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Inositol

Nutrient Name: Inositol.
Synonyms: cis-1,2,3,5- trans-4,6-cyclohexanehexol, cyclohexanehexol, hexahydroxycyclohexane, inositol monophosphate, mouse antialopecia factor, myo-inositol, vitamin B⁸.
Related Substances: Inositol hexaphosphate, IP6, phytic acid;D-chiro-inositol; inositol hexaniacinate, inositol niacinate, inositol nicotinate (see Vitamin B³monograph).

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Lithium /	Lithium inhibits inositol monophosphatase and depletes brain stores of inositol. Coadministration may reduce adverse effects associated with chronic lithium therapy, especially psoriasis and polydipsia-polyuria, without reducing treatment efficacy. Long-term, well-designed clinical trials are warranted.	Coadminister. Monitor.

nutrient description

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.

nutrient in clinical practice

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.

safety profile

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.

interactions review

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).

nutrient-drug interactions

Lithium Carbonate

Lithium carbonate (Camcolit, Carbolith, Duralith, Eskalith, Li-Liquid, Liskonum, Litarex, Lithane, Lithobid, Lithonate, Lithotabs, PMS-Lithium, Priadel).

	Prevention or Reduction of Drug Adverse Effect
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

Lithium's activity in bipolar disease may involve depletion of brain stores of inositol through inhibition of inositol monophosphatase, the enzyme that returns inositol monophosphate back to myo-inositol. ¹¹ Inositol can reverse or mitigate adverse effects of lithium therapy, such as psoriasis and polyuria-polydipsia syndrome and lithium-pilocarpine–induced seizures. ¹² However, concern has been raised that such concomitant administration might interfere with the therapeutic effects of lithium by increasing the concentration of inositol, thereby causing a return of manic or depressive symptoms.

Research

In a 6-week randomized clinical trial involving 24 adult men and women with DSM-IVbipolar depression, Chengappa et al. ¹³ compared inositol (12 g/day) with placebo and demonstrated that among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects showed improved depression, as indicated by a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of “much” or “very much” improved, compared to three (30%) subjects assigned to placebo. However, this study was underpowered to detect a statistically significant difference.

In a double-blind placebo-controlled study involving healthy volunteers and using magnetic resonance spectroscopy to measure the concentration of both myo-inositol and phosphomonoesters, Silverstone et al. ¹⁴ demonstrated that lithium therapy depletes brain stores of inositol by blocking the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent after phosphoinositol cycle stimulation. Subsequently, using high-resolution nuclear magnetic resonance (NMR) spectroscopy, O’Donnell, Silverstone, et al. ¹⁵ observed a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration in the brains of rats chronically treated with lithium (and/or sodium valproate) compared to saline-treated controls.

Polyuria-polydipsia syndrome is a common adverse effect associated with lithium therapy and can affect up to 60% of patients taking the medication for at least 1 year. ^16,17 Preliminary research indicated that low-dose inositol could reverse polyuria-polydipsia in rats treated with lithium and that oral inositol (3 g/day) ameliorates lithium-induced polyuria-polydipsia as rated subjectively by patients. ¹¹ Levine et al. ¹⁸ injected daily inositol or “artificial CSF i.c.v.” to rats exhibiting lithium-induced polydipsia and observed that inositol i.c.v. reversed lithium-induced polydipsia, but that kidney inositol levels in lithium-treated rats were not different from controls. These findings suggest that inositol may alleviate symptoms of lithium-induced polydipsia via a central effect, but has no direct effect on lithium-induced polyuria. These researchers also conducted a double-blind crossover study involving seven patients that compared 6 g oral inositol daily versus placebo, each given for 2 weeks. Inositol did not reverse lithium-induced polyuria, as measured by 24-hour urine volume and urine specific gravity. However, subjective report of symptomatology was significantly improved in subjects taking inositol versus placebo, possibly resulting from alleviation of polydipsia.

Psoriasis is an adverse effect associated with long-term use of lithium in many patients. In a randomized, double-blind, placebo-controlled, crossover clinical trial, Allan et al. ¹⁹ compared the effects of inositol administration in 15 patients with psoriasis while undergoing lithium therapy with the effects in 11 patients with psoriasis not taking lithium. The inositol had a significantly beneficial effect on the psoriasis of patients taking lithium, in contrast to a lack of effect on psoriasis of patients not receiving lithium.

Some animal studies suggested that administration of pharmacological doses of inositol reverses behavioral effects of lithium. ²⁰ Inositol derived from inositol phosphate breakdown appears to be recycled for use in membranous phosphatidylinositol. Belmaker et al. ^21,22 proposed that inositol depletion was central to the action of lithium action and relevant to treatment of adverse effects associated with lithium therapy. Within this hypothesis, lithium's depletion of the recyclable inositol pool would affect hyperactivated systems while leaving isosystems unaffected. Berridge ²³ similarly found that lithium only inhibits phosphoinositide-derived second messengers of activated systems. These findings and those of clinical trials consistently indicate that concomitant administration of inositol during lithium therapy does not interfere with the efficacy of the treatment of individuals with bipolar disorder.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing lithium for patients with bipolar affective disorders are advised to consider concomitant inositol administration, especially when intractable psoriasis occurs and continued lithium therapy is deemed necessary. Inositol (e.g., 500 mg three times daily) could ameliorate adverse effects of lithium therapy without reducing the drug’s therapeutic effectiveness; such nutrient administration may also provide therapeutic value independent of conventional pharmacological treatment.

Although the beneficial effects of inositol coadministration from clinical trials are encouraging, further research through well-designed clinical trials is warranted to investigate further the safety and efficacy of this combination and to develop clinical guidelines for therapeutic application. Pending findings from such investigations, it would be premature generally to recommend concomitant use of lithium and inositol for treatment or prevention of adverse effects.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

5-Hydroxytryptamine Receptor Agonists (Triptans)

Almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), zolmitriptan (Zomig).

Triptans (5-hydroxytryptamine receptor agonists) are a primary pharmacological therapy for migraines within conventional practice. Theoretically, concomitant administration of high-dose myo-inositol and medications in this class may produce additive effects. Evidence from qualified case reports or human trials is lacking to determine the occurrence, conditions, and clinical significance of this potential interaction.

Careful monitoring is advised for concurrent or consecutive use of high-dose myo-inositol with triptans. Either or both agents should be discontinued if symptoms suggestive of serotonin syndrome develop. This has not been reported, but there is little clinical experience in this area. Human trials are warranted.

Antibiotics/Antimicrobials

Antibiotics and Antimicrobials

Intestinal microflora play a critical role in biosynthesis of many B vitamins, particularly converting phytate/phytic acid from dietary sources into inositol. The adverse impact of repeated courses or high doses of broad-spectrum antibiotics on these commensal microbiota, and thus conversion of phytic acid to inositol, is probable. However, evidence is lacking to determine the frequency, character, and implications of such effects. Current knowledge suggests that the probability of a clinically significant adverse effect is low for most individuals because this inositol production pathway accounts for a minor part of inositol formation. Nevertheless, specific evidence is lacking to disprove or confirm the occurrence and clinical implications of this potential interaction. Further research is warranted. Physicians prescribing broad-spectrum antibiotics are generally advised to restore healthy intestinal ecology by administering diverse and vigorous cultures, providing 10 billion viable organisms daily of probiotic flora for a minimum of 3 weeks, although in many cases it may take 6 months of daily probiotic intake to reestablish optimal bowel flora.

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants

Citalopram (Celexa), escitalopram (S-citalopram; Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Faurin, Luvox), paroxetine (Aropax, Deroxat, Paxil, Seroxat), sertraline (Zoloft).

In a randomized, controlled, double-blind augmentation trial, Nemets et al. ²⁴ found that inositol coadministration did not improve depression in SSRI treatment failures. Comparing single-photon emission computed tomography (SPECT) on 14 subjects diagnosed with OCD before and after 12 weeks of treatment with inositol, Carey et al. ²⁵ concluded that “inositol effects a clinical response through alternate neuronal circuitry to the SSRIs.” Some research has suggested that inositol helps reverse desensitization of serotonin receptors. ²⁶ Theoretically, high-dose myo-inositol might have additive effects with SSRIs and, in fact, has been recommended as an adjunctive therapy for people diagnosed with OCD who do not respond to SRIs (clomipramine and SSRIs). ²⁷ Doses of 18 g/day have been well tolerated in conjunction with SSRIs for the treatment of OCD, although the addition of inositol did not provide any added benefit over SSRI alone. ²⁸

Careful monitoring is advised for concurrent or consecutive use of high-dose myo-inositol with SSRIs. Either or both agents should be discontinued if symptoms suggestive of serotonin syndrome develop. This has not been reported, but there is little clinical experience in this area.

Valproic Acid and Related Anticonvulsant Medications

Evidence: Divalproex semisodium, divalproex sodium (Depakote), sodium valproate (Depacon), valproate semisodium, valproic acid (Depakene, Depakene Syrup).

Extrapolated, based on similar properties: Carbamazepine (Carbatrol, Tegretol), clonazepam (Klonopin), clorazepate (Tranxene), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), levetiracetam (Keppra), mephenytoin, mephobarbital (Mebaral), methsuximide (Celontin), oxcarbazepine (GP 47680, oxycarbamazepine; Trileptal), phenobarbital (phenobarbitone; Luminal, Solfoton), phenytoin (diphenylhydantoin; Dilantin, Phenytek), piracetam (Nootropyl), primidone (Mysoline), topiramate (Topamax), trimethadione (Tridione), vigabatrin (Sabril), zonisamide (Zonegran).

O’Donnell et al. ¹⁵ found that the brains of rats treated with sodium valproate exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration compared with saline-treated controls. These unexpected results suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder through actions on the phosphoinositol cycle.

Chengappa et al. ¹³ reported doses of 12 g/day inositol being well tolerated in combination with either valproic acid or carbamazepine. ¹³

Clinical trials of concomitant use of valproate and myo-inositol in bipolar disorder would be of interest because inositol might be useful in preventing or treating the depressive cycles.

nutrient-nutrient interactions

Calcium, Iron, and Zinc

Phytic acid or phytate, the form of inositol in plant food sources, has the strong ability to chelate multivalent metal ions, especially calcium, iron, and zinc. The resultant binding can produce very insoluble salts that are poorly absorbed from the gastrointestinal tract. Thus, high dietary intake of phytate can result in poor bioavailability of these minerals. However, available evidence indicates that standard oral preparations of inositol do not exert a similar effect on absorption of these nutrients. ²⁹

Citations and Reference Literature

1.Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 2001;21:335-339.View Abstract
2.Levine J, Umansky R, Ezrielev G, Belmaker RH. Lack of effect of inositol treatment in chronic schizophrenia. Biol Psychiatry 1993;33:673-675.View Abstract
3.Jope RS, Song L, Grimes CA et al. Selective increases in phosphoinositide signaling activity and G protein levels in postmortem brain from subjects with schizophrenia or alcohol dependence. J Neurochem 1998;70:763-771.View Abstract
4.Levine J, Ring A, Barak Y et al. Inositol may worsen attention deficient disorder with hyperactivity. Hum Psychpharmacol 1995;10:481-484.
5.Levine J, Witztum E, Greenberg BD, Barak Y. Inositol-induced mania? Am J Psychiatry 1996;153:839.
6.Greene ND, Copp AJ. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med 1997;3:60-66.View Abstract
7.Reece EA, Khandelwal M, Wu YK, Borenstein M. Dietary intake of myo-inositol and neural tube defects in offspring of diabetic rats. Am J Obstet Gynecol 1997;176:536-539.View Abstract
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11.Kofman O, Belmaker RH. Ziskind-Somerfeld Research Award 1993. Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression. Biol Psychiatry 1993;34:839-852.
12.Bersudsky Y, Einat H, Stahl Z, Belmaker RH. Epi-inositol and inositol depletion: two new treatment approaches in affective disorder. Curr Psychiatry Rep 1999;1:141-147.View Abstract
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