1Sources and Significance
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).
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, including:
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), and other supplemental forms that are generally not labelled 'inositol' include scyllo-inositol itself (ELND005) 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 thought to exist in the diet at around 900mg per every ingested 2500kcal. It can be found in:
Dried prunes (4.70mg/g)
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)
Grapefruit (1.99mg/g) and its juice from concentrate (3.80mg/g)
Dark cherries (1.27mg/g)
Navy beans (2.83mg/g), red kidney beans (2.49mg/g), lima (1.10mg/g) and great northen beans (3.27-4.40mg/g)
Green beans (1.05-1.93mg/g), although canned products are near 0.55mg/g
Artichoke (0.6mg/g) and the heart (1.16mg/g)
Brussel sprouts (0.81mg/g)
Collard Greens (0.64mg/g)
Bell pepper (0.57mg/g)
Beet root (0.12mg/g)
Stone ground wheat (11.5mg/g)
Hamburger bun (4.78mg/g) and hot dog buns (1.15mg/g)
Bran flakes (2.74mg/g)
Whole wheat (1.42mg/g) and mixed whole wheat (0.47mg/g)
Raisin bran (1.07mg/g)
Wild or brown rice (0.27-0.30mg/g) and specifically white rice (0.02-0.17mg/g)
White bread (0.25-0.26mg/g)
Meat and Alternatives
Beef liver (0.64mg/g)
Ground beef (0.37mg/g)
Sirloin steak (0.30mg/g) or round steak (0.15mg/g)
Eggs (0.09mg/g) mostly in the yolk (0.34mg/g)
Chicken breast (0.30mg/g) and turkey (0.08mg/g)
Pork chops (0.42mg/g)
Clams (0.03mg/g) and oysters (0.25mg/g)
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
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.
If D-chiro-inositol is methylated at the 3-carbon, then the molecule that results is known as D-pinitol.
1.3. Biological Significance
Myo-inositol is the precursor to various phosphorylated derivatives such as inositol-1,4,5-triphosphate (IP3). 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). 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.
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. Visualizing inositol in this manner prevents confusion between the numerous enantiomers.
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.
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 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.
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.
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, gestational diabetes, and PCOS as well as any insulin resistant state that is not necessarily diagnosed; due to this and how increasing urinary concentrations are directly correlated to reduced insulin receptor activity in skeletal muscle, urinary levels of inositol derivatives (D-chiro-inositols and myo-inositols) are seen as a biomarker for insulin resistance.
Myo-inositol and D-chiro-inositol are said to exist in plasma in a 40:1 ratio, 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
Inositol is taken up into tissue via a sodium-dependent inositol co-transporter that also mediates glucose uptake (can competitively inhibit inositol uptake) similar to D-chiro-inositol, although myo-inositol has 10-fold greater affinity for this transporter than does D-chiro-inositol.
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) has been shown to reduce the requirements of 2-4g myo-inositol powder down to 600-1,200mg of the myo-inositol via softgel 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).
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.
Beyond Myo-inositol and epi-inositol there is D-chiro-inositol (DCI), converted from myo-inositol via an epimerase which is decreased in states of insulin resistance.
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.
Myo-inositol does not increase plasma concentrations of scyllo-inositol.
Scyllo-inositol appears to be able to convert into Myo-inositol in the body, but the reverse reaction may not exist
Myo-inositol is normally present around 3-5mM concentrations in neural tissue in rats 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. Scyllo-inositol is at lower concentrations, 0.30+/-0.10mM and 0.43+/-0.15mM in younger and older subjects respectively.
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. Interestingly, this increase in the cortex is greater than the increase seen after six hours of a 10g/kg injection to rats (25%) and comparable or slightly less than a 5g/kg injection which raised levels in the hippocampus (30%), cortex (57%), and hypothalamus (50%). 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 as direct injections of 10mg inositol to the brain have resulted in 77-115% increases in the cortex.
12g inositol daily over the course of one week is sufficient to elevate cerebrospinal fluid concentrations of inositol 70%.
3.1. Depression and Mood
In depressive and bipolar persons who have committed suicide, inositol concentrations in the frontal cortices seem to be reduced and at least in depressive persons this has been noted in vivo.
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). 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 and when these patients were followed up it was noted that half of the subjects relapsed upon inositol discontinuation.
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. There was a lone male patient in this study, and he did not respond to treatment.
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 and the combination of inositol with SSRIs failed to outperform SSRIs by themselves over the same time period.
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). The mean scores were reduced from 31.7 to 16.2, but no placebo control was used.
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, 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. 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).
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 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).
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 although due to the observed trend towards significance it has been noted by some reviewers 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%).
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 and later replicated by epi-inositol. 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.
Supplementation of 18g inositol daily in persons with panic disorders, supplementation is as effective as 150mg fluvoxamine in reducing anxiety symptoms associated with panic.
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 despite 18g daily for a period of one month reducing panic attacks (in persons susceptable to them) with a potency greater than 150mg fluvoxamine. Somewhat lower doses of 12g over the course of a month have also shown efficacy in panic disorder but have failed in persons with post tramautic stress disorder (PTSD).
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
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.
Supplementation of 6g inositol (sufficient to aid in depressive symptoms) is ineffective in schizophrenic persons and this same dose has elsewhere failed to show benefit in medicated persons with chronic schizophrenia over ten days and double the dose over the course of a month similarly failed.
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.
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.
In persons who are not responsive to serotonin reuptake inhibiting pharmaceuticals, inositol doesn't show too much promise in improving response rates
While acute intravenous administration of inositol has mixed evidence for whether it works or not (a failure and increase), 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.
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.
3.9. Alzheimer's Disease
Scyllo-inositol is one of the steroisomers of inositol found in the brain and seems to accumulate in the brain with ageing, being measured at 0.3mM in youth while being 0.43mM in elderly. This increase correlates with myo-inositol, which also increases during aging. Supplementation, however, has been noted to increase concentrations up to 10-fold in mice.
Scyllo-inositol is able to bind to and inhibit formation of Aβ42 fibrils, which is a property that also extends to myo-inositol in vitro, and studies in rodents using supplemental scyllo-inositol have reported reductions in synaptic losses, losses in long-term potentiation, and the memory impairments associated with Alzheimer's.
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. 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).
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.
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
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.
For the most part, there does not appear to be a therapeutic benefit of supplemental inositol to autism
Plasmalogens are components of lipoproteins synthesized in the liver and known to be decreased in aging and hyperlipidemia as well as familial hypercholesterolemia. They are phospholipids (specifically 1-alkenyl-2-acyl-sn-glycero-3-phospholipids) that can be divided into choline plasmalogen and ethanolamine plasmalogen and while overall plasmalogens are positively correlated with HDL-C concentrations the ratio of choline:ethanolamine plasmalogen is positively associated with LDL-C.
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). These changes did not occur in persons without metabolic syndrome.
Possibly secondary to an increase in plasmalogens in serum, circulating LDL-C can be decreased in persons with metabolic syndrome
5Interactions with Glucose Metabolism
Inositol (refering to myo-inositol) is a secondary messenger of insulin signalling (after the receptor) via inositol phosphoglycans. There are various types of inositol phosphoglycans which fall into either the P-type family (D-chiro-inositol bound to galactosamine) or the A-type family (known to be eluted at a pH of 1.3 to the P-type's 2.0).
P-IPG activates the pyruvate dehydrogenase complex (PDC), which is an enzyme complex involved in glycolysis that is positively regulated (increased in activity) by mitochondrial pyruvate dehydrogenase phosphatases (PDPs) and negatively regulated (suppressed) by pyruvate dehydrogenase kinases (PDKs); the activity of the PDC is dependent on the latter two groups of regulatory proteins.
This is relevant as P-IPGs activate PDPs, which then activate the PDC (in a manner that is actively suppressed by A-IPGs). The state of insulin resistance is well known to be associated with an increase in urinary 'inositol metabolites' which are primarily P-IPG class, and this causes the ratio to shift towards A-IPGs and an overall suppression of PDC activity.
As this is thought to be due to a deficiency in myo-inositol provision, supplementation is thought to normalize the ratio of P-IPG to A-IPG and thus increase the activity of the PDC when the body is in a state of insulin resistance.
There are two classes of signalling molecules derived from inositol, the P-IPGs and the A-IPGs, and they tend to be antagonistic to each other and generally regulate body functions. The state of insulin resistance seems to be associated with an increase of A-IPG relative to P-IPG and supplementation of inositol is thought to normalize this ratio
5.2. Glucose Uptake
It is known that when the insulin receptor is activated, that in the signalling process that results inositol derivatives are used. Specifically, the insulin receptor can activate PI3K pathway which ultimately activates both Akt and PDK1 which are required for GLUT4 translocation and glucose uptake (via AS160) but the ability of PI3K to influence Akt/PDK1 is via a phosphatidide called Phosphatidylinositol (3,4,5)-trisphosphate or PIP3. Specifically, PI3K produces phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) which then produces PIP3 (or it could produce diacylglycerol if it doesn't produce PIP3) and anything that inhibits PI3K (such as wortmannin) inhibit insulin-stimulated glucose uptake in part due to inhibiting PIP3 formation.
PIP3 then works upon its receptor, the IP3 receptor of which there are three isoforms that regulate calcium release from the endoplasmic reticulum, where the receptors are expressed.
This above pathway (specifically, PIP3 and its contribution) are negatively regulated by PIP3 phosphatases such as PTEN (overexpression hinders insulin signalling and abolishing it causes insulin hypersensitivity), SHIP2 (expression hinders glucose uptake and abolishing it causes hypersensitivity to insulin), and SKIP (expression hinders and abolishing it enhances insulin signalling as well) which is mostly expressed in muscle tissue.
Activation of the insulin receptor causes glucose uptake by mobilizing GLUT4 vesicles, and this occurs after a sequence of events involving intermediates such as PI3K and Akt; between the PI3K and Akt stages, and inositol signalling molecule known as PIP3 is required and its levels seem to help determine overall activity of insulin signalling
Endogenous phosphatidyl-3-phosphate (PIP3 with two less phosphates) can also independently promote GLUT4 mobilization.
Glypican3, glycosyl phosphatidyl inositol (GPI)-linked proteoglycan, appears to stimulate GLUT4 translocation when it is overexpressed.
There may be other inositol derivatives beyond PIP3 that contribute to GLUT4 mobility.
D-chiro-inositol and its methylated derivative D-pinitol are known to possess insulin-mimetic properties, which appears to extend to all inositol metabolites (although epi and muco-inositol have the most efficacy). 1mM of many of these metabolites is as potent as 100nM insulin in translocating GLUT4 to the cell membrane.
It was later noted that GLUT4 translocation occurs in vivo with oral ingestion of 1,000mg/kg Myo-inositol in mice when measured 30 minutes after ingestion with or without an additional 2g/kg glucose and elsewhere a dosage of 1,000mg/kg in mice has reached a concentration of 2.67+/-0.72mM (without raising D-chiro-inositol concentrations) to a near doubling, a potency that was comparable to 1,000mg/kg D-chiro-inositol.
Oral ingestion of Myo-inositol appears to induce GLUT4 translocation rapidly when used with or without additional orally ingested glucose
5.3. Serum Glucose
Oral ingestion of 1,000mg/kg of myo-inositol in mice is able to exert an acute hypoglycemic effect when paired with 2g/kg glucose (without inherently reducing blood glucose by itself and with slightly less efficacy than the same oral dose of D-pinitol) which is thought to be related to an increase in GLUT4 translocation.
In animal studies, it appears that large oral doses of myo-inositol (human dose of 80mg/kg) may aid in glucose deposition when taken alongside carbohydrates with no inherent hypoglycemic effect
5.4. Diabetes and Insulin Resistance
Supplementation of 2,000mg myo-inositol twice daily for six months in postmenopausal women with metabolic syndrome is associated with improvements in all biomarkers of glucose metabolism (insulin and glucose as well as sensitivity to insulin) and the benefits appear to be slightly greater when the trial is extended to a full year.
In women with insulin resistance, supplemental myo-inositol appears to be effective in improving insulin sensitivity
Similar to how increased urinary inositol metabolites are seen in insulin resistant state (type II diabetes and PCOS), it is also observed in gestational diabetes.
Supplementation of 4,000mg inositol daily to women during pregnancy is associated with improved biomarkers of gestational diabetes (specifically, the decline in insulin sensitivity and rise in glucose were significantly attenuated) and later a study in women with PCOS who became pregnant (for the duration of pregnancy) this same dose is associated with a significantly reduced risk of developing gestational diabetes, reducing the 52% occurrence in control down to 17.2%.
There is no overall influence on the weight gained during pregnancy associated with supplementation.
Supplementation of inositol throughout pregnancy appears to be able to half the risk of developing gestational diabetes, and even when the user does not develop gestational diabetes there may be a bettering of insulin sensitivity
5.5. Comorbities of Diabetes
Myo-inositol appears to be crucial for the development of peripheral nerves (due to the transporter taking it up into the cell being vital) and in part due to an inherent role at nerves as well as the general insulin sensitizing effects of myo-inositol it is thought to aid diabetic neuropathy.
Myo-inositol is thought to be beneficial for diabetic neuropathy (degradation of peripheral neurons that results in impaired sensory capacities)
Supplementation of 4,000mg myo-inositol to diabetic men experiencing erectile dysfunction (a common side-effect of type II diabetes and insulin resistance in men, thought to be related to neuropathy) appears to be more effective than placebo in promoting erections; folic acid was used in this study (400mcg) although its role in promoting erectile function not ascertained.
Myo-inositol has limited but promising evidence for reducing the effects of diabetes-related erectile dysfunction at a fairly reasonable oral dosage
6Interactions with Fat Mass
Many studies have been conducted in women with PCOS given supplemental myo-inositol, with doses as low as 200mg being shown effective and most studies in the range of 1,200-2,000mg. Although there have been some successes with obese women in particular and failures in normally overweight women, it seems that as a general statement the weight-loss properties of inositol in women with PCOS are resisted in heavier weight women as those with a BMI exceeding 37 fail to find benefit with supplementation.
Supplementation of inositol to women who are insulin resistant but not due to PCOS have currently failed to find a therapeutic benefit with 4,000mg daily for a year.
Women with PCOS are known to have more difficulty in losing weight, and supplementation of inositol is able to alleviate this difficulty. It may not be effective in any other scenario
7Interactions with Disease States
7.1. Polycystic Ovarian Syndrome (PCOS)
Polycystic ovarian syndrome (PCOS) is a condition affecting females with a prevalency thought to be as high as 10%. It is associated with abnormalities in glucose metabolism (elevated fasting blood glucose and reduced insulin sensitivity) and androgen metabolism (excessive circulating testosterone) which result in difficulties losing fat, impaired fertility, and acanthosis nigricans (velvety hyperpigmentation of the skin usually found in folds). To be diagnosed, two of the following three requirements of anovulation, androgen excess or polycystic ovarian morphology must be met. While the condition is not immediately harmful, it can predispose one to chronic metabolic complications such as metabolic syndrome and significantly impaired quality of life.
The impairments in insulin sensitivity are thought to precede the elevated androgens and reduced fertility as insulin sensitizing drugs (the first line of treatment in PCOS) can reduce androgens in this disease state only. As there is impaired urinary excretion of inositol metabolites in women with PCOS and diabetics in general, it is thought that supplementation can be therapeutic.
PCOS is a condition affecting women that is associated with high androgens, reduced fertility, impaired weight loss, and these problems seem to stem from insulin resistance. As myo-inositol is thought to alleviate insulin resistance, it is being investigated for its role in PCOS
Other studies have noted improvements in androgen and glucose metabolism (the main concerns with PCOS from a health perspective) that exceed placebo with 12 weeks usage of 1,200mg myo-inositol, 8-12 weeks usage of 2,000mg myo-inositol, up to three months supplementation of 4,000mg myo-inositol, and combined therapy with myo-inositol (550mg) and D-chiro-inositol (13.8mg) over 12 weeks. Studies that have failed to find benefit to glucose metabolism have used doses of 200mg myo-inositol over 12 weeks.
Supplementation of myo-inositol and D-chiro-inositol (550mg and 13.8mg, respectively) was able to significantly improve the lipid profile with reductions in LDL-C (14.3%) with a concomitant increase in HDL-C (45%) while changes in blood pressure and triglycerides were nonsignificant. The increase in HDL-C has been noted elsewhere with 200mg myo-inositol.
When looking at studies assessing biomarkers of androgen and glucose metabolism (both significantly perturbed in PCOS), supplementation appears to have a therapeutic benefit at more modest dosages; it takes a while (12 weeks or longer) for it to work, however
PCOS is known to impair female fertility over the long term and supplementation of inositol (2,000mg over 12 weeks) has been noted to restore menstruation in women who have transiently lost their periods due to PCOS.
1,100mg inositol paired with 27.6mg D-chiro-inositol in women with PCOS was able to improve subsequent oocyte and embryo quality prior to in vitro fertilization, and increase pregnancy rates and elsewhere 2,000mg inositol paired with 200mg folic acid for twelve weeks was capable to reversing ovarian dysfunction (folic acid by itself ineffective) and improve pregnancy rate to 32% of the study group by improving ovarian qualities (oocyte maturation) and three months supplementation of this combination (although in the dosages of 4,000mg myo-inositol and 400μg folic acid) has been shown effective elsewhere.
Doses as low as 200mg (100mg twice daily) appear effective in improving ovulation in women over the course of twelve weeks and when compared to other drugs inositol at 4,000mg (plus 400mcg folic acid) has been noted to be better than Metformin (1,500mg) by increasing pregnancy rates to 36.6% rather than 18.3%.
In vitro fertilization as well as overall pregnancy rates in women with PCOS are improved with supplementation of myo-inositol, and it appears that the symptom of oligo/amenorrhea (disrupted or absent periods) from PCOS can also be alleviated with supplementation
There are many studies that use a brand name called INOFERT (myo-inositol paired with 200mg folic acid) or pair supplemental myo-inositol with 400mcg folic acid which show benefit with combination supplementation. One study that divided the groups into INOVERT and folic acid by itself noted that the inclusion of myo-inositol was vital for improvements in glucose metabolism and fertility, and a comparative study between inositol plus folic acid against folic acid noted the latter group was ineffective.
In these latter studies, folic acid is being added due to the increased fertility with women supplemented with inositol. The supplementation of folic acid around the time of conception reduces the risk of birth defects, and doesn't seem to modify the influence of myo-inositol supplementation.
The usage of folic acid in inositol studies is just to prevent birth defects in any pregnancy that might occur secondary to inositol therapy
7.2. Hepatic Encephalopathy
Hepatic encepalopathy is a liver condition which produces excess ammonia, and the excess ammonia can reach the brain and cause neuronal damage. This damage is associated with low myo-inositol concentrations and high glutamate concentrations as well as low scyllo-inositol concentration, and reduced inositol concentrations in general are thought to contribute to the pathology of this condition.
Depletion of inositol in the brain from excessive ammonia concentrations is thought to contribute to the pathology of hepatic encephalopathy; there are currently no interventions to investgiated if myo-inositol has therapeutic potential
8Interactions with Cancer Metabolism
Low doses of dietary myo-inositol in mice (0.3%) have been noted to reduce lung tumor formation induced by benzo(a)pyrene when inositol ingestion started a week prior to exposure although myo-inositol also appears to be effective in suppressing lung tumor formation in the post-initiation phases with no inhernet requirement for being before, during, or after exposure to a carcinogen. It may be synergistic with budesonide, an inhaled glucocorticoid.
In a pilot study of smokers with bronchial dysplasia (n=10), supplementation of 18g Myo-inositol daily for three months is associated with a 91% rate of clinical regression which is significantly more than the expected rates observed with placebo in other trials (48%); beneficial trends were noted for progression rates and complete response rates.
Myo-inositol oral ingestion may reduce tumor formation in the lungs. While human evidence is very preliminary at this point in time, it suggests that the reduced risk of developing lung cancer does hold true
9Interactions with Aesthetics
A side-effect of PCOS is acanthosis nigricans, which is a velvety darkening of skin (usually in folds of the body) associated with the state of insulin sensitivity.
Acne associated with PCOS also appears to be reduced, with 4,000mg of myo-inositol causes a reduction in severe (68% to 34%) and moderate (32% to 13%) acne while causing 53% of subjects to have no acne whatsoever (none at baseline).
Skin related side-effects of PCOS are alleviated when this state is being treated
Lithium carbonate for the treatment of bipolar disorder is known to either cause or aggravate psoriasis, and due to lithium acting via inositol depletion and inositol therapy being useful for treating peripheral (not brain) related side-effects of lithium it has been investgiated for psoriasis.
Supplementation of 6g myo-inositol daily was able to significantly reduce the psoriasis induced by lithium when taken during lithium therapy over the course of four weeks.
The psoriasis induced by lithium appears to be significantly reduced with supplementation of myo-inositol
Excessive body hair on women is known as hirsutism, which is known to occur in women with PCOS due to the excessive levels of androgen hormones.
Supplementation of myo-inositol for six months at a dose of 2,000mg twice daily in women with hirsutism (not diagnosed with PCOS, but did have excessive circulating androgens with insulin resistance) decreased symptoms by 18%.
Secondary to reducing androgens in women with PCOS, supplementation of inositol appears to be efficacious in reducing hirsutism (somewhat random and excessive growth of body hair)
Lithium is a famous medication of bipolar disorder, and it is proposed to work via inositol depletion. Unfortunately this occurs systemically (all over the body) and due to the poor transportation of inositol across the blood brain barrier it is thought that supplemental inositol can negative the influence of lithium in the periphery (all regions but the brain) without necessarily negating neural effects.
This has been shown to be beneficial in psoriasis, which is a side-effect of lithium therapy and appears to be treated with 6g myo-inositol, and for polyuria at 3g daily (another side-effect of lithium therapy).
Lithium is a bipolar medication that works via depleting inositol in the brain, and side-effects of lithium therapy are thought to be related to excessive inositol depletion. Low dose inositol supplementation that cannot easily get into the brain due to poor transportation is able to effectively reduce side-effects in other body areas
10.2. Oral Contraceptives
The addition of 4,000mg myo-inositol to an oral contraceptive (75μg gestodene and 30μg estradiol) appears to be more effective than the contraceptives alone in treating PCOS, although this study did not measure fertility rates.
550mg myo-inositol paired with 13.8mg D-chiro-inositol appears to be similarly effective as 2g myo-inositol when measured after six months, but is effective quicker (at three months time) and requires a lower overall dosage. This is likely a synergist role, as elsewhere the combination has shown efficacy in the same 40:1 ratio while a higher dose of D-chiro-inositol by itself (500mg) seems ineffective and may be adverse for ovarian function by itself.
Adding in D-chiro-inositol at 1/40th the weight of myo-inositol appears to reduce the overall dose of myo-inositol required and speed up the time required for it to work
10.4. Phytic Acid
Phytic Acid or Phytate are the colloquial names for inositol hexaphosphate (IP6), which is the only phorphorylated derivative of inositol with six phosphate groups; it is an intracellular signalling molecule and potential chemotherapeutic but is most commonly known for being an antinutrient as the phosphate groups bind readily to dietary minerals in the intestines.
At least in vitro, myo-inositol appears to potentiate the anti-cancer effects of IP6 and since IP6 inhernetly is synergistic with some chemotherapeutics (doxorubicin and tamoxifen) it is commonly thought to be a useful adjuvant to anti-cancer therapy.
Supplementation of myo-inositol and IP6 (6g total, appears to be a 1:3.6 ratio) in a pilot study on women with breast cancer appears to be able to enhance quality of life and functionality in day to day living conditions as assessed by survey, and side-effects of chemotherapy (assessed by symptomatic scale) were also significantly reduced. Supplementation also preserved leukocyte and red blood cell count during chemotherapy relative to placebo (Vitamin C).
Phytic acid (IP6) and myo-inositol are known to be synergistically anti-cancer in vitro, and while there is very limited evidence in humans at this moment in time the combination may be useful for improving quality of life during chemotherapy
Melatonin has been used alongside Myo-inositol (as well as folic acid) for the purposes of improving oocyte quality in infertile women as the addition of 3mg melatonin to the standard dosing protocol for infertility (4,000mg myo-inositol and 400mcg folic acid) appears to increase the amount of mature oocytes. Total oocyte count and fertilization rates did not differ, however.
The pro-fertility effects of myo-inositol in women appear to be either additive or synergistic with supplemental melatonin
In general, myo-inositol supplementation is very well tolerated up to doses of around 12g where mild gastrointestinal side-effects may occur at a frequency of around 5% with other studies noting that doses of up to 30g daily are still only associated with mild gastrointestinal distress.
The LD50 of myo-inositol in mice is approximately 10g/kg bodyweight.
Several human studies have been conducted in which inositol (4,000mg daily) have been used during pregnancy from near conception to delivery with no clinically relevant adverse effects.