ProEndorphin: Energy, Mood and Neurotransmitters
Inositol in PROENDORPHIN
What is Inositol? 
Inositol is a nutrient that is often referred to as a B vitamin compound, but is not a true vitamin in that small amounts are manufactured in the human body and biosynthesized primarily from glucose. Inositol works within cells, assisting in the processes of cellular communication, regulation of metabolism, and growth. It is known to exist in several different forms called stereoisomers, or chemicals with similar structural makeup yet different biologic function. [55] Myo-inositol is the most widely available stereoisomer of the brain. Inositol is found widely in foods derived from both plants and animals. A standard American diet will provide roughly one gram of the nutrient per day. More specifically, inositol is found in the largest amounts in cereals, legumes, and other rich sources of dietary fiber. [56]
General Functions
Inositol in the body exists as part of the cell membrane, phospholipid arrangement. It can work as a weak lipotropic agent, meaning it has the ability to move fat from the liver and intestinal cells. [57] Because of its roles in cellular communication, inositol is used in several different neurological related conditions. Inositol plays a key role in cellular signals, which involve serotonin, norepinephrine, and cholinergic receptors in the brain. [58] In fact, some research points to the ability of inositol to act similarly to the selective serotonin reuptake inhibitor (SSRI) drugs in certain neurological conditions such as depression. For persons with obsessive-compulsive disorder (OCD), inositol supplementation may improve their symptoms after a minimal duration; usually several weeks of treatment. [59] Similarly, in people with panic disorder, inositol supplementation can decrease the number and intensity of panic attacks after only 4 weeks of treatment. [60] Studies have also compared inositol to a commonly used drug for panic attacks (fluvoxamine), deeming it equally effective. [61]
Inositol and Depression, Mood
The prevalence of depression in the United States is not definitively known. Depressive symptoms occur in 13-20 percent of the U.S. population. Depression is twice as likely to occur in females, average age of onset being 35-45; whereas it is 55 years of age for men. The biological origin of depression is believed to be linked to a deficiency of neurotransmitters at postsynaptic receptor sites. In the catecholamine theory the deficiency is norepinephrine; in the indolamine theory the deficiency is serotonin. Receptors linked to the inositol signaling system include serotonin and norepinephrine. Therefore, inositol may be an important participant in this neurological arena. Presently, SSRIs are the primary class of drugs used for depressed patients. [55] However, orgasm dysfunction, nausea, vomiting, somnolence, and sweating are frequently reported side-effects. [62] In 1978, researchers demonstrated that depressed patients had significantly decreased cerebral spinal fluid (CSF) levels of inositol as compared to healthy patients. [63] In 1993 this theory was expanded to conclude that administration of high-dose inositol could increase CSF levels by as much as 70%. [64] This led to the study of inositol for treatment of depression. [57,65]
*In 1995, Levine et al completed a doubleblind study for treatment of depression using inositol at a dose of 12 grams daily compared to placebo. Patients receiving inositol showed significant improvement in depression as ranked by the Hamilton Depression Rating Scale. Side-effects experienced by the inositol group were nausea and flatus. There were no hematological abnormalities in laboratory. parameters. A few patients experienced mild elevations in fasting serum glucose concentrations. The researchers concluded that 12 grams daily was well-tolerated. Another important observation was the absence of manic episodes in the bipolar patients treated with inositol. This lack of manic episodes may suggest that when the signaling system is not overactive, addition of inositol will not increase the signaling system's activity. [66]
*Another study reported in 1995 by Levine et al evaluated the potential for relapse of depression once inositol therapy was discontinued. In this study, patients treated with 12 grams inositol daily experienced significant antidepressant effects. Half of the patients who responded to therapy relapsed rapidly on discontinuation of inositol. [67]
Inositol and Panic Disorder
Panic disorder is a common condition in which a person has episodes of intense fear or anxiety that occur suddenly, often without warning. These episodes - called panic attacks - can last from minutes to hours. They may occur only once in a while, or they may occur quite frequently. The cause, or "trigger," for these attacks may not be obvious. [68] The disorder is usually progressive and patients may develop anticipatory anxiety as a result. Most patients will eventually develop symptoms of avoidance behavior or agoraphobia. Several drugs for the treatment of panic disorders are available, although response is often unpredictable. These include SSRIs, antidepressants, or monoamine oxidase inhibitors (MAOls). [55] The drug paroxetine (brand name Paxil) was evaluated for panic disorder by Ballenger et al who reported adverse drug reactions consistent with those most commonly reported for the class as a whole. [69] Rosenbaum et al concluded clonazepam (anti-anxiety medication) in higher doses was more likely to cause somnolence (sleepiness) and ataxia (lack of coordination), while normal maintenance doses were more likely to be associated with depression, dizziness, fatigue, and irritability. [70]
Propelled by incredible advances in the understanding of the pathological causes and characteristics of psychiatric disorders, prospects for treatment have brightened considerably in the last 18 years. It is known that a change in the central nervous system concentration of inositol may lead to modified brain cell signaling pathways, and possibly to the development of a psychiatric disorder. The evidence indicates inositol has psychoactive effects by interacting with the second messenger system and ultimately regulating the cytosolic concentration of calcium. The signaling by calcium is known to mediate an anay of cellular functions involving a number of active and passive transport systems. Inositol is now established as a significant mediator of calcium mobilization in the endoplasmic reticulum. Modifying this mobilization of calcium may be effective in treating some central nervous system disorders like depression, panic disorder, and as an analgesic for pain control. [55]
*Benjamin et al expanded the clinical use of inositol by evaluating its effectiveness in panic disorder. This was an eight week double-blind, crossover study whereby patients were treated with 12 grams inositol daily for four weeks and then crossed over to the other study arm. Improvement was assessed using patient diaries, the MarksMatthews Phobia Scale, the Hamilton Anxiety Rating Scale, and the Hamilton Depression Scale. The frequency and severity of panic attacks and the severity of agoraphobia declined significantly more after inositol than after placebo (a decrease from 10 attacks per week to 3 per week in the treated group compared to a decrease from 10 to 6 in the placebo group). The authors conclude inositol's efficacy and safety, and the fact that inositol is a natural component of the human diet make it potentially attractive therapeutic agent for panic disorder. [60]
*A double-blind, controlled, random- order crossover study was undertaken to compare the effect of inositol with that offluvoxamine in panic disorder. Twenty patients completed one month of treatment with inositol up to 18 g/day and one month offluvoxamine up to 150 mg/day. Improvements on Hamilton Rating Scale for Anxiety scores, agoraphobia scores, and Clinical Global Impressions Scale scores were similar for both treatments. In the first month, inositol reduced the number of panic attacks per week by 4.0 compared with a reduction of2.4 with fluvoxamine (p = 0.049). Nausea and tiredness were more common with fluvoxamine (p=0.02 and p=O.OI, respectively). Because inositol is a natural compound with few known side effects, it is attractive to patients who are ambivalent about taking psychiatric medication. Continuing reports of inositol's efficacy in the treatment of depression, panic disorder, and OCD should stimulate replication studies. [61]
SAFETY
Inositol supplementation is generally well tolerated. Gastrointestinal effects are occasionally reported. Because of a lack of long-term safety data, inositol should be avoided by pregnant women and nursing mothers. Also, high-dose inositol may induce uterine contractions. Theoretically, high-dose inositol may have additive effects with SSRIs. [71]
GUIDLELINES FOR USE
For the management of depression and panic attacks, 12 grams of inositol daily, in divided doses, were used in clinical studies. In the clinical studies performed with inositol, effects were seen in about one month. [71]
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