Thursday, October 18, 2007

LISTENING TO INOSITOL: CLINICAL NOTES

The following is a revised and updated version (as of December 30, 2019) of my article published in the Medical Post on April 24, 2007.

 Dedicated to the researchers in Israel and Italy who inspire me.

What if, in the future, a drug with the therapeutic properties of an SSRI, but free of SSRI side-effects was developed? What if it was available over the counter? What if the future is already here?

In the mid 1990's, I came across scientifically valid reports from researchers in Israel on the use of inositol for the treatment of depression and anxiety disorders, and I began prescribing it to my patients for those indications. The results impressed me. In speaking with colleagues, I am struck by a general lack of awareness of this therapeutic option, but a willingness to learn more. In order to fill this void, I offer the following as a summary of the medical literature (for details, search PubMed at http://www.ncbi.nlm.nih.gov/pubmed ), as well as my own clinical experience with what one of my teenage patients dubbed “psycho-powder.”

Indications: Inositol has been shown to be useful for the treatment of depression, obsessive compulsive disorder, panic disorder and bulimia. In bipolar depression and PMS, results have been mixed (but it is useful to treat lithium-induced psoriasis and lithium induced polyuria).
My clinical experience is that inositol can have a calming effect in patients with hypervigilant states such as generalized anxiety disorder, borderline personality disorder, hypochondriasis and chronic anger states. As inositol has a powerful tension reducing effect, it is not surprising that it has been used successfully to treat trichotillomania and compulsive skin picking, two behaviors that are rooted in habits aimed at tension reduction.
An area where there is no research at this time is its use in teenagers (where SSRI use is problematic) and in geriatrics (where polypharmacy is a significant issue). My experience with both of these patient populations, while limited, shows reason for optimism with inositol helping such patients.

When I prescribe inositol, the target symptom I ask my patients to pay attention to is repetitive mental "looping". Inositol seems to clear the mind of "chatter," a term that resonates with the my patients. It seems particularly effective at reducing "pillow chatter," the repetitive yackity-yack that emanates from the mind when trying to fall asleep at night. This response is seen in patients whether inositol is taken in the morning or at night.


I have found that inositol augmentation of SSRIs and SNRIs can be very useful (despite literature published to the contrary). When a patient is at the maximum recommended SSRI dose, rather than risk serotonin syndrome with higher dosage or by mixing SSRIs, I have successfully added inositol. In fact, I have had a few cases where remission of both depression and OCD have been achieved with this combination. See the comments on drug interactions for warnings about this.

Mechanism of action: Similar to SSRIs, the exact mechanism by which inositol exerts its positive effect on neurons is unclear. Inositol is a key component of cellular signalling systems via the phosphatidyl-inositol second messenger cycle (thus influencing not just serotonin signalling, but other neurotransmitter systems as well).
It can also influence hormones that can affect brain activity, such as has been demonstrated with the use of 600 mg. of inositol in combination with selenomethionine to treat Hashimoto's thyroiditis: the inositol increases TSH sensitivity.

Inositol is a "gliotransmitter," or more precisely, a neuromodulator through its action via glial cells. Glial cells regulate synaptic function Since the brain is composed mostly of glial cells, I would suspect that glial cells are a therapeutic target for inositol.
Glial cells modulate the firing of neurons, increasing "synaptic fidelity," whereby important brain signals become crisper and clearer because there is less unwanted activity or "chatter" among neurons that should not be firing. This clinically correlates quite well with what my patients treated with inositol describe.

Inositol is endogenously produced from glucose, and the average diet contains one gram daily.

Dosage: The original studies used 12 g daily for depression and panic disorder and 18 g daily for OCD. Some of my patients have responded to doses as small as 500 mg daily (the dose usually found in tablets).
I usually start my patients on one teaspoon of inositol POWDER daily (approximately 3 g) mixed with the beverage of their choice. Inositol does not dissolve very well, so I usually recommend that users put the entire daily dose in a glass of water, stir, and drink the water while it is still in motion.
I have had patients add the powder to their morning tea or coffee (antioxidant bonus) as a sweetener. Despite claims that caffeine makes inositol ineffective, my clinical experience does not support this.
I encourage my patients to increase the dosage by one teaspoon every three or four days, although most prefer to increase the dose every week or two. Some have aggressively increased it by one teaspoon daily with no negative effects. Once a dose is reached where there is no improvement on the previous dose, I usually recommend staying at the previous dose for one month, and then reduce until there is some loss of effect, in which case the recommendation is to stay at the minimal effective dose for another month and try again next month to reduce it. The principle is to take as little as needed without losing any effect. I leave the pace of increase and decrease up to the individual.
It has been hard to tell at times what my patients are taking in terms of dosage, as I rarely can get anybody to use a measuring spoon (although by my measure a “heaping teaspoon” can amount to two teaspoons).
There is no maximum dosage.
I suggest taking the entire dose in the morning, based on my suspicion that this is chronotherapeutically the best time of day to deliver the inositol to the body. The powder is usually mixed with water or juice. As inositol powder is sweet, some sensitive people find it best to mix it with unsweetened cranberry juice or add some lemon juice to the water to cut down on the sweetness. It is important to let patients know that they will not gain weight from this "sugar" as it has zero calories.
It does not  matter if it is taken on an empty stomach or with food.
If gastrointestinal symptoms emerge (gas, bloating, diarrhea), I suggest that the dose be split to bid up to qid, although this type of splitting usually becomes a psychological barrier to its use. One alternative is to put the mixture in a drinking bottle and sip on it throughout the day.
Treatment duration depends on the chronicity of the condition being treated, but in contrast to SSRIs, inositol seems to stabilize the brain as a biological "system restore."
There is a different exit strategy for this medication as opposed to the SSRIs. In sharp contrast to the SSRIs, I have never seen any discontinuation syndrome/withdrawl symptoms from missed doses or even discontinuation of inositol. Symptoms of the original condition may re-emerge once the inositol is discontinued, but this should not be confused with inositol withdrawal.
In fact, I have used inositol to successfully manage discontinuation from SSRIs, using an aggresive dosing regimen.


Side-effects: Inositol’s side-effects are usually limited to the gastrointestinal system (gas, bloating, loosening of the stools, diarrhea) but these symptoms usually pass with time. Patience in dose titration usually overcomes these obstacles.

One side effect that I have noticed on occasion over the years is inositol's property of inducing paradoxical panic in those vulnerable to this side effect. In these cases, the calming effect can be overwhelming: the patient feels out of control, not being familiar with a state of relaxation. I have seen the same paradoxical panic in patients with chronic anxiety who are being taught relaxation exercises (e.g. progressive muscle relaxation, breathing techniques). As such, it is not a drug reaction as much as a part of the anxiety picture.

Rarely patients have complained of feeling "stoned" when first starting inositol. This is a transient effect, so the pace of dosing has to be modified. I would also proceed cautiously in patients with a tendency towards dissociation.

People who gave a tendency to bottle up/stuff their emotions can experience disinhibition while taking inositol initially. This can be quite disturbing as the patient will often blame the medication instead of realizing that it is time to let go of some of these toxic feelings as they emerge for processing. My only advice is to go slow with the dose in these cases.

I have had one patient develop a transient case of hippus that cleared with discontinuation of the inositol. I am not sure what to make of this.

I had one interesting case of a patient whose asthma resolved while on inositol. Asthma may involve the second messenger system, and perhaps the inositol acted in a positive way on this system in this patient. Another alternative explanation was that the patient's anxiety was a major trigger of his asthma, but I was not impressed in this case that his anxiety responded particularly well to the inositol, so I tend to favour the former explanation. I would love to hear from colleagues if they have ever observed this effect in their patients.

One of my patients complained that she had to shave her legs more often due to hair growth stimulation she attributed to inositol. Unfortunately, I have never had a male patient happily note that his baldness has been cured by inositol.

Drug Interactions: As already mentioned, inositol can boost the effects of SSRIs. When adding inositol to an SSRI, be aware that SSRI side effects can emerge, similar to what happens when starting or increasing an SSRI. That means that symptoms such as headaches, nausea, weirder dreams, etc are not due to the inositol but due to the juiced up SSRI, and usually pass within 7-14 days as is the usual cases with SSRI dosage adjustments.

On a completely different note, some of my marijuana using patients have noticed a decreased urge to smoke when on inositol. Some have even been able to use inositol to break free from their marijuana addiction. Furthermore, patients who are regular or even recent past users of marijuana have responded to smaller doses of inositol than non-users. This evidence makes me suspect that inositol may have an effect on the endocannabinoid system. I have not been able to find any literature to support this hypothesis, but I suspect that inositol ingestion in some people may stimulate 2-AG production. An alternative hypothesis is that, since inositol is a gliotransmitter, and glial cell stimulation has been impicated in marijuana's effect of  making users feel "stoned," stimulation of glial cells by inositol may have similar effects to marijuana through a shared mechanism (Possibly through impacting the gliolymphatic system??). As noted earlier in this article, some inositol users complain of feeling stoned initially, but this effect wears off over time (although it may take days to weeks, it is usually mild and tolerable).

Contraindications: In high doses, inositol may cause uterine contractions and is therefore theoretically contraindicated in late pregnancy. However, Italian researchers have been using inositol successfully in pregnancy for women with PCOS, as well as women with gestational diabetes, without the feared consequence of uterine contractions. The dosages they have used have been on the low side, so at this time I cannot make any recommendation on its use in pregnancy.
Of note, recent research from Cavalli in Italy has shown that inositol may be useful in the prevention of neural tube defects (spina bifida, anencephaly), especially in those for whom folic acid supplementation alone is ineffective. Again, the dosage used throughout pregnancy was small (1 gram of inositol per day along with 5 mg folic acid).
When it comes to pregnancy, Italian researchers have presented some evidence that, in cases of male infertility due to OAT (olligi -astheno-teratozoospermia), inositol may be of benefit.

Of related interest, premature infants born with high blood levels of inositol or those fed with high dose inositol formula have less severe retinopathy and bronchopulmonary dysplasia compared with other premature infants.

There is no safety data on the use of inositol in breastfeeding as far as I know.

One study in patients with ADD showed worsening of this condition. I do not see this a contraindication but something the prescriber should be aware of. My experience with patients with the attention deficit disorderS (ADD is not one uniform condition) is that inositol may reduce the impulsivity and anxiety that often accompany attention maintenance deficits of ADD, and as such, can improve the clinical picture, especially for patients already on stimulants.

Structurally, inositol is a sugar and tastes sweet. Some reports in the literature suggest slight elevation of blood glucose levels with its use, while most of the others suggest it may be useful in normalizing blood glucose levels. Myo-inositol oxygenase, the enzyme responsible for inositol’s catabolism, is primarily found in the kidneys. Diabetic complications have been correlated to low inositol levels but there is no proof that inositol supplementation can prevent the long-term complications of diabetes. Future diabetic treatment may target this enzyme with inhibitors.
Of note, inositol has been used to treat PCOS and seems to be effective in reducing insulin resistance in these patients, some to the point of re-establishing normal menstrual cycles, with some patients able to become pregnant with its use.
There is interesting research that using inositol in combination with alpha lipoic acid (2 gm. inositol with 100 mg. ALA) was shown to decrease insulin resistance better than using either agent alone, and that this was therefore suggested as a strategy to prevent breast cancer in woman at increased risk of this cancer because of metabolic syndrome. In this paper by Capasso, improved metabolic parameters such as increased HDL and decreased triglycerides were also noted.
As for breast cancer, Kesler et al have observed disturbed inositol dynamics in brains of women treated for breast cancer with chemotherapy. That being the case, in those suffering from "chemo brain," inositol may theoretically aggravate this poorly understood but real problem, and caution in the use of inositol in such patients is advised.
Disturbed inositol brain dynamics are also observed in those with Down's Syndrome, due to duplication of the inositol transporter gene, so I would caution against its use in this patient population. Adding extra inositol to an already inositol compromised brain is ill-advised, as there is an association between this elevated inositol and the dementia associated with this condition (inositol is not associated with dementia under any other circumstances, and scyllo-inositol may actually some day soon be used as a treatment for dementia. However, myo-inositol is not scyllo-inositol and the two should not be confused).

It is probably wise to proceed with caution in patients with renal failure as inositol is both produced and catabolized in the kidney and the overall balance in this state is unclear. Nevertheless, at therapeutic doses inositol has not been shown to impact hematological, renal or liver function tests in otherwise healthy individuals.

Purchasing: With all products bought at the health food store, the rule is, buyer beware, until effective federal regulations ensuring safety and quality control are in place. In a study in Italy by Papaleo, of the 4 inositol products tested, none contained the amount of inositol promised on the label.
I have found that side effects attributed to inositol often clear up when the same dose is used from a different manufacturer, so quality of product can vary from batch to batch and between different companies.
Patients buying in bulk should be aware that cocaine dealers buy inositol powder to dilute their product because it has a similar consistency. I have had patients who have had comments directed at them by sales clerks about this when making larger purchases.
As well, make sure that you direct patients to buy myo-inositol (usually labeled as inositol), not IP6, which is much more expensive and not studied for mental health conditions.

The Future: From its use to restore precancerous lung cell changes in smokers to their former healthy state, to its ability to improve fertility (both by increasing the maturity of oocytes for IVF harvesting and by improving sperm function in those with OAT), the future clinical applications of inositol outside of its mental health benefits are encouraging.
As for its use in mental health, inositol should be offered to all patients as an initial alternative to SSRIs for any condition where repetitive "looping" is a feature. Primum non nocere.

Hopefully this article will motivate you to start prescribing inositol. I would appreciate feedback on your successes and, just as importantly, your failures with the use of inositol. I have yet to accurately predict who will benefit and who will be wasting their money by using this product. Any insights from my colleagues will be appreciated.
I can be reached at dr pupko (one word) at g mail. I check my mail there about once per month.

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