic Stress Disorder
- Respiratory Health Maintenance     


Overview:     

Inositol is a useful sugar (simple carbohydrate) that has recently been identified as an important dietary and cellular constituent. Inositol was originally thought to be essential for good health, but has since been shown not to be a vitamin. In the body, inositol is metabolized into phosphatidyl-inositol, which acts as a messenger to stimulate the release of calcium from its storage site in the cellular organelle called the endoplasmic reticulum. Inositol has also been shown to improve the transmission of neural signals in individuals afflicted with diabetic nerve damage and numbness. Other functions of phospho-inositol in cell membranes include regulation of cellular responses to external stimuli and mediation of enzyme activity. There are no known deficiency symptoms in humans; however, a change in central nervous system availability of inositol has been shown to produce altered brain signaling and eventually lead to the development of neurological disorders. Studies evaluating the effectiveness of inositol for treating disease states indicate that it may be effective in the treatment of depression, Alzheimer's disease, panic disorder, obsessive compulsive disorder, autism, post-traumatic stress disorder, and pain control. Inositol has been studied extensively as a potential treatment to alleviate some negative effects associated with lithium therapy. Inositol also has documented benefit for use in pediatric respiratory depression or distress syndrome. Recent studies with premature babies show that inositol supplementation results in statistically significant reductions in death, breathing disorders, retinopathy of prematurity and intraventricular hemorrhage without increasing infections. In addition, recent studies have evaluated its usefulness as an analgesic. Although its benefit in preventing neural tube defects in embryonic mice is documented, the use of inositol in pregnant women remains controversial due to the risk of inducing uterine contractions. Altered production of inositol has also been documented in patients with diabetes, chronic renal failure, galactosemia and multiple sclerosis.


Chemistry:     

Inositol is a simple carbohydrate or sugar. In mammals, inositol exists as phosphorylated derivatives, various phosphoinositides, and in its free form. Inositol is particularly important as a precursor for brain myo-inositol. Myo-inositol is a natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. Inositol has six carbon atoms that are capable of binding phosphate molecules; when all six carbons are occupied by six phosphate groups the compound is called IP6. When only three of the carbon groups are bound by phosphate it is called IP3. Inositol hexaphosphate (IP6) is a component of fiber primarily found in whole grains and legumes.     


Suggested Amount:     

Based on controlled clinical studies with positive results, the dosage of inositol for treating neurological disorders generally ranges from between 12 to 18 grams daily. However, if inositol is taken in the form of inositol hexaphosphate, then the required dosages are much reduced. Experts recommend taking a daily dose of 800 - 1,200 mg of inositol hexaphosphate along with 200 - 300 mg inositol as a general preventative measure. In patients with cancer or at high risk for cancer, experts recommend a dose in the range of 4,800 - 7,200 mg IP6 along with 1,200 - 1800 mg inositol. This should be taken on an empty stomach.     


Drug Interactions:     

None known.     


Contraindications:     

Inositol appears to have no clinical advantages for the treatment of ADHD and may even antagonize the condition. Therefore, inositol supplements are not recommended for children suffering from ADHD. Inositol also appears to provide no significant benefit for persons suffering from schizophrenia and may be detrimental. Inositol supplements are also contraindicated during pregnancy as inositol may stimulate uterine contractions. (Oxytocin is a potent uterine stimulator whose clinical use in labor and delivery is well documented. Researchers have shown that oxytocin's clinical effectiveness is due to the activation of phospholipase C to produce inositol-1,4,5-triphosphate which releases calcium from intracellular stores and stimulates uterine contractions. The activation of the phosphatidylinositol signaling system by calcium agonists is also supported by the work of other researchers).     


Side Effects:     

None known.     


References:     

Bersudsky Y, Einat H, Stahl Z, and Belmaker RH. 1999. Epi-Inositol and Inositol Depletion: Two New Treatment Approaches in Affective Disorder. Curr Psychiatry Rep 1999 Dec; 1(2): 141-147.
 
Colodny, L. and R. L. Hoffman 1998. Inositol ­ Clinical Applications for Exogenous Use. Altern Med Rev 1998; 3(6): 432-447.
 
Einat H, Belmaker RH, Zangen A, Overstreet DH, Yadid G. 2002. Chronic inositol treatment reduces depression-like immobility of Flinders Sensitive Line rats in the forced swim test. Depress Anxiety 2002; 15(3): 148-151.
 
Gill DL, Ghosh TK, Mullaney JM. Calcium signaling mechanisms in endoplasmic reticulum activated by inositol 1,4,5 triphosphate and GTP. Cell Calcium 1989; 10: 363-374.
 
Howlett A, Ohlsson A. 2000. Inositol for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev 2000; (4): CD000366.
 
Shamsuddin A., Ulah A., Chakravarthy A. 1989. Inositol and inositol hexaphosphate suppresses cell proliferation and tumor formation in CD-1 mice. Carcinogenesis 10: 1461-1463.
 
Vandal R. Role of inositol in the treatment of psychiatric disorders. CNS Drugs 1997; 7: 6-16.


Additional Information:     

Special Role in Intracellular Calcium Metabolism:
Recent evidence indicates inositol ultimately regulates the intracellular (cytosolic) concentration of calcium. Signaling by calcium is known to mediate an array of cellular functions (secretion, contraction, and conduction). Due to the role calcium plays, its regulation intracellularly is known to be a complex phenomenon involving a number of active and passive transport systems. Inositol is now established as a significant mediator of calcium mobilization in the endoplasmic reticulum. Modifying this mobilization of calcium may be effective in treating some central nervous system (CNS) disorders like Alzheimer's disease, depression, panic disorder, obsessive compulsive disorder, and as an analgesic for pain control. As new clinical studies involving inositol are concluded and the research is evaluated, the understanding of inositol's role in intracellular and extracellular signaling may provide even better insight into the therapeutic applications of inositol and inositol-based products.
 
What are Inositol Triphosphate (IP3) and Inositol Hexaphosphate (IP6) Molecules?
Inositol has six carbon atoms that are capable of binding phosphate molecules; when all six carbons are occupied by six phosphate groups the compound is called IP6. When only three of the carbon groups are bound by phosphate it is called IP3. Inositol hexaphosphate (IP6) is a component of fiber primarily found in whole grains and legumes. Studies indicate that the cancer protective effects of high fiber diets are partly due to the presence of higher levels of IP6 in the fiber. Supplementation with purified IP6 and the correct amounts of inositol offers several advantages over dietary sources of these compounds, including enhanced bioavailability and absorption. IP6 has strong antioxidant and immune enhancing effects as well as exerting a number of interesting anticancer actions. IP6 taken together with inositol inhibits the ability of cancer cells to multiply. The combination of IP6 with inositol was originally discovered by Dr Shamsuddin M.D., Ph.D., from the University of Maryland, USA. When combined with IP6, inositol dramatically increases the anticancer and immune enhancing effects of IP6. Although IP6 is gaining media attention, it is really IP3 that is doing all the work. Dr Shamsuddin discovered that when properly combined with inositol, IP6 forms two molecules of inositol triphosphate (IP3) in the body. IP3 plays an important role inside the cells of our bodies. It basically functions as an on/off switch for human cancers according to studies in cell cultures. When IP3 levels are low (as in cancer cells), the cells replicate out of control. That basically is what occurs in cancer. When cancer cells are bathed in a broth of IP3, they literally turn themselves off. This action reflects the central role that IP3 plays in controlling key cell functions, including replication and the communication between cells. Dr Shamsuddin has discovered the correct ratio of IP6 and inositol to ensure the formation of IP3 within the body. Based on extensive studies in animals and cell cultures, the combination of IP6 and inositol exerts anticancer effects against virtually all types of cancers including cancers of the breast, prostate, lung, skin, colon and brain as well as lymphomas and leukemia. IP6 reduces the manufacture of new DNA in cancer cells but does not exert the same inhibition in normal cells. IP6 is superior in this way to chemotherapy agents because it helps cancer cells to function normally without damaging healthy cells.

Recent Positive Clinical Results for Treating Respiratory Distress Syndrome:
BACKGROUND: Inositol is an essential nutrient required by human cells in culture for growth and survival. Inositol promotes maturation of several components of surfactant and may play a critical role in fetal and early neonatal life.
OBJECTIVES: To assess the effectiveness/safety of supplementary inositol in preterm infants with RDS in reducing adverse neonatal outcomes.
SEARCH STRATEGY: Medline, Embase, and Reference Update Databases were searched in August 1997 using key words: inositol and infant-newborn and random allocation or controlled trial or randomized trial (RCT). The reference lists of identified RCTs, personal files and Science Citation Index were searched. Unpublished additional information was obtained from the authors of one RCT published in abstract form.
SELECTION CRITERIA: All randomized controlled trials of inositol supplementation to preterm infants with a control group that received a placebo or no intervention were included. Outcomes of interest were bronchopulmonary dysplasia (BPD), death, BPD or death, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and sepsis.
DATA COLLECTION AND ANALYSIS: Data on neonatal outcomes were abstracted independently by the two researchers and any discrepancy was resolved through consensus. Revman was used for analysis of the data.
MAIN RESULTS: Four reports of three RCTs were identified. One report was a duplicate publication. The outcome of death or bronchopulmonary dysplasia was reported in two trials, and was found to be significantly reduced (RR 0.56, 95% CI 0.42, 0.77; RD -0.215, 95% CI -0.323, -0.107). The outcome of death was reported in two trials and was found to be significantly reduced (RR 0.48, 95% CI 0.28, 0.80; RD -0.131, 95% CI -0.218, -0.043). Retinopathy of prematurity, stage 4 or needing therapy, was reported in two trials, and was found to be significantly reduced (RR 0.09, 95% CI 0.01, 0.67; RD -0.078, 95% CI -0.128, -0.027). Intraventricular hemorrhage, grade III-IV, was significantly decreased (RR 0.55, 95% CI 0.32, 0.95; RD -0.090, 95% CI -0.170, -0.010). Neither sepsis nor necrotizing enterocolitis outcomes were increased. When a secondary analysis was done excluding a study published in abstract form, the results differed only in that there was a significant reduction in retinopathy of prematurity, any stage (RR 0.53, 95% CI 0.29, 0.97; RD -0.082, 95% CI -0.159,-0.005).
REVIEWER'S CONCLUSIONS: Inositol supplementation results in statistically significant and clinically important reductions in important short-term adverse neonatal outcomes. A multi-center RCT of appropriate size is justified to confirm these findings. [Howlett A, Ohlsson A. 2000. Inositol for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev 2000; (4): CD000366.Paediatrics (Division of Neonatal Paediatrics), Izaak Walton Killam-Grace Health Centre, 5850/5980 University Avenue, Halifax, Nova Scotia, Canada, B3J 3G9. aahowlet@is.dal.ca].
 
Recent Positive Findings for Inositol Against Affective Disorder
Abstract from Medline:
Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myo-inositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol. [Bersudsky Y, Einat H, Stahl Z, Belmaker RH. 1999. Epi-Inositol and Inositol Depletion: Two New Treatment Approaches in Affective Disorder. Curr Psychiatry Rep 1999 Dec; 1(2): 141-147].
 
Recent Positive Findings for Inositol Against Depression
Abstract from Medline:
Inositol, a precursor of the PIP cycle that was reported to have therapeutic effects in depressive patients and to be effective in two animal models of depression, was evaluated in the forced swim test using the genetic Flinders Sensitive Line (FSL) rats model of depression. Groups of rats were tested in a 2 x 2 design with Strain (FSL or Control) as one factor and Drug (Inositol or Placebo) as the second factor. Rats received chronic treatment (daily for 14 days) with inositol (1.2 g/kg) or placebo (1:2 glucose/mannitol solution). On day 14 rats were exposed to the forced swim test for 5 min and their behavior videotaped. Tapes were analyzed for three levels of activity: immobility, swimming, and vigorous struggle. Inositol countered the exaggerated immobility of FSL rats in the forced swim test, without affecting control animals. Data support our previous suggestion of inositol as a potential antidepressant. [Einat H, Belmaker RH, Zangen A, Overstreet DH, Yadid G. 2002. Chronic inositol treatment reduces depression-like immobility of Flinders Sensitive Line rats in the forced swim test. Depress Anxiety 2002; 15(3): 148-151. Research conducted by Beer Sheva Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel].


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