Chemistry and Forms

First recognized as an essential nutrient in 1940, inositol is a sugar-like, water-soluble substance member of the B-vitamin complex. The nine isomers of inositol are ubiquitous, cyclic carbohydrates with a basic 6-carbon ring structure. Three forms of inositol occur in nature: phytic acid, free myo-inositol, and inositol-containing phospholipids. Phytic acid, the hexaphosphate ester of inositol, is present in the leaves and seeds of most plants. In mammal tissues, inositol appears as phosphorylated derivatives, various phosphoinositides, and in its free form. The highest concentrations of inositol are in the heart and brain, with free myo-inositol predominantly found in the brain and kidney, and phospholipid inositol (phosphatidylinositol) concentrated in liver, pancreas, skeletal muscle, and cardiac muscle.

Physiology and Function

Although the distribution of inositol within the human body has long been known, its functions and mechanisms of action have yet to be fully elucidated.

Inositol production occurs through three known pathways. Dietary sources primarily enter the system as phytate or phytic acid (inositol hexaphosphate, or IP6) in plant foods, which is converted in the intestinal tract through the action of endogenous bacterial flora. However, oral intake of inositol is considered a minor pathway. The majority of inositol is produced, as inositol monophosphate, via a receptor-mediated salvage system and from glucose-6-phosphate; these two pathways are regulated by polyphosphate-1-phosphomonoesterase, a lithium-sensitive enzyme.

Inositol plays key roles in lipid transport, hepatic fat metabolism and cell membrane function, nerve transmission, and neurotransmitter activity. Along with choline (tetramethylglycine), methionine and betaine (trimethylglycine), inositol is considered a member of the group of compounds called lipotropics, which are closely involved in lipid metabolism. As an essential component of phospholipids, phosphatidylinositol participates in regulating the function of cell membranes, where it is particularly important in mediating cellular responses to external stimuli and/or nerve transmission. Inositol with various numbers of bound phosphate groups are also widely involved in cell-signaling processes.

Phosphatidylinositol (PI) mediates the activity of numerous membrane enzymes through interactions with specific proteins. The PI cycle is a second-messenger system integral to the function of several noradrenergic, serotonergic, and cholinergic receptors. Thus, PI participates in the action of serotonin; low cerebrospinal fluid (CSF) levels of inositol have been observed in individuals diagnosed with depression. Phosphatidylinositol also facilitates the synthesis of arachidonic acid.

Known or Potential Therapeutic Uses

Inositol has been used in clinical trials with several central nervous system (CNS) disorders, such as Alzheimer's disease, binge eating, bulimia, depression, obsessive-compulsive disorder (OCD), and panic disorder, as well as concurrently with lithium treatment of bipolar disorder.

Historical/Ethnomedicine Precedent

Inositol has not been used historically as an isolated nutrient.

Possible Uses

Alzheimer's disease, bulimia, depression, diabetes mellitus, diabetic neuropathy, lithium-related psoriasis, OCD, panic disorder, pediatric respiratory depression syndrome, premenstrual dysphoric disorder, trichotillomania.

Deficiency Symptoms

Consensus is lacking on specific signs and symptoms of inositol deficiency. Deficiency is considered unlikely in most individuals because of its widespread occurrence in foods. However, loss of intestinal flora necessary for conversion of such plant sources to inositol could reduce inositol levels.

Individuals with diabetes have increased inositol excretion, whereas those with depression exhibit significantly lower-than-normal CSF levels of inositol.

Dietary Sources

Nuts, beans, seeds, whole grains (especially wheat and wheat bran), cantaloupe, and citrus fruits (especially oranges) are excellent plant sources of inositol in the form of phytate or phytic acid (inositol hexaphosphate, IP6). Organ meats are the richest animal sources.

Dosage Forms Available

Capsule, powder, tablet.

Source Materials for Nutrient Preparations

The dominant commercial process for producing myo-inositol is purification of phytic acid (IP6) from grain such as corn, and then dephosphorylating it with proprietary enzymes.

Dosage Range

Adult

Dietary: No dietary or nutritional requirement for inositol has been established. Average adult intake in the United States has been estimated at 1000 mg daily as phytate or phytic acid.

Supplemental/Maintenance: 100 to 1000 mg per day. Inositol usually is not recommended for general nutritional supplementation. Doses found in multivitamins, if at all present, are generally insufficient to exert any clinically significant effect.

Pharmacological/Therapeutic: 100 to 1000 mg per day, usually 250 to 500 mg twice daily; 12 to 18 g per day have been used in clinical trials investigating treatment of anxiety, depression, and obsessive-compulsive disorder. Palatnik et al. ¹ (2001) found that 18 g daily was well tolerated with minimal adverse effects.

Toxic: No toxic dose level for inositol has been reported. Large amounts (>3 g), if quickly ingested, can have a laxative effect, similar to that of sugar alcohols (e.g., maltitol, xylitol).

Pediatric (<18 Years)

Dietary: No minimal dietary requirement for children has been established.

Supplemental/Maintenance: Inositol is not currently recommended for children.

Pharmacological/Therapeutic: Specific treatment recommendations have not established.

Toxic: No toxic dosage level for inositol has been established specifically for infants and children.

Laboratory Values

Blood and CSF inositol levels can be done in research laboratories, but are not in clinical use.

Overview

No toxic effects reported or observed, even though some clinical trials have used a therapeutic dosage that equals about 18 times the average dietary intake. Gastrointestinal effects such as nausea and diarrhea are occasionally reported with larger doses. Because of the hypothetical possibility that inositol may exacerbate hypomanic or manic symptoms in those with bipolar disorder, these individuals should use larger amounts (>1 g) of inositol with caution and under medical supervision. There have been no long-term safety studies to confirm the lack of adverse effects with chronic administration.

Nutrient Adverse Effects

General Adverse Effects

No general adverse effects from inositol have been confirmed in the scientific literature.

Pregnancy and Nursing

The use of inositol in pregnant women remains controversial because of possible effects on oxytocin and uterine contractions.

Infants and Children

Evidence is lacking in the scientific literature to suggest or confirm any adverse effects related to fetal development during pregnancy or to breast-fed infants and associated with inositol administration. Caution still is advised.

Contraindications

Attention deficit–hyperactivity disorder (ADHD), chronic renal failure, schizophrenia; pregnancy.

Following up on research by Levine et al. ² that found a lack of efficacy with the use of inositol in the treatment of schizophrenia, research by Jope et al. ³ and others indicates that schizophrenia involves elevated activity of the phosphoinositol signaling system; thereby suggesting that inositol administration may be contraindicated.

In a double-blind, crossover study involving 11 children with ADHD, Levine et al. ⁴ found that inositol administration was associated with a trend toward the aggravation of the disorder.

Preliminary, but pharmacologically plausible, evidence suggests inositol may trigger manic episodes in individuals diagnosed with bipolar disorder. ⁵ These individuals should use myo-inositol with caution and only under medical supervision because of the theoretical possibility of exacerbating hypomanic or manic symptoms.

The issue of inositol administration during pregnancy raises complex and as-yet unresolved issues. Animal experiments indicate that inositol may significantly reduce the incidence of embryonic neural tube defects, including those resistant to folate alone. ^6,7However, as reported by Phaneuf et al., ⁸ oxytocin's clinical effectiveness is caused by the activation of phospholipase C to produce inositol-1,4,5-triphosphate, which in turn releases calcium from intracellular stores and stimulates uterine contractions. Consequently, inositol may stimulate uterine contractions. Using a rodent model, Chien et al. ⁹ also observed dose-related myometrial contractions related to activation of the phosphatidylinositol signaling system by calcium agonists. Further research is warranted; inositol administration during pregnancy should be avoided out of prudence until safety factors are clarified and confirmed.

Precautions and Warnings

It has been suggested that exogenous inositol may stimulate uterine contractions, but evidence from human research is lacking to demonstrate such an adverse effect. ¹⁰ Thus, the usefulness of inositol in preventing neural tube defects (as supported by animal experiments) is limited.

Strategic Considerations

Although much is known about the physiological roles of myo-inositol, therapeutic strategies using inositol remain largely within the realm of clinical trials, clinical experience, anecdote, and conjecture. Myo-inositol may have antidepressant and antianxiety activity, but the mechanism of action has yet to be fully elucidated. Furthermore, no clinically available means exist to assess inositol status, or even normal ranges of nutrient concentration in blood. Data are available on inositol levels in CSF, but routine lumbar punctures for determining inositol concentration are impractical. Dietary intake typically supplies about a gram per day but relies on bowel flora to dephosphorylate it, which is not necessarily a valid assumption given the disproportionate ratio of antibiotic/probiotic use among most patients. Endogenous synthesis from glucose is the major source, but this depends on assumptions as to how intact that pathway is in any given individual. Inositol synthesis and regulation also involve salvage-recirculating pathways known to be inhibited by lithium and perhaps other substances. Inositol and its phosphates are ubiquitous in cell-signaling pathways, and its phosphatides in membrane signaling.

Experienced clinicians report that a major proportion of individuals diagnosed with depression, anxiety/panic disorder, and OCD appear to improve when given prescribed inositol in multigram quantities per day. Unfortunately, the CSF level does not appear to predict who will and will not respond, even though it is known that inositol levels in CSF are lower in depressed patients than in euthymic individuals. This differential response may be influenced or determined by cofactors that are adequate in some individuals and low in others. One relevant action of inositol may derive from its apparent ability to reverse desensitization of serotonin receptors. As with other antidepressant agents, the logical course, treating patients with mild symptoms of depression, anxiety, and/or obsessive-compulsive thoughts/behavior, is to start with a low dose (1 g/day) and gradually increase to maximum dose (animals models have used 1.2 g/kg with no adverse effects).

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