Inositol

Last Updated: November 14 2022

Inositol refers to a group of molecules that are involved in various regulatory and metabolic processes. The most commonly supplemented forms of inositol are Myo-inositol and D-chiro-inositol, but all forms are interchangeably referred to as inositol. It’s best known for its effects on insulin resistance and is often supplemented in the context of polycystic ovarian syndrome (PCOS).

Inositol is most often used for.



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    1.

    Sources and Significance

    1.1

    Sources

    Inositol (1,2,3,4,5,6-cyclohexanehexol or simply cyclohexanehexol) is a molecule commonly referred to as a B-vitamin, although this is not a legitimate claim and it is more of a pseudovitamin due to its prevalence in the diet and importance in the body. It is known as a cyclic polyol that is a precursor for phosphorylated compounds known as phosphoinositides, which are involved in signal transduction, and other secondary messengers including diacylglycerol (DAG) and inositol triphosphate (IP3).[1]

    Inositol is a small molecule with structural similarity to glucose. It is a vitamin-like compound (pseudovitamin) that is sometimes said to belong to the class of B-complex vitamins and it is involved in cellular signalling and as a component of cell membranes

    There are nine different inositol molecules, known as stereoisomers,[2] including:

    • Myo-inositol
    • Epi-inositol
    • Cis-inositol
    • Allo-inositol
    • Muco-inositol
    • Scyllo-inositol
    • Neo-inositol
    • L-Chiro-inositol
    • D-Chiro-inositol

    The majority of supplementation is in the form of myo-inositol as this is the body's main steroisomer (comprising over 90% of cellular inositol with scyllo-inositol coming in second place[3]), and other supplemental forms that are generally not labelled 'inositol' include scyllo-inositol itself (ELND005[4]) and D-chiro-inositol.

    'Inositol' refers to a group of molecules, rather than a single molecule; the molecules in this group are all called 'stereoisomers' of inositol. While they may all have biological importance, myo-inositol is by far the most plentiful and that specific stereoisomer is most commonly supplemented. In regards to marketing and lay person discussion, 'inositol' and 'myo-inositol' are interchangeable

    Inositol is a component of the diet in low concentrations[5] thought to exist in the diet at around 900mg per every ingested 2500kcal.[6][7] It can be found in:

    Milk Products

    • Chocolate milk (0.19mg/g)[7]
    • Milk (0.04mg/g)[7]
    • Yogurt (0.06-0.16mg/g)[7]

    Fruits

    • Dried prunes (4.70mg/g)[7]
    • Cantaloupe (3.55mg/g)[7]
    • Orange at 3.07mg/g, it's frozen juice from concentrate (2.04mg/g) and appreciable levels in both mandarin oranges (1.49mg/g) and nectarines (1.18mg/g)[7]
    • Grapefruit (1.99mg/g) and its juice from concentrate (3.80mg/g)[7]
    • Lime (1.94mg/g)[7]
    • Blackberry (1.73mg/g)[7]
    • Kiwi (1.36mg/g)[7]
    • Mango (0.99mg/g)[7]
    • Dark cherries (1.27mg/g)[7]
    • Pear (0.73mg/g)[7]
    • Peach (0.53mg/g)[7]
    • Apricot (0.52mg/g)[7]
    • Watermelon (0.31-0.46mg/g)[7]
    • Honeydew (0.46mg/g)[7]
    • Pineapple (0.33mg/g)[7]
    • Apple (0.24mg/g)[7]
    • Papaya (0.08mg/g)[7]

    Vegetables

    • Navy beans (2.83mg/g), red kidney beans (2.49mg/g), lima (1.10mg/g) and great northen beans (3.27-4.40mg/g)[7]
    • Rutabaga (2.52mg/g)[7]
    • Green beans (1.05-1.93mg/g), although canned products are near 0.55mg/g[7]
    • Artichoke (0.6mg/g) and the heart (1.16mg/g)[7]
    • Okra (1.17mg/g)[7]
    • Eggplant (0.84mg/g)[7]
    • Brussel sprouts (0.81mg/g)[7]
    • Cabbage (0.70mg/g)[7]
    • Asparagus (0.68mg/g)[7]
    • Spinach (0.66mg/g)[7]
    • Collard Greens (0.64mg/g)[7]
    • Bell pepper (0.57mg/g)[7]
    • Tomato (0.54mg/g)[7]
    • Avocado (0.46mg/g)[7]
    • Squash (0.32mg/g)[7]
    • Onions (0.27mg/g)
    • Lettuce (0.16mg/g)[7]
    • Cucumber (0.15mg/g)[7]
    • Cauliflower (0.15mg/g)[7]
    • Mushrooms (0.09-0.29mg/g)[7]
    • Carrots (0.12mg/g)[7]
    • Beetroot (0.12mg/g)[7]

    Grains

    • Stone ground wheat (11.5mg/g)[7]
    • Hamburger bun (4.78mg/g) and hot dog buns (1.15mg/g)[7]
    • Bran flakes (2.74mg/g)[7]
    • Pumpernickel (1.6mg/g)[7]
    • Whole wheat (1.42mg/g) and mixed whole wheat (0.47mg/g)[7]
    • Raisin bran (1.07mg/g)[7]
    • Rye (0.39-0.47mg/g)[7]
    • Oatmeal (0.34-0.42mg/g)[7]
    • Pasta (0.31mg/g)[7]
    • Wild or brown rice (0.27-0.30mg/g) and specifically white rice (0.02-0.17mg/g)[7]
    • White bread (0.25-0.26mg/g)[7]

    Meat and Alternatives

    • Beef liver (0.64mg/g)[7]
    • Ground beef (0.37mg/g)[7]
    • Sirloin steak (0.30mg/g) or round steak (0.15mg/g)[7]
    • Eggs (0.09mg/g) mostly in the yolk (0.34mg/g)[7]
    • Chicken breast (0.30mg/g) and turkey (0.08mg/g)[7]
    • Pork chops (0.42mg/g)[7]
    • Tuna (0.12-0.15mg/g)[7]
    • Sardines (0.12mg/g)[7]
    • Crab (0.05mg/g)[7]
    • Clams (0.03mg/g) and oysters (0.25mg/g)[7]

    Food products tend to contain myo-inositol more often than not, and the most prevalent food products for this nutrient are whole grain products and citrus fruits whereas dairy and meat products are relatively poor sources

    1.2

    Structure

    Inositol is a polyol by the name of cyclohexanehexol, and is a cyclohexane group (hexagon) with six hydroxyl groups surrounding the structure. Myo-inositol is particularly defined by having a lone axial hydroxyl group (on C2) whereas the other eight possible isomers of inositol are equatorial.[2]

    {OLD-IMG-ID:366}

    If D-chiro-inositol is methylated at the 3-carbon, then the molecule that results is known as D-pinitol.[8]

    1.3

    Biological Significance

    Myo-inositol is the precursor to various phosphorylated derivatives such as inositol-1,4,5-triphosphate (IP3).[9][10] The phosphorylated derivatives are numerous, and the 63 possible variants are divided into groups as to how many phosphate groups they possess (six variants of IP1, fifteen of IP2, twenty for IP3, fifteen for IP4, six for IP5, and a single IP6 molecule known as inositol hexaphosphate or phytic acid).[10] Based on the structures of IP5 and IP6, enzymes may create pyrophosphorylated derivatives by adding pyrophosphate groups in the D1, D3, or D5 carbons; these derivatives are referred to as IP7-IP9.[11][12][13]

    It appears that a mnemonic for these phosphorylated inositol derivatives is a turtle, which has the axial group of the carbon as the turtle's head (carbon 2) and the first carbon being the right frontal flipper which is usually anchored to the cell membrane.[10][14] Visualizing inositol in this manner prevents confusion between the numerous enantiomers.[15]

    {OLD-IMG-ID:364}

    Myo-inositol initially does not possess any phosphate groups, and the addition of varying phosphate groups to different positions can result in over 70 different signalling molecules within cells. They are categorized into groups based on how many phosphates they possess which are referred to as IP1-IP9

    Another group of derivatives include the phosphatidylinositol polyphosphates or PIPS, which are lipid based signalling molecules.[16]

    1.4

    Deficiencies

    Since lithium therapy (the first treatment for bipolar disorder) is hypothesized to work via depletion of inositol monophosphate, there have been instances where an inositol-deficient diet have been used in rats[17] and a human diet that is 90% deprived of inositol can reduce brain levels of this molecule (10.8% in the frontal cortex) without causing any significant health complaints.[17]

    The lack of adverse effects despite the importance of inositol may be due to how it can simply be synthesized in the human body from glucose-6-phosphate, a derivative of glucose.[18][19]

    Although there is limited human evidence for intentional inositol depletion, there does not appear to be a disease state associated with depletion of this molecule nor does dietary deprivation cause any adverse health effects in the short term (longer term not studied)

    There are reduced urinary D-chiro-inositol concentrations in the urine of persons with type II diabetes,[20][21] gestational diabetes,[22] and PCOS[23] as well as any insulin resistant state that is not necessarily diagnosed;[24] due to this and how increasing urinary concentrations are directly correlated to reduced insulin receptor activity in skeletal muscle,[25] urinary levels of inositol derivatives (D-chiro-inositols and myo-inositols) are seen as a biomarker for insulin resistance.[26]

    Myo-inositol and D-chiro-inositol are said to exist in plasma in a 40:1 ratio,[27][28] and the particular molecules that are urinated to a larger degree (referred to as D-chiro-inositol) would be the P-IPG class of inositols that are molecules of galactosamine bound to D-chiro-inositol (see glucose metabolism section for more information).

    In pretty much all instances where insulin resistance is present, there is an increased urinary excretion of inositol metabolites (usually D-chiro-inositol and a conjugate which includes the aforementioned, which is called P-IPG). Due to this information, it is thought that persons who are insulin resistant are in a state of relative inositol deficiency due to an increased excretion rate

    2.

    Pharmacology

    2.1

    Absorption

    Inositol is taken up into tissue via a sodium-dependent inositol co-transporter that also mediates glucose uptake (can competitively inhibit inositol uptake)[29] similar to D-chiro-inositol, although myo-inositol has 10-fold greater affinity for this transporter than does D-chiro-inositol.[30]

    The application of a soft gel to inositol (a shell filled with a liquid or semi-solid fluid to remove any dissolution rate-limiting steps[31]) has been shown to reduce the requirements of 2-4g myo-inositol powder down to 600-1,200mg of the myo-inositol via softgel[32] and this 30% oral dose has been found to be equally efficacious in a trial on women with PMS related dysphoria (12g myo-inositol powder performing equally to 3.6g via softgels).[33]

    2.2

    Serum

    Oral ingestion of myo-inositol powder has resulted in serum levels (Cmax) of myo-inositol of 36.3+/-3.2µM (2,000mg) and 45+/-3.5µM (4,000mg) at a Tmax of 183+/-10 and 122+/-12 minutes respectively.[32]

    2.3

    Metabolism

    Beyond Myo-inositol and epi-inositol there is D-chiro-inositol (DCI), converted from myo-inositol via an epimerase[34] which is decreased in states of insulin resistance.[35]

    Myo-inositol can convert into D-chiro-inositol in the body via an epimerase

    It has been noted in mice that orally ingested scyllo-inositol has elevated plasma levels of myo-inositol when ingested at 500-2,000mg/kg, with all doses increasing myo-inositol to 0.94mM while scyllo-inositol dose-dependently increased; suggesting that the enzyme that mediates this conversion is saturated.[36]

    Myo-inositol does not increase plasma concentrations of scyllo-inositol.[36]

    Scyllo-inositol appears to be able to convert into Myo-inositol in the body, but the reverse reaction may not exist

    2.4

    Neural

    Myo-inositol is normally present around 3-5mM concentrations in neural tissue in rats[37] and in humans it has been confirmed that myo-inositol is around 3.93+/-1.13mM in youth and 4.69+/-0.69mM in older subjects.[3] Scyllo-inositol is at lower concentrations, 0.30+/-0.10mM and 0.43+/-0.15mM in younger and older subjects respectively.[3]

    In rats, 1.5g/kg inositol for 22 days has been noted to increase concentrations of inositol in the hippocampus (27%) and frontal cortex (36%) while there were no significant increaes in the caudate or cerebellum.[37] Interestingly, this increase in the cortex is greater than the increase seen after six hours of a 10g/kg injection to rats (25%)[38] and comparable or slightly less than a 5g/kg injection which raised levels in the hippocampus (30%), cortex (57%), and hypothalamus (50%).[39] These relatively low increases in cerebral stores despite high doses are thought to be related to how only around 3% of peripheral inositol crosses the blood brain barrier[40] as direct injections of 10mg inositol to the brain have resulted in 77-115% increases in the cortex.[41]

    12g inositol daily over the course of one week is sufficient to elevate cerebrospinal fluid concentrations of inositol 70%.[42]

    3.

    Neurology

    3.1

    Depression and Mood

    In depressive and bipolar persons who have committed suicide, inositol concentrations in the frontal cortices seem to be reduced[43] and at least in depressive persons this has been noted in vivo.[44]

    Inositol concentrations in depressed persons may be lower than normal

    Significant improvements in depressive symptoms have been found on the HDS rating scale with 12g inositol daily over four weeks in a double-blind trial where patients discontinued their antidepressants (benzos allowed to be continued).[45] The overall score on the HDS was reduced from 33.4 to 21.6, or to 64% of baseline, with inositol (32.9 to 28.9 in placebo; 87% of baseline) and appeared to affect female patients more than male patients[45] and when these patients were followed up it was noted that half of the subjects relapsed upon inositol discontinuation.[46]

    Relative to placebo, inositol appears to be somewhat effective in reducing depressive symptoms in unmedicated persons. It appears moderately to weakly potent, and only seems transiently effective (benefits stop upon supplement discontinuation)

    In a study on bulimia and binge eating (considered a mood disorder of sorts), six weeks supplementation of high dose inositol (18g daily) was able to significantly improve symptoms as assessed by the GCI and EDI rating scales, and both depressive and anxiety scores were also reduced more with inositol than with placebo.[47] There was a lone male patient in this study, and he did not respond to treatment.[47]

    High dose inositol may be able to reduce depressive symptoms in persons with eating disorders, resulting in less bulimic symptoms

    Studies that use inositol in persons who were resistant to SSRIs specifically have failed to find an antidepressant effect of 12g inositol over the course of four weeks[48] and the combination of inositol with SSRIs failed to outperform SSRIs by themselves over the same time period.[49]

    One study that used treatment resistant persons who continued their therapy of mostly tricyclic-based antidepressants noted that supplementation of 6g myo-inositol over four weeks was associated with improvements in 9/11 subjects (assessed by a 15 point or more reduction on the HDS).[50] The mean scores were reduced from 31.7 to 16.2, but no placebo control was used.[50]

    Myo-inositol does not appear to augment the efficacy of SSRIs and in persons who do not response to SSRIs it seems inositol doesn't provide any further benefits. There may be an interaction with TCA-based antidepressants

    3.2

    Premenstrual Syndrome

    Premenstrual dysphoric disorder is a mood disorder associated with PMS,[51] and supplementation of 4,000mg myo-inositol thrice daily (total dose of 12g) or the bioequivalent dose in gel caps (1.2g thrice daily) were able to reduce depressive symptoms as well as improve both subjective and clinically rated symptoms over six months.[33] This has elsewhere failed to show benefit with the same oral dose of inositol where it was preloaded for 14 days prior to the luteal phase of the menstrual cycle (and alternated monthly with placebo over six months).[52]

    The observed differences may be due to a possible loading effect of myo-inositol, as although both trials lasted six months the one showing benefit was uninterrupted[33] while the one showing no significant effect alterated in a cross-over design every month (giving supplemental inositol either on either odd or even months only, placebo at other times).[52]

    Mixed results when looking at dysphoria associated with PMS, although the more statistically sound evidence suggests there is a benefit. It may require continued supplementation over a prolonged period of time

    3.3

    Bipolar Disorder

    A trial using inositol at 12g daily as an add-on therapy for a period of six weeks failed to outperform placebo in reducing depressive and bipolar symptoms[53] although due to the observed trend towards significance it has been noted by some reviewers[54][55] that larger trials are needed. Subsequently, a trial conducted using inositol in persons with bipolar disorder undergoing a major depressive episode noted that supplementation was associated with a 17.4% rate of improvement (nonsignificantly underperforming lamotrigine at 23.8%).[56]

    Although there may be a role for inositol in the treatment of bipolar disorder (specifically the depressive symptoms), this is not adequately studied and the magnitude of benefit seems fairly small

    3.4

    Anxiety and Panic Disorders

    Inositol was initially found to be anxiolytic (anxiety reducing) in a rat model of the elevated maze plus test using myo-inositol[57] and later replicated by epi-inositol.[58] At 5% of the diet in rats, inositol seems more anxiolytic in instances where the stressor is perceived as more significant, and less effective with mild stressors.[59]

    Supplementation of 18g inositol daily in persons with panic disorders, supplementation is as effective as 150mg fluvoxamine in reducing anxiety symptoms associated with panic.[60]

    There appears to be some anxiety reducing properties associated with high dose myo-inositol

    A single dose of 20g inositol has failed to significantly influence m-CPP induced panic disorder[61] despite 18g daily for a period of one month reducing panic attacks (in persons susceptable to them) with a potency greater than 150mg fluvoxamine.[60] Somewhat lower doses of 12g over the course of a month have also shown efficacy in panic disorder[62] but have failed in persons with post tramautic stress disorder (PTSD).[63]

    While there appears to be benefit to panic attacks associated with chronic inositol ingestion, it has elsewhere failed to show benefit in persons with PTSD

    3.5

    Schizophrenia

    The alterations seen in cerebrospinal fluid myo-inositol seen in depressive persons does not appear to extend to schizophrenic persons, as those with schizophrenia have the same concentration as healthy controls.[64]

    Supplementation of 6g inositol (sufficient to aid in depressive symptoms) is ineffective in schizophrenic persons[50] and this same dose has elsewhere failed to show benefit in medicated persons with chronic schizophrenia over ten days[65] and double the dose over the course of a month similarly failed.[64]

    Currently, all evidence on inositol and schizophrenia suggest no therapeutic effect whatsoever

    3.6

    Obsessive Compulsive Disorder (OCD)

    Supplementation of 18g inositol daily in persons with diagnosed obsessive compulsive disorder (OCD) over a period of six weeks has led to significant improvements in symptoms as assessed by the Yale-Brown Obsessive Compulsive Scale.[66]

    One study using 18g inositol daily alongside serotonin reuptake inhibitors (SRIs) noted that while some patients responded favorably, it was a minority of the group as a whole.[67]

    In persons who are not responsive to serotonin reuptake inhibiting pharmaceuticals, inositol doesn't show too much promise in improving response rates

    3.7

    Locomotion

    While acute intravenous administration of inositol has mixed evidence for whether it works or not (a failure[68] and increase[69]), ingestion of around 1.5g/kg inositol daily for 22 days was associated with increases in locomotion and rearing with no significant differences between myo-inositol and epi-inositol.[37]

    3.8

    Memory and Learning

    6g of myo-inositol taken daily for five days prior to electroconvulsive therapy (ECT) failed to prevent ECT-induced losses in memory, suggesting no relevant anti-amnesiac effects.[70]

    3.9

    Alzheimer's Disease

    Scyllo-inositol is one of the steroisomers of inositol found in the brain[71][72] and seems to accumulate in the brain with ageing,[73] being measured at 0.3mM in youth while being 0.43mM in elderly.[3] This increase correlates with myo-inositol, which also increases during aging.[3] Supplementation, however, has been noted to increase concentrations up to 10-fold in mice.[74]

    Scyllo-inositol is able to bind to and inhibit formation of Aβ42 fibrils,[74][75] which is a property that also extends to myo-inositol in vitro,[75] and studies in rodents using supplemental scyllo-inositol have reported reductions in synaptic losses,[76] losses in long-term potentiation,[76] and the memory impairments associated with Alzheimer's.[77][78]

    Scyllo-inositol, and to a degree myo-inositol as well, can prevent aggregation of Aβ42 fibrils and are thought to be therapeutic against Alzheimer's disease due to this

    Supplementation of 2,000mg Scyllo-inositol twice daily reaches steady state concentrations in plasma within five days and can increase neural concentrations in otherwise healthy persons.[79] When subsequently tested in persons with Alzheimer's disease, supplementation of scyllo-inositol at 500mg (250mg twice daily) was unable to significantly reduce symptoms of Alzheimer's over the course of 78 weeks despite reducing concentrations of Aβ42 in cerebrospinal fluid (no significant influence on Tau).[4]

    One month of myo-inositol at 6g daily has been noted to trend towards improvements in the CAMCOG rating scale, but this did not reach statistical significance over the course of one month.[80]

    Preliminary evidence using scyllo-inositol for Alzheimer's disease fail to show significant benefits and myo-inositol doesn't appear to have statistically significant benefits

    3.10

    Autism

    Supplementation of 200mg/kg Myo-inositol daily in children with autism failed to show a therapeutic effect over the course of four weeks; the lone responder to myo-inositol therapy was a boy and the response was mild in nature.[81]

    For the most part, there does not appear to be a therapeutic benefit of supplemental inositol to autism

    4.

    Cardiovascular Health

    4.1

    Lipoproteins

    Plasmalogens are components of lipoproteins synthesized in the liver and known to be decreased in aging and hyperlipidemia[82][83] as well as familial hypercholesterolemia.[84] They are phospholipids (specifically 1-alkenyl-2-acyl-sn-glycero-3-phospholipids) that can be divided into choline plasmalogen and ethanolamine plasmalogen[85] and while overall plasmalogens are positively correlated with HDL-C concentrations the ratio of choline:ethanolamine plasmalogen is positively associated with LDL-C.[83]

    Supplementation of myo-inositol (5g for one week and double the next week) in persons with metabolic syndrome was able to decrease apolipoprotein B and LDL-C while increasing choline plasmalogen (ratio unaffected).[86] These changes did not occur in persons without metabolic syndrome.[86]

    Possibly secondary to an increase in plasmalogens in serum, circulating LDL-C can be decreased in persons with metabolic syndrome

    5.

    Interactions with Glucose Metabolism

    5.1

    Mechanisms

    Inositol (refering to myo-inositol) is a secondary messenger of insulin signalling (after the receptor) via inositol phosphoglycans.[87] There are various types of inositol phosphoglycans which fall into either the P-type family (D-chiro-inositol bound to galactosamine[88]) or the

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