Definitive INOSIOL post.

[GaryWary]

Definitive INOSITOL post.

Definitive INOSITOL post.

DOUBLE-BLIND CONTROLLED CROSSOVER TRIAL OF INOSITOL VERSUS FLUVOXAMINE IN PANIC DISORDER
Alex Palatnik, MD1, Ari Lauden, MD2 and Jonathan Benjamin, MD2
1Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheba, Israel. 2Department of Psychiatry, Soroka Medical Center of the Kupat Holim Sick Fund, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheba, Israel.
Panic disorder is a frequent (1.5-5%) anxiety disorder that consists of recurring unexpected attacks of severe anxiety without apparent cause and typical somatic complaints. In 30-50-% of cases there is accompanying irrational fearful avoidance of multiple situations such as crowds and travel (agoraphobia), which can be extremely disabling. The recommended treatment is either pharmacological (e.g. serotonin reuptake inhibitors (SSRI) and other antidepressants), psychotherapy (cognitive-behavioral), or both. The need for long term therapy and drug side effects often complicates the compliance.
Inositol phospholipids and their degradation products DAG and IP3 constitute a secondary messenger system. myo-Inositol (inositol), a natural isomer of glucose that is found normally in the average diet (1 gm/day), is a precursor for this system. Key 5-HT receptor sub-types that relate to anxiety and depression therapy are linked to the phosphatidyl-inositol (PI) second-messenger system. Inositol has previously been found superior to placebo in the treatment of depression, panic disorder and obsessive-compulsive disorder (OCD). A direct comparison with an established drug has never been performed. A double-blind controlled random-order crossover study was undertaken to compare the effect of inositol with that of the SSRI fluvoxamine in panic disorder. Twenty patients completed one month of inositol to 18 grams/day and one month of fluvoxamine to 150 mg/day. Improvements on Hamilton anxiety scores, agoraphobia scores and Clinical Global Impressions scores were similar for both treatments. In the first month inositol reduced the number of panic attacks per week by 4.0 (2) compared to a reduction of 2.4 (2) on fluvoxamine (p = 0.049). Nausea and tiredness were more common on fluvoxamine (p = 0.02 and p = 0.01 respectively). Because inositol is a natural compound with few known side-effects, it is attractive to patients ambivalent about taking psychiatric medication. These results support the idea that inositol could be a natural substitute for SSRIs.
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Archived Articles: 08-03-2001
Inositol for Panic Attacks
By Steven Bratman, M.D.
Inositol, unofficially referred to as "vitamin B8," is present in all animal tissues, with the highest levels in the heart and brain. Inositol participates in the action of serotonin, a neurotransmitter known to be a factor in various psychological conditions. (Neurotransmitters are chemicals that transmit messages between nerve cells.) For this reason, inositol has been tried as a treatment for a number of emotional illnesses, including depression, obsessive-compulsive disorder, and anxiety.
A recent preliminary study suggests that inositol might be as effective as standard medications for the treatment of an anxiety-related disorder: panic attacks. This condition involves sudden episodes of anxiety accompanied by racing heartbeat, chest pressure, sweating, and other physical symptoms. A panic attack can be so intense that it is mistaken for a heart attack. Conventional treatment involves antianxiety and antidepressant drugs.
This double-blind crossover study of 20 individuals compared inositol to the antidepressant drug fluvoxamine (Luvox), a medication related to Prozac.1 Each participant received 1 month of inositol (adjusted up to 18 g daily) and a separate month of fluvoxamine (adjusted up to 150 mg per day), in random order. The results showed that the supplement was at least as effective as the drug.
These results are consistent with those of a previous small double-blind study.2 This trial of 21 participants found that people given 12 g of inositol daily had fewer and less severe panic attacks as compared to those given placebo.
While these studies are too small to prove inositol effective, they definitely indicate a need for further research into this promising supplement.
For dosage and safety information, see the full article on inositol.
1. Palatnik A, Frolov K, Fux M, et al. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21:335–339.
2. Benjamin J, Levine J, Fux M, et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry. 1995;152:1084–1086.


Inositol
Inositol functions very closely with another B-complex vitamin, choline. Because it is not essential in the human diet, it cannot be considered a vitamin. It is a fundamental ingredient of cell membranes and is necessary for proper nerve, brain, and muscle function. Inositol is lipotropic, and works in conjunction with folacin, Vitamins B-6 and B-12, choline, betaine and methionine to prevent the accumulation of fats in the liver. It exists as the fiber component phytic acid, which has been investigated for its anti-cancer properties. Inositol is primarily used in the treatment of liver problems, depression, panic disorder, and diabetes. Studies of inositol as a treatment for liver disorders are forthcoming.
Inositol compounds have demonstrated stunning qualities in the prevention and treatment of cancer. Inositol can increase the differentiation and normalization of cancer cells, according to recent research. The abundance of inositol hexaphosphate in fiber may explain in part why high-fiber diets are associated with a lower incidence of certain cancers.1
Neurotransmitters such as serotonin and acetylcholine in the brain depend on inositol to function properly. Low levels of this nutrient may result in depression. Boosting inositol levels appears to be a promising treatment for depressive conditions. Its effect on depression led to a study designed to test its effectiveness against panic disorder. The 1995 study reported that inositol can reduce the frequency and severity of panic attacks in patients with panic disorders.2
Diabetic neuropathy is a nerve disease caused by diabetes. The loss of inositol from the nerve cell is a major cause of the decreased nerve function. Researchers found in 1983 that inositol supplements may improve nerve conduction velocities in diabetics. This condition may be treated partially, though not exclusively, by inositol supplements.3
1 Shamsuddin AM, Journal of Nutrition, 1995;125 (suppl):725S-32S.
2 Benjamin J, et al., Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152, 1084-1086, 1995, as cited in Podell, R, Inositol found effective for depression and panic-anxiety, NFMÕs Nutritional Science News, 1996; 1:8, 18.
3 Gegerson G, Harb H, Helles A, and Christensen J, Oral supplementation of myoinositol: Effects of peripheral nerve function in human diabetics and on the concentration in plasma, erythrocytes, urine and muscle tissue in human diabetics and normals. Acta Neurol Scand 67, 164-171, 1983.

INOSITOL: SOURCES
 Beans, dried
 Calves' liver
 Cantaloupe
 Citrus fruit, except lemons
 Garbanzo beans (chickpeas)
 Lecithin granules
 Lentils
 Nuts
 Oats
 Pork
 Rice
 Veal
 Wheat germ
 Whole-grain products
Available as:
 Capsules: Take with meals or 1 to 1-1/2 hours after meals unless otherwise directed by your doctor.
 Available as inositol monophosphate.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.

INOSITOL: PROVEN BENEFITS
 Plays a role similar to choline in helping move of fats out of liver.
What this supplement does:
 Inositol forms an important part of phospholipids, which are compounds manufactured in our bodies.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
INOSITOL: UNPROVED SPECULATED BENEFITS
 Protects against cardiovascular disease.
 Protects against peripheral neuritis associated with diabetes. (Some studies have shown promise for this use, but definitive, well-controlled studies have not been done.)
 Protects against hair loss.
 Helps maintain healthy hair.
 Functions as mild anti-anxiety agent.
 Helps control blood-cholesterol level.
 Promotes body's production of lecithin.
 Treats constipation with its stimulating effect on muscular action of alimentary canal.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.

INOSITOL: SPECIAL CONSIDERATIONS
 Heavy drinkers of coffee, tea, cocoa and other caffeine-containing substances.
 Miscellaneous information:
 Caffeine in large quantities may create an inositol shortage.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.

INOSITOL: DEFICIENCY SYMPTOMS
Symptoms develop only in some animals; none are known in humans.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
INOSITOL: UNPROVED SPECULATED SYMPTOMS
 Eczema
 Constipation
 Abnormalities of the eyes1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
INOSITOL: LAB TESTS TO DETECT DEFICIENCY
None available, except for experimental purposes.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.

INOSITOL: OPTIMAL LEVELS
Up to 100 mg.
INOSITOL: MINIMUM DOSAGE
No RDA has been established.
For liver conditions a therapeutic dose of 100-500mg daily is advised. For depression and panic disorder the recommended dosage is 12g daily. To supplement diabetic treatment, 1000-2000mg a day is recommended.

INOSITOL: WARNINGS AND PRECAUTIONS
Consult your doctor if you have:
 Diabetes with peripheral neuropathyÑpain, numbness, tingling, alternating feelings of cold and hot in feet and hands. Medical supervision is necessary.
Effect on lab tests:
 None known.
Storage:
 Store in cool, dry place away from direct light, but don't freeze.
 Store safely out of reach of children.
 Don't store in bathroom medicine cabinet. Heat and moisture may change action of supplement.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
INOSITOL: OVERDOSE/TOXICITY
Signs and symptoms:
 Unlikely to threaten life or cause significant symptoms.
What to do:
 For symptoms of overdosage: Discontinue supplement, and consult doctor.
 For accidental overdosage (such as child taking entire bottle): Call your nearest Poison Control Center.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
INOSITOL: ADVERSE REACTIONS OR SIDE EFFECTS
None known at this time.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
INOSITOL: INTERACTION WITH OTHER SUBSTANCES
Caffeine-containing foods and beverages may create inositol shortage in the body.1
1 From Griffith HW, Vitamins, Minerals, and Supplements.
©2000 HealthHelper

Epi-Inositol and Inositol Depletion: Two New Treatment Approaches in Affective Disorder
by
Bersudsky Y, Einat H, Stahl Z, Belmaker RH
Beer-Sheba Mental Health Center,
PO Box 4600, Beer-Sheba, Israel.
Curr Psychiatry Rep 1999 Dec;1(2):141-147

ABSTRACT
Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myo-inositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol.

THE RESPONSIBLE PARENT'S GUIDE
TO HEALTHY MOOD-BOOSTERS
FOR ALL THE FAMILY


INTRODUCTION
Could we live happily ever after? Perhaps. One's interest in the genetically pre-programmed states of sublimity sketched in The Hedonistic Imperative is tempered by the knowledge that one is unlikely to be around to enjoy them. It's all very well being told our descendants will experience every moment of their lives as a magical epiphany. For emotional primitives and our loved ones at present, most of life's moments bring nothing of the sort. In centuries to come, our baseline of emotional well-being may indeed surpass anything today's legacy wetware can even contemplate. Right now, however, a future Post-Darwinian Era of paradise-engineering can seem an awfully long way off. Mainstream society today has a desperately underdeveloped conception of mental health.
There's clearly a strong causal link between the raw biological capacity to experience happiness and the extent to which one's life is felt to be worthwhile. High-minded philosophy treatises should complicate but not confuse the primacy of the pleasure-pain axis. So one very practical method of life-enrichment consists in chemically engineering happier brains for all in the here-and-now. Yet how can this best be done?
Any strategy which doesn't subvert our inbuilt hedonic treadmill of inhibitory feedback mechanisms in the CNS will fail. Political and socio-economic reforms offer at best a lame stopgap. To the scientific naturalist, all routes to happiness must ultimately be biological: "culture" must be neurochemically encoded to exert its effects. Some of these routes to happiness involve the traditional environmental detours. They are too technical, diverse and futile to tackle here. If the quality of our lives is to be significantly enhanced in the long term, then the genetically predisposed set-point of our emotional thermostats needs to be recalibrated. The malaise-ridden norm typically adaptive in humanity's ancestral environment must be scrapped. So while we wait for germ-line gene-therapy to become standard, it's worth considering instead how ordinary early twenty-first century Homo sapiens can sustainably maximise emotional well-being with only present-day pharmacology to rely on. No less importantly, how is it possible to combine staying continuously high with retaining one's sense of social and ethical responsibility to other people and life-forms?
Extracting reliable information on this topic is extraordinarily difficult for laity and professionals alike. The layman is more likely to be given heavily slanted propaganda. Unvarnished fact might supposedly confuse his uneducated and functionally diminutive brain. Career-scientists, on the other hand, are bedevilled by a different problem. Access to funds, laboratories, raw materials, journal publication, professional preferment, and licenses to conduct experimental trials is all dependent on researchers delivering results their paymasters want to hear. The disincentives to intellectual integrity could scarcely be greater; and they are cloaked in such reputable disguise.
By way of illustration, it's worth contemplating one far-fetched scenario. How might an everlasting-happiness drug - a drug which (implausibly!) left someone who tried it once living happily-ever-after - find itself described in the literature?
"Substance x induces severe, irreversible structural damage to neurotransmitter subsystem y. Its sequelae include mood-congruent cognitive delusions, treatment-resistant euphoria, and toxic affective psychosis."
Eeek! Needless to say, no responsible adult would mess around with a potent neurotoxin under this description.
Several excellent researchers play the game by the rules. They keep their heterodox opinions to themselves. Others find such cognitive dissonance too unpleasant. So they gradually internalise the puritanical role and tendency to warped scientific prose expected of them. [Whereas horribly-tortured experimental animals, for instance, blandly get "used" and "sacrificed", certain drugs always get "abused" by "drug-abusers"] On the other hand, some of the most original and productive minds in the field of psychopharmacology - pre-eminently Alexander Shulgin - have already been silenced. Many more careers have been intellectually strangled at birth or consigned to professional oblivion. The danger of poisoning the wells of information, for whatever motives, is straightforward. When young people discover they have been lied to or deceived, over cannabis for instance, they will pardonably assume that they have been lied to or deceived over the dangers of other illegals too. And this, to put it mildly, would be exceedingly rash.
Most recently, the Internet daily delivers up an uncontrollable flood-tide of fresh ideas to counter official misinformation. Unfortunately, a lot of it isn't much more objective in content or style than the professional journals it complements. Devising one's own system of filtering and quality-control to drown out the noise is a challenging task for anybody.
SOME DEAD ENDS
One spectacularly incompetent route to a lifetime of happiness involves taking unsustainable psychostimulants such as cocaine or the amphetamines. In the short term, their activation of the sympathetic nervous system tends to elevate mood, motivation and energy. Users tend to talk a lot. Self-confidence is enhanced: these are "power drugs". Physical strength and mental acuity are variably increased. Whereas cocaine blocks the neuronal re-uptake of the catecholamine neurotransmitters noradrenaline and dopamine, amphetamine triggers to a much greater extent their synaptic release. It feels coarser, lasts longer and costs less.
In either case, libertarian indignation that the State presumes to subject its citizens to totalitarian-style mind-control should not obscure the fact that for most purposes these are not useful drugs. This is because the central nervous system supports a web of mutually inhibitory feedback-mechanisms. In response to a short-term increase of mood-mediating monoamines in the synapses, the genes and neuronal receptors re-regulate. So at best no real long-term benefit is derived from the use of such compounds. Neither cocaine nor amphetamine yield the sustained activation of intracellular signal-transduction cascades needed to cheat the hedonic treadmill.
Some people continue to take psychostimulants casually for years without serious harm. Yet the potential risks of adverse physical, psychological and social ill-effects are high. Hence their use is best discouraged.
The "depressant" opioids are somewhat more benign. They are effective painkillers. They can also be extremely pleasurable. In classical antiquity, Aristotle - admittedly not always the soundest authority on medical matters - classified pain as an emotion. Opium was a traditional remedy for melancholic depression; its efficacy is arguably superior to Prozac, though controlled clinical trials are lacking. In "animal models", opioids reverse the depressed behavior, learned helplessness and neuroendocrine responses associated with clinical depression. By contrast, opioid antagonists such as naloxone exacerbate them. To confuse matters further, sufferers of depression typically share an increased sensitivity to pain; and modern so-called "antidepressants" can themselves act as "physical" painkillers. Conversely, mu-opioid receptor agonists offer both unsurpassed pain-relief and extraordinary emotional well-being. There is clearly an intimate link between "physical" and "emotional" pain. In defiance of dualist metaphysics, the opioids tend to be best at banishing both.
Contemporary medical orthodoxy classifies drug-induced bliss as an "adverse side-effect" of analgesics - even in the terminally ill. Yet we could all do with having our native endorphin systems enriched. Next century and beyond, the customised site-selective successors to today's opioid drugs will play a critical role in promoting emotional superhealth.
Unfortunately, present-day opioids are flawed. Taken at fixed dosage, they lose some their euphoriant and analgesic effect as tolerance sets in; opioid drugs are physiologically addictive. Overdoses can cause respiratory depression; physical pain, by contrast, is a potent respiratory stimulant. When taken recreationally, opioids inspire a dreamily contented disengagement from the problems of the world. Their use diminishes the drive to constructive activity as consumers in today's competitive global marketplace. More insidiously, excess consumption of narcotics inhibits the release of endogenous opioids normally induced by social interaction with friends and family. By diminishing the craving for human companionship, the addict substitutes one form of opioid addiction for another. Thus junkies are usually "selfish".
The physical risks of opioid use shouldn't be exaggerated. Most of the problems that users suffer ultimately derive less from their choice of drug itself than from the illegal status of narcotics in prohibitionist society. Yet even if they were legal and given away in cereal packets, opioids wouldn't make a good choice of mood-booster - or at least not in their present, crudely non-specific guise. Kappa-agonists, for instance, impair dopamine function. They have dysphoric and psychotomimetic effects: one might as well drink ethyl alcohol spiced with meths. The paradise-engineers of posterity will surely weed out such adulterants from their elixirs altogether.
By contrast to today's opioids, marijuana isn't usually addictive in the traditional sense of the term. It can still be habit-forming. Marijuana has euphoriant, psychedelic and sedative properties. Experiments with stoned rats suggest the drug reduces the amount of corticotrophin-releasing factor (CRF) in the amygdala. Excess secretion of CRF is associated with abnormalities in the HPLA axis and depression. The rebound surge of CRF on ceasing cannabis-use is associated with increased vulnerability to stress and a withdrawal-reaction, arguably one good reason not to stop in the first instance. A dysfunctional response to stress, linked to a chronically overactive HPLA axis, causes anxiety disorders and depression; CRH-type 1 receptor antagonists like antalarmin are being investigated as potential anxiolytics and antidepressants. The deeper roots of our malaise lie in the evolutionary past.
The primary psychoactive ingredient in marijuana is THC, tetrahydrocannabinol. Smoking or eating marijuana and its complex cocktail of compounds may rarely trigger episodes of depersonalisation, derealisation and psychosis. Sometimes it can induce paranoia, particularly in advocates of The War Against Drugs. More commonly, marijuana just leaves the user pleasantly and harmlessly stoned. It's fun. Sleepiness, pain relief and euphoria are typical responses. Indeed the first brain-derived substance found to bind to our cannabis receptors was christened "anandamide", a derivative of the Sanskrit word for internal contentment. Getting high may thus serve as an innocent recreational pastime in an uncaring world.
Yet marijuana is not a wonderdrug. Cognitive function in the user is often impaired, albeit moderately and reversibly. Marijuana interferes with memory-formation by disrupting long-term potentiation in the hippocampus. One of the functions of endogenous cannabinoids in the brain is to promote selective short-term amnesia. Forgetting is not, as one might have supposed, a purely passive process. Either way, choosing deliberately to ingest an amnestic agent for long periods is scarcely an ideal life-strategy. It's especially flawed given the centrality of memory to human self-identity. Some artists and professional bohemians, it is true, apparently do find smoking grass an adjunct to creative thought. For persons of a more philistine temperament, on the other hand, it's hard to see such a drug as a major tool for life-affirmation or the self-development of the species. This does not, one ought scarcely need to add, suggest users should be persecuted and criminalised.
The disparate drugs we label “psychedelics” - lysergamides like LSD-25, tryptamines like DMT and psilocybin, and phenethylamines such as mescaline - are sometimes exhilarating. At best, they are life-transforming and soul-enriching. They are certainly mind-wrenching. Taking major psychedelics can generate experiences too outlandish for our conceptual framework to accommodate. We haven't even names for the strange new modes of perception, selfhood and introspection their biochemical pathways disclose.
Unfortunately, one can’t look after the kids, fill in one’s tax forms or carry out one’s social responsibilities while tripping on LSD. Psychedelics are typically too bizarre, exotic and ineffable to integrate into the rest of one’s life. By trapping most of us in "ordinary" waking consciousness, selfish DNA stumbled on a cunning trick to help its vehicles leave more copies of itself. Worse, the psychedelics aren't primarily euphoriants. They don’t directly stimulate the pleasure-centres and guarantee the user a good trip. Both the serotonin- and catecholamine-like families trigger psychedelia mainly via their role as partial agonists of the 5-HT2 receptors in the central nervous system; 5-HT2 heteroreceptors exert a tonic inhibitory effect on the striatal dopaminergic neurons. Such agents aren’t a dependable choice of clinical or recreational mood-brightener, whether in the short- or long-term. Depressives, neurotics and other troubled souls in search of enlightenment are most likely to undergo nightmarish freak-outs. Psychotic derealisation isn't illuminating - or fun. The drug-naive mind can’t make an informed choice of whether to explore radically altered states. For aspiring psychonauts can’t know, in advance, the true nature of what they may be choosing - or missing.
Ultimately, when our well-being is genetically hardwired and invincible, psychedelia can be safely explored. The study of consciousness can become an experimental discipline. The synthesis of tomorrow’s designer-psychedelics may unleash a revolution without precedent. Until then, psychedelic drugs are too unpredictable - and our dark, darwinian minds are too poisoned - responsibly to promote their use.
Apparently by contrast, the empathogen "hug-drug" ecstasy (methylenedioxymethamphetamine; MDMA) offers a wonderfully warm, sensuous, loving, and empathetic peak experience to the first-time user - "a brief fleeting moment of sanity" [Dr Claudio Naranjo]. MDMA enhances the release of serotonin and dopamine from the presynaptic vesicles. In consequence, distrust, suspicion and jealousy evaporate. They are replaced by a serene sense of universal love. The sensorium remains clear. Emotion is intensified. Much recreational drug-use tends to be self-centred. It is often branded as selfish. Yet here is a "penicillin of the soul" which promises to subvert our DNA-driven tendency to self-aggrandisement.
Disappointingly, whether due to enzyme-induction or other causes not fully understood, most users never fully recapture the magic of their first few trips. Moreover ecstasy is neurotoxic to serotonergic axons. It may even be harmful at sub-therapeutic doses. As the uncertain process of neural recovery sets in, heavy users in particular may experience the subtle long-drawn-out reversal of all the good effects they initially enjoyed from the drug. Taking a post-trip selective serotonin re-uptake inhibitor (SSRI) such as fluoxetine (Prozac) 2-6 hours afterward is prophylactic against the measurable post-E serotonin dip otherwise experienced some 48 hours later. Yet taking SSRIs on a regular basis largely nullifies the already attenuated benefits of prolonged ecstasy use. In any case, the duration of the peak experience is a mere 90 minutes. So taking ecstasy scarcely amounts to a full-scale strategy for life either. It does, on the other hand, deliver an exquisite foretaste of the beautiful forms of consciousness that ultimately await us.
Another tantalising and deliciously sensuous hint of the sublime is offered - infrequently and unpredictably - by gamma-hydroxybutyrate (GHB). GHB usually takes the form of a clear, odourless, slightly salty-tasting liquid. It's also an endogenous precursor and metabolite of the inhibitory neurotransmitter GABA. GHB is non-toxic; but it mustn't be mixed with alcohol or other depressants. It's metabolised quickly to carbon dioxide and water. GHB's steep dose-response curve means naive users run the severe risk of falling asleep. When used lightly in recreational rather than stuporific or anaesthetic doses, GHB is a touchy-feely compound which typically induces deep muscular relaxation, a sense of serenity, and feelings of emotional warmth. Often it enhances emotional openness and the desire to socialise. Tactile sensitivity and the appreciation of music are enriched. Most remarkably, the moderate user may awake refreshed after a deep restful sleep: GHB appears temporarily to inhibit dopamine-release while increasing storage, leading to the brightened mood and sharpened mental focus of a subsequent "dopamine-rebound". GHB acts both as a disinhibitor and an aphrodisiac. The intensity of orgasm is heightened. Hence GHB is potentially useful in relieving the psychopathologies of prudery and sexual repression. Unfortunately, its therapeutic value has been eclipsed by its demonization in the mass-media. Stories of chaste virgins turning into sex-crazed nymphomaniacs make great copy and poor medicine. Moreover GHB is sometimes confused with the amnestic "date-rape" benzodiazepine, flunitrazepam - better-known as the potent and fast-acting sedative-hypnotic "forget pill", Rohypnol. Bought on the street, GHB may be confused with all sorts of other substances too.
Yet even pure GHB is no magic elixir. Not everyone likes it. GHB's psychological effects are unpredictable and poorly understood. Nausea, dizziness, inco-ordination are common; reaction-time is slowed. GHB does not usually promote great depth of thought. Its very status as "an almost ideal sleep inducing-substance" makes it of limited use to those who aspire instead to be more intensely awake. The lack of any discernible body-count to fuel the periodic moral panics its use induces may allow a partial rehabilitation. Yet GHB evokes - at best - only a faint, fleeting parody of the life-long chemical nirvana on offer to our transhuman successors.
Alcohol - the traditional date-rape drug of choice - and, most insidiously of all, cigarettes are the really sinister mass-killers. Their total human death-toll so far is around 100 million and climbing. With that poker-faced Alice-In-Wonderland logic popular amongst the world's sleazier governments, not merely do the authorities preserve the legal status of cigarette sales here in the UK on grounds of upholding personal liberty. The slickly expensive marketing and glamorisation of tobacco products to potential victims is sanctioned on similar grounds too. We ought to be as shocked at tobacco promotion as we'd certainly feel if instead the billboards urged kids to try heroin because it's cool. Yet familiarity breeds moral apathy. Youngsters are typically hooked before they are in any position to make an informed choice of their preferred poison - or even to abstain altogether. Meanwhile a state-supported export drive targets the poor in vulnerable Third World countries. With a cynicism that almost beggars belief, one celebrated British ex-Prime Minister accepted a million-dollar bribe from a leading member of the drug-cartels for her services. Her party's ineffable Home Secretary then delivered himself of blood-curdling calls for a crack-down on evil drug-pushers(!). He went on to increase the draconian penalties already available for personal users of cannabis.
So long as our governments collude with the organised drug cartels to share out the billions of dollars of tax revenues mulcted from nicotine-addicts - thereby keeping direct taxes visibly down and themselves visibly in office - there seems little hope of a more intelligent approach to psychoactive drugs as a whole.
DIRTY MOOD BRIGHTENERS
The commonly recognised legal and illegal recreational drugs offer poor prospects for sustained biological mood-enhancement. So what about the heterogeneous group of compounds uninvitingly labelled as anxiolytics and antidepressants? Have they potentially anything significant to add to most people's quality of life? Official medical doctrine says no. Allegedly, only sufferers from clinically-sanctioned psychiatric disorders will benefit from such agents; though in recent years it has at last been formally recognised that depressive disorders are under-diagnosed and under-treated even by the twentieth century's abjectly poor standards of acceptable ill-being. Most of humanity, however, still doesn't fit any of the official diagnostic boxes. So can "diagnostic creep" triumph over therapeutic minimalism and enhance their quality of life? Yes. Must the goal of pharmacotherapy be as limited as Freud's aspiration for psychotherapy: "to transform hysterical misery into common unhappiness"? No.
First, the boring but crucial preliminaries. Optimal nutrition and exercise will increase the efficacy of all the potential life-enhancers touted here. A rich supply of precursor chemicals (e.g. tryptophan, the rate-limiting step in the production of serotonin) can also reduce their effective dosages. By choosing to eat an idealised "stone-age" diet rich in organic nuts, seeds, fruit and vegetables, and drastically reducing one's consumption of saturated fat (red meat, fried foods), sugar (sweets etc) and hydrogenated oils (found in margarine and refined vegetable oils), then one's baseline of well-being - or at least relative ill-being - can be sustainably lifted. Visitors to HedWeb probably don't expect to be assailed by sermons on the benefits of exercise any more than food-faddism. Yet regular and moderately vigorous physical exertion releases endogenous opioids, enhances serotonin function, stimulates nerve growth factors, and leads to a livelier, better-oxygenated brain.
Alas, clean living and wholesome thoughts typically aren't enough. We need stronger medicine to flourish. At first glance, however, the standard, State-rationed chemicals aren't a brilliant bunch.
The so-called minor tranquillisers, the benzodiazepines such as diazepam (Valium) and the shorter-acting temazepam (Restoril), are sometimes useful but still dreadfully crude anti-anxiety agents. They act primarily on the GABA (gamma aminobutyric acid) receptor complex. GABA functions as the main inhibitory neurotransmitter in the central nervous system. The progress of molecular biology and neurogenetics in unravelling the fiendish complexity of GABA's receptor sub-types should eventually allow more targeted compounds to be developed. These more selective and site-specific drugs will lack the sedative and hypnotic properties of today's marketed brands. In the meantime, benzodiazepines in current use tend to induce dependence, dull consciousness and impair the intellect. So there's not much chance of radical life-enrichment here.
Buspirone (Buspar), is somewhat more promising. It acts to desensitise the inhibitory autoreceptor 5-HT1A subtype of serotonin receptor. It thereby promotes serotonin release. This means buspirone has mood-brightening properties too. Thus it is useful in anxious depressive states. Buspirone lacks the intellect-clouding effects of other clinical and alcoholic anti-anxiety agents. Yet its weak and equivocal effects on sub-types of dopamine function, while useful for the purposes of commercially touting its lack of "abuse-potential", mean it isn't very exciting or popular. Researchers hope that newer 5-HT1A agonists in the pipeline will be more effective.
The so-called antidepressants fall into several categories. Their delayed-onset mood-brightening effect is correlated with alterations in the concentration of catecholamines and/or serotonin in the central nervous system, long-term receptor re-regulation, and new nerve-cell growth in the hippocampus.
The tricyclics, prototypically imipramine (Tofranil), and their allies are relatives of the neuroleptic drug chlorpromazine. Chlorpromazine is also known as Largactil, the notorious "chemical cosh". Tricyclics block to varying degrees the reuptake of serotonin and noradrenaline into the nerve cell terminals from where they are released. The consequent changes in pre- and post-synaptic receptor sensitivity lighten the spirits of 60-70% of the depressives who take them. Perhaps unsurprisingly given their parentage, the tricyclics are all dirty drugs, though some are dirtier than others. Their anti-cholinergic effects harm memory, concentration and intellectual performance. Their anti-histamine action induces drowsiness and sedation. Their adverse effect on cardiac function makes them dangerous in overdose. Most "euthymic" volunteers on whom they have been tested don't like their dulling effects of consciousness. Unlike chlorpromazine, the tricyclic antidepressants don't noticeably block the dopamine receptors. But with one notable exception, they do precious little to stimulate dopamine function either. Hence they're not much fun even for the severely depressed people who can benefit from taking them. For three decades they were the mainstay of the treatment of clinically-acknowledged depression. They contributed to the widely-held medical opinion that anything classed as an antidepressant won't help "normal" people; unless of course they were "really" depressed. Basically, tricyclics are cheap, nasty and best avoided.
Much better, but still in some ways deeply flawed, are the selective serotonin reuptake inhibitors [SSRIs]. Serotonin, "the civilising neurotransmitter", plays a vital role in mood, memory, appetite, sleep, pain perception and sexual desire.
Fluoxetine (Prozac), fluvoxamine (Luvox, Faverin), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral), and citalopram (Cipramil, Celexa) are currently licensed and marketed. More of their tweaked and enhanced relatives are on the way from pharmaceutical companies eager for a lucrative piece of the action. The SSRIs all differ in their half-lives, chemical structure and precise specificities. Their functional effects are broadly similar, though Prozac is the most activating, longest-lasting and least selective. The mood-brightening, resilience-enhancing and anti-anxiety properties of the SSRIs really can make a (very) modest percentage of the population feel "better than well". As a class, SSRIs don't have the physically unpleasant and cognitively debilitating anti-cholinergic effects of the tricyclics. SSRIs don't demand the dietary restrictions of the MAOIs. Their dependence potential and withdrawal reaction is milder than the opioids. A much larger section of the community - folk who daily knock back huge quantities of ethyl alcohol in the socially accepted fashion - could surely gain from the durably enhanced serotonin function that SSRIs can yield. Such a switch would necessitate a big change in marketing strategy.
The beneficent properties of the SSRIs are celebrated in Peter Kramer's contemporary classic Listening to Prozac. Kramer has written a remarkably honest book. It's a discursive memoir by a therapist who is forced to admit that many of his clients seemed rapidly to fare far better on a pill than on his industrial-strength regimen of caring talk-therapy. Kramer's discussion of "cosmetic psychopharmacology" and "designer personalities", however, enraged traditionalists. For chemical Calvinist orthodoxy finds the notion that people should have a right to choose pharmacologically who and what they want to be profoundly offensive.
Two common problems limit the usefulness of SSRIs, at least when taken on their own. The problems stem from the indirect inhibitory effect of Prozac-style drugs on dopamine function, a consequence of deliberate selective targeting of the serotonin system.
 First, SSRIs can compromise libido and sexual performance. This isn't always a disadvantage in over-excitable young males. It can still be a very distressing phenomenon for people too embarrassed to talk about it. Technical performance difficulties can sometimes be counteracted by taking the blood vessel dilators apomorphine or phentolamine; the alpha2-adrenergic antagonist yohimbine; the phosphodiesterase inhibitor sildenafil (better known as the sexual rocket-fuel Viagra); or a dopamine agonist, licit or otherwise, before bedtime action. Yet this is scarcely an ideal solution.
 Second, though some subjects may feel mildly euphoric, in other users the SSRIs serve more as mood-stabilisers and -flatteners in their lives. By increasing the user's emotional self-sufficiency, too, SSRIs may subtly change the "balance of power" in personal relationships - for good or ill. In some cases, SSRIs may even act as thymoanaesthetisers which diminish the intensity of felt emotion; by contrast, a mood-brightening serotonin reuptake-enhancer like tianeptine may intensify emotion instead. Affective flattening may be welcome to someone in the pit of unmitigated clinical depression. It is scarcely a life-enriching property for "normal" people who lack any convenient diagnostic category which acknowledges their malaise.

THE DOPAMINE CONNECTION
What's missing, crucially, is vigorous and prolonged stimulation of meso(cortico-)limbic dopamine function.
This is really much more fun than it sounds. The currently available experimental evidence has persuaded many - but not all - researchers that the mesolimbic dopamine system serves as the final common pathway for pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine D2/D3 receptors is crucial to long-term emotional well-being. All "serotonergic" and "noradrenergic" mood-brighteners eventually act on the mesolimbic dopamine pathway, albeit in differing degrees and with varying delay. And new anti-Parkinsonian and anti-Alzheimer's agents, notably roxindole and pramipexole, owe their potential role as fast-acting antidepressants to their dopaminergic action.
The full story is inevitably complex. Dopamine agonists and reuptake inhibitors are often inadequate mood-brighteners by themselves. Dopamine isn't itself the magic pleasure-chemical, though its functional role is crucial. Researchers into affective disorders readily get over-attached to a particular neurotransmitter, its receptor sub-types and their signal-transduction cascades. Traditionally, serotonin and noradrenaline have attracted the fiercest rival partisans. "Dopaminergic" (and opioid) agents, by contrast, are suspect. They are politically incorrect since they are potentially "abusable". Moreover safe and sustainable empathogens and socialbilizers are arguably as morally urgent as safe and sustainable mood-boosters. At any rate, mesolimbic activation, exclusively or otherwise, enhances the intensity of experience; increases pleasure and libido, and boosts cognitive performance. Even better, certain dopamine-enhancing drugs may have neuro-protective properties as well.
So what are the other contemporary options for chemical life-enhancement?
METHYLPHENIDATE; MINAPRINE; NOMIFENSINE
A SSRI can be combined ("augmented" sounds more soothing to the official medical ear) with a dopaminergic such as methylphenidate. As Ritalin, methylphenidate is prolifically dispensed to American schoolchildren for different purposes altogether. In spite of its structural relationship to amphetamine, methylphenidate resembles in many ways a benign version of cocaine, yet with a much longer half-life. It blocks the reuptake, but doesn't significantly release, the catecholamines noradrenaline and dopamine. If it is taken in sustained-release form or combined with an SSRI, all of which have anti-obsessive-compulsive properties too, then the likelihood of dose-escalation is minimised.
Chewing coca leaves with a dash of powdered lime is a nutritious and energising way to sustain healthy mood. Unfortunately, it is not very good for one's teeth.
A more cautious but still interesting option might be minaprine (Cantor). Minaprine blocks the reuptake of both dopamine and serotonin. It is also in some degree cholinomimetic. Thus it may exhibit both mood-brightening and nootropic properties. Much more research is needed.
Merital (nomifensine) showed great promise as a pleasantly stimulating dopaminergic that also potently inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It was marketed by its manufacturers Hoechst with the slogan "vive la difference!" Merital was withdrawn from licensed use after the discovery of its rare side-effect of precipitating a serious blood-disorder. For retarded melancholics, however, it was typically a very effective and well-tolerated mood-brightener with minimal side-effects. The risk/reward ratio of its carefully-monitored use may have been misjudged.
BUPROPION; AMINEPTINE
Bupropion (Wellbutrin) is possibly less effective than nomifensine. Yet it's useful because it lacks the adverse effects on sexual function characteristic of the SSRIs. In some subjects - particularly women - libido, arousal, and the intensity and duration of orgasm may actually increase. Bupropion mildly blocks the reuptake, but diminishes the release, of dopamine. This may account for reports of its diminished propensity to induce mania in the genetically susceptible. Its active metabolites block the reuptake of noradrenaline. Marketed as Zyban, bupropion is good for giving up smoking. Scandalously, bupropion isn't licensed and marketed as an antidepressant in Europe - though doctors may prescribe Zyban to non-smoking depressives "off-label".

Amineptine (Survector) is a clean-ish, (relatively) selective dopamine reuptake blocker. Higher doses promote dopamine release too. Amineptine is liable occasionally to cause spontaneous orgasms. It is a mild but pleasant psychostimulant and a fast-acting mood-brightener. Unlike other tricyclics, it doesn't impair libido or cognitive function. Unlike typical stimulants and other activating agents, it may actually improve sleep architecture. Scandalously, amineptine isn't licensed and marketed in Britain and America. For it is feared it might have "abuse-potential". FDA pressure recently led to its withdrawal in Europe too. This drove it onto the pharmaceutical grey market, discomfiting doctors and patients alike.
REBOXETINE; ADRAFINIL; MODAFINIL
Reboxetine (Edronax) is a well-tolerated, highly selective "noradrenergic" agent. Crudely, whereas serotonin plays a vital role in mood, noradrenaline is essential to maintaining drive, vigilance and the capacity for reward. There's a fair bit of evidence that chronically depressive people have dysfunctional and atypical noradrenergic systems - particularly their alpha2- and beta-adrenoceptors. Reboxetine itself typically doesn't have the disruptive effects on cognitive function or psychomotor performance common to older clinical mood-brighteners - though alas antimuscarinic effects are still not completely absent. Indeed the new NorAdrenaline Reuptake Inhibitors (NARIs) are possibly under-used and under-hyped. NARIs - and dopaminergics like amineptine (Survector) - may be especially good for drive-deficient "anergic" states where the capacity for sustained motivation is lacking; and for melancholic depressives with a poor ability to cope with stress. Reboxetine may be safely combined with an SSRI. More surprisingly, preliminary studies suggest reboxetine can actually reverse tranylcypromine-induced hypertensive crises. The "cheese effect" is triggered by ingesting tyramine-rich foods. Thus NARIs plus MAOIs may prove a potent form of combination-therapy.
Depressive hypersomniacs who fare poorly on SSRIs, or can't get hold of amineptine or EC-licensed reboxetine, might consider trying a so-called eugeroic ("good arousal") agent instead. Alpha1-adrenergic agonists like adrafinil (Olmifon) and modafinil (Provigil) are centrally-acting psychostimulants that can brighten mood and sharpen mental focus. They stimulate the noradrenergic post-synaptic receptors, increase glutamatergic transmission, and activate the wakefulness-promoting orexinergic neurons, thereby boosting alertness, memory and energy. At sensible dosages, they are remarkably free of side-effects. However, the approval process in the USA is so slow, costly and bureaucratic, and the marketing hurdles typically so formidable, that foreign companies are often deterred from seeking FDA acceptance. [modafinil was licensed by the FDA as Provigil for the treatment of narcolepsy in Dec 1998] So elderly people continue to suffer the prescription of mildly dementing anticholinergics like the dumb-drug tricylcic imipramine. Adrafinil, by contrast, is at least as successful as hepatotoxic Anglo-Saxon products at treating the cognitive and memory impairments of incipient senility. Fortunately, a "French" drug like adrafinil can now be ordered over the Net; but it ought to be available at the local corner-store. It has the commercial disadvantage of being cheap.
MIRTAZAPINE; NEFAZODONE; VENLAFAXINE; ROLIPRAM
NARIs are normally activating. Anxious and depressive insomniacs, on the other hand, may benefit more from "dual-action" mirtazapine or nefazodone.
Mirtazapine (Remeron) is a structural analogue of the off-patent mianserin (Bolvidon). It is a comparatively new drug - a so-called NaSSA. By blocking the inhibitory presynaptic alpha2 adrenergic autoreceptors and stimulating only the 5-HT1A receptors, mirtazapine enhances noradrenaline and serotonin release while also blocking two specific (5-HT2 and 5-HT3) serotonin receptors implicated in dark moods and anxiety. By contrast, stimulation of the 5-HT2A receptors accounts for the initial anxiety, insomnia and sexual dysfunction sometimes reported with the SSRIs; stimulation of the 5-HT3 receptors causes nausea. Unfortunately, mirtazapine is a potent blocker of the histamine H1 receptors too. So it tends to have a somewhat sedative effect. This profile may be good for agitated depressives and insomniacs. Again, it is scarcely a recipe for life-affirmation.
Nefazodone (Serzone) is another newish, "dual action", mainly serotonergic agent. It inhibits the reuptake of serotonin while displaying post-synaptic 5-HT2A-receptor antagonism. This may be useful for anxious depressives; but again, it may cause feelings of weakness, drowsiness and lack of energy. Nefazodone is less likely to cause priapism than its older cousin trazodone (Desyrel). It is less likely to cause sexual dysfunction than the SSRIs.
Venlafaxine (Effexor) is a phenethylamine. Thus it's a benign if distant chemical cousin of MDMA. Its manufacturers launched it as "Prozac with a punch". Venlafaxine inhibits the neuronal reuptake of serotonin, noradrenaline and dopamine in descending order of potency. If dopaminergically augmented, it offers another opening for creative psychopharmacology. Such augmenation-therapy remains (almost) clinically unexplored. Taken on its own at low dosage, venlafaxine acts primarily as a serotonin re-uptake inhibitor. At the high-level dosages most suitable for melancholic and hypersomnic temperaments, its noradrenergic (and weakly dopaminergic) action becomes more pronounced. Like the SSRIs, it is useful for a broad spectrum of disorders beyond clinical depression.
Phosphodiesterase-inhibitors, both selective (e.g. rolipram) and unselective, are another under-used option. Next century will take us much closer to the real intra-cellular action. For it is here that our minds will ultimately be healed, genetically or otherwise.
HYPERICUM
Hypericum is important for a different reason altogether. Many constitutionally unhappy people refuse to have anything to do with orthodox western medicine. They won't take "unnatural" pharmaceutical products at all. In consequence, they spend much of their lives trapped in a squalid psychochemical ghetto of chronic low spirits. The only sort of remedy that they'll conceivably contemplate taking must carry a "natural" label and soothingly "herbal" description.
Unfortunately, most folk remedies are only marginally effective. The few that work - Cannabis sativa, coca and Papaver somniferum - are typically if perversely illegal. Plants tend to manufacture psychotropics because they poison or debilitate creatures tempted to eat them - not to heal our psychic woes. Thus the Wisdom Of Nature is a quaint piece of make-believe. Even so, hypericum, the active ingredient in St John's Wort, appears to be an effective mood-brightener and anxiolytic - by today's standards at least. Its side-effect profile and efficacy in mild-to-moderate depression compares favourably with its synthetic counterparts. Hypericum's blend of serotonin-reuptake inhibiting and (mild) MAO-inhibiting properties (not a combination otherwise to be explored with potent synthetics: the risk of the potentially fatal serotonin syndrome is too great) contributes to - without wholly explaining - its generally benign effects. Once again, much more research is needed, preferably not bankrolled by the makers of lucrative competing products.
INOSITOL
One further remedy, albeit at "unnatural" doses, is worth noting. Inositol levels tend to be low in depressives and high in euphoric people. Taking myo-inositol as a food supplement in doses of 12g and more per day represents perhaps the first successful use of the precursor strategy for a second messenger rather than a neurotransmitter in the search for long-term mood-brightening agents. Inositol and its derivatives serve as messenger molecules within the nervous system. The molecule itself is a naturally occurring isomer of glucose. It is a key intermediate of the phosphatidyl-inositol cycle. This is a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. Adult westerners typically consume about one gram of inositol per day in their food. The richest dietary sources are fruits, nuts, beans and grains. The mood-darkening ("stabilising") effect of lithium in manically euphoric people may be explicable in terms of its inositol-depleting effect. Potentially, if taken in high doses, inositol seems to be a good way of lightening the spirits and diminishing anxiety in "euthymic" and depressed people alike. Dosages of even 50g and more reportedly produce no toxic side-effects. This regimen shouldn't be attempted unsupervised by people with a history of bipolar disorder. As usual, much more research is in order. One "problem" is that naturally-occurring compounds - such as inositol and SAMe - can't be patented. So the scope for high profit-margins is diminished. Progress is unlikely to be brisk.


THE MAO INHIBITORS
A further option involves using both some of the oldest and the newest drugs on the block, the monoamine oxidase inhibitors (MAOIs). The older irreversible MAOIs certainly shouldn't be combined with SSRIs, and inadvisably with stimulants and many other drugs. Yet both old and new, they do have some very interesting properties.
Monoamine oxidase has two main forms, type A and type B. They are coded by separate genes. MAO may be inhibited with agents that act reversibly or irreversibly; and selectively or unselectively; these categories are not absolute. MAO type-A preferentially deaminates serotonin and noradrenaline, and also non-selectively dopamine; type B primarily metabolises dopamine, phenylethylamine (the "chocolate amphetamine") and various trace amines.
The substantial mood-elevating properties of the MAOIs were discovered quite by chance in a US veterans hospital early in the 1950's. Many patients given the anti-tuberculotic drug iproniazid were not merely cured of their tuberculosis. They became exceptionally happy as well. The animated enthusiasm for life of a previously crotchety bunch of old soldiers disconcerted their doctors. For it transpired that their new-found euphoria wasn't just an understandable reaction to being cured of physical disease. MAOIs typically have mood-brightening properties as well. At the time, there was no accepted and clinically-effective treatment for depression. Fortunately, via the usual circuitous routes, the appropriate lessons were eventually drawn. Many millions of people were successfully treated with MAOIs in consequence.
Sadly, the role of MAO in deaminating tyramine (from the Greek word tyros, meaning cheese) wasn't at first understood. Certain MAOI-treated patients suffered hypertensive crises after eating varying amounts of tyramine-rich aged cheese; and several died. It is now recognised that the use of any MAOI which is both irreversible and unselective must be accompanied by dietary restrictions. But the adverse publicity of the initial inexplicable fatalities, combined with the introduction of a succession of dirty but sometimes tolerably effective tricyclic compounds, sent the use and reputation of MAOIs into a precipitous decline from which they still haven't fully recovered.
The older non-selective and (more-or-less) irreversible inhibitors tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan) are nonetheless valuable drugs. Outside the USA, they tend to have been eclipsed by the selective and reversible moclobemide. Similar therapeutic agents are in the pipeline. Of greater interest still are central-nervous-system-selective compounds, notably one known (not indeed especially widely) as MDL-72394. MAOIs which lack the peripheral effects of currently explored drugs herald an exciting new therapeutic window of opportunity.

SELEGILINE (l-deprenyl)
A recent New York study showed that smokers had on average 40% less of the enzyme, monoamine oxidase type-B, in their brains than non-smokers. Levels returned to normal on their giving up smoking. Not merely is the extra dopamine in the synapses rewarding. The level of MAO-b inhibition smokers enjoy apparently contributes to their reduced incidence of Parkinson's and Alzheimer's disease. Unfortunately they are liable to die horribly and prematurely of other diseases first.
One option which the dopamine-craving nicotine addict might wish to explore is switching to the (relatively) selective MAO-b inhibitor selegiline, better known as l-deprenyl. Normally the brain's irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. Their death diminishes the quality and intensity of experience. It also saps what in more ontologically innocent times might have been called one's life-force. Eighty percent loss of dopamine neurons results in Parkinson's disease, often prefigured by depression. Deprenyl has an anti-oxidant , immune-system-boosting and dopamine-cell-sparing effect. Its use boosts levels of tyrosine hydroxylase, growth hormone, superoxide dismutase and the production of key interleukins. Deprenyl offers protection against DNA damage and oxidative stress by hydroxyl and peroxyl radical trapping; and against excitotoxic damage from glutamate.
Whatever the full explanation, deprenyl-driven MAOI-users, unlike cigarette smokers, are likely to be around to enjoy its distinctive benefits for a long time to come, possibly longer than their drug-naïve contemporaries. For in low doses, deprenyl enhances life-expectancy, of rats at least, by 20% and more. It enhances drive, libido and motivation; sharpens cognitive performance both subjectively and on a range of objective tests; serves as a useful adjunct in the palliative treatment of Alzheimer's and Parkinson's disease; and makes you feel good too. It is used successfully to treat canine cognitive dysfunction syndrome (CDS) in dogs. At dosages of below 10-15 mg daily, deprenyl retains its selectivity for the type-B MAO iso-enzyme. At MAO-B-selective dosages, deprenyl doesn't provoke the "cheese-effect"; tyramine is also broken down by MAO type-A. Deprenyl isn't addictive, which probably reflects its different delivery-mechanism and delayed reward compared to inhaled tobacco smoke. Whether the Government would welcome the billions of pounds of lost revenue and a swollen population of energetic non-taxpayers that a switch in people's MAOI habits might entail is unclear.

MOCLOBEMIDE
Humans now have the capacity to choose their own individual level of activity or inhibition of the two primary monoamine oxidases. This does not quite enable the fine-tuning of personality variables with the functional equivalent of a graphic equaliser. It still represents a promising start. In MAO-inhibition, as in life, more is not always better. Excessive dosages of l-deprenyl intake, for instance, may actually shorten, not increase, life expectancy - at least in Parkinsonians if it's combined with l-dopa. And levels of above 80% inhibition of MAO-A may lead to a sharp and possibly unwanted fall in dopamine synthesis. Repairing Nature's niggardliness will be a priority for the decades ahead.
Moclobemide (Manerix, Aurorix), the "gentle MAOI", is both a selective and reversible inhibitor of MAO-A. It marks the first RIMA to win clinical acceptance. It lacks anti-cholinergic side-effects. No dietary restrictions are needed. It is valuable as more than a mood-enhancer. For moclobemide is often useful in overcoming social phobia, panic disorder, obsessive-compulsive symptoms, irritability and aggression owing to the way it enhances serotonin function. (The casual use of gobbledygook such as "enhanced x function" will rightly alert the reader that many complications are being skirted or omitted. Those hungry for the greater technical detail of a non-popular account can rest assured the literature will leave them feeling abundantly well-nourished).

TRANYLCYPROMINE
Gentleness doesn't suit everyone. Moclobemide isn't much good at lifting deep melancholy. Tranylcypromine (Parnate), on the other hand, is one of the older and non-selective MAOIs - and is often none the worse for it. Structurally related to amphetamine, it's generally the most stimulating, dopaminergic and relatively fast-acting of the MAOIs. Some doctors are uncomfortable with its properties. This isn't just because of the dietary restrictions it demands. In adequate doses, it tends to induce a mild euphoria even in "normal" subjects. In fact, its nicest effects, as for all of the compounds cited here, will vary in nature and extent from person to person. To some extent, optimal dosage and long-term drug-regimen of choice can be discovered only by cautious empirical investigation.
Tranylcypromine is of course vastly preferable to the amphetamines and cocaine. Yet frequently and perversely, the more hazardous the drug, then the easier it is to get hold of in our society. The carcinogenic cocktail that carries off more people than all other toxins combined can be purchased quite legally and effortlessly at any tobacconist or newsagent. Obtaining the less lethal - but scarcely desirable - street opioids and psychostimulants requires a little more exertion. Yet they can still be readily purchased in pubs and clubs in all the big towns and cities. Most of the more beneficent drugs discussed here, on the other hand, are available on a prescription-only basis. They're not illegal to possess. But they are hard to obtain short of visiting countries where they're available over-the-counter or paying high mail-order prices for an uncertain service.
If the central principle at stake were the preservation of a drug-free society, then some sort of totalitarian (or, more euphemistically, paternalistic) argument could be cobbled together for violating personal freedom so oppressively. Yet that's rarely the issue. For in most cases, the issue effectively amounts, not to drugs or no drugs, but to allowing people the choice to opt for better ones. Perhaps 80% of the population in Western countries currently drink alcohol or smoke cigarettes. Often they do both. Whether viewed in terms of mortality, morbidity or overall quality of life, we'd be far better off if we switched to enhancing dopaminergic, serotonergic and cholinergic function by the relatively safe and often crudely effective agents touched on here; and to the much more exciting products currently in the pipeline. As a basic minimum, people shouldn't be legally robbed of the right to do so.
This freedom of choice isn't conventional wisdom. It will be suggested that the level of medical expertise required to make informed choices exceeds that of the average layperson; and a quasi-priestly caste wielding the power of the prescription-pad would doubtless wish to keep it that way. But the intrinsic difficulty and complexity of psychopharmacology or nutritional medicine, say, doesn't demand greater mental effort than, for instance, all those thousands of grimly unnatural hours spent by school students learning mathematics. Moreover it's far more interesting to study something palpably relevant to one's emotional well-being than something that demonstrably isn't. The notion of an education system geared to schooling people in, and for, happiness would nonetheless strike adherents of the reigning educational orthodoxy as abhorrent were it not so largely incomprehensible.
WORKING FOR A DRUG-FREE FUTURE
Suppose, for a moment, that the reproductive success of our DNA had been best served by coding for ecstatically happy vehicles rather than malaise-haunted emotional slum-dwellers. If this had been the case, then none of the pharmacological interventions discussed in The Good Drug Guide would be necessary. Life-long well-being would seem only "natural". We would all enjoy gloriously fulfilled lives. Each day would be animated by gradients of bliss. Unpleasant states of mind would be viewed as a tragic aberration. They'd be diagnosed as a freakish but clinically treatable type of psychopathology.
Of course, it didn't work out that way. Instead, the inclusive fitness of our genes has been promoted by the "natural" manufacture of some of the most vicious psychological adaptations imaginable.
The rot goes deeper. Selfish DNA can count on innumerable dupes to act as its distal representatives even today. The need for "character-building" emotional pain gets justified with all manner of sophistries, both religious and profane. Suffering is good for you, one may be told. It's all part of life's rich tapestry.
It exists because it was good for our genes. Apologists for mental pain are serving as the innocent mouthpieces of the nasty bits of code which spawned them. If pressed, DNA's unwitting spokesmen would presumably disavow the connection. Yet if one were purposely building an intelligent robotic survival-machine, then endowing it with the illusion of free-will would prove a highly fitness-enhancing adaptation. It's a trick which our genes merely stumbled upon; and then blindly exploited.
Fortunately, within the next few centuries humanity will be able to outwit its ancient genetic masters. Our present status as throwaway genetic vehicles will finally be subverted. When heavenly well-being becomes the genetically predestined norm of mental health, then the very notion of tampering with our new-won "natural" condition and feeling "drugged" will come to seem immoral. It will also seem perverse. Why should anyone want to contaminate the divine ecstasy of their spirituo-biological soul-stuff with chemical pollutants? No thanks.
Today's twisted victims of the primordial genetic code, on the other hand, view the notion of sullying their natural state of being through drugs with a much more deep-seated ambivalence. They adopt it as a near-universal practice. Given the inadequacy of the third-rate stopgaps on offer, and the lack of serious drug-education, it's scarcely surprising we're so poor at using them. Thus concerned parents are surely right to worry about the trashy street drugs taken by their kids. Yet with the right new genes and designer-drugs, there's no reason why mature Post-Darwinian life shouldn't just get better and better.

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Inositol
Psychoactive
Description: Adopted member of B-Vitamin (B-3 Niacinamide) family and ubiquitous component of living cells. It’s chemical structure is C6/H12/06. Myo-Inositol (the form is use for psychological disorders) is an ubiquitous carbohydrate present in large amount in brain tissue and a naturally occurring isomer of glucose. It is involved in neuronal signaling and osmoregulation.
Method of Action: Most conventional psychotropics in use today act at receptors on the cell membrane. Inositol, which acts at the second-messenger intracellular level, is a truly novel psychotropic agent. Chronic inositol administration has been found to induce a significant increase in striatal dopamine2 receptor density (Bmax), but not affinity, with a slight increase in 5HT2 receptor density, but not affinity. The changes observed in striatal D1-D2 balance will result in marked changes in activity in the cortical-striatal-thalamic circuit - and in the modultation of thalamic activation of the cortex and striatum. Inositol’s effect on mGlu-1 receptors may modulate dopaminergic function indirectly and resent with biochemical and behavioral consequences of DA hyperactivity. (It is possible that Inositol and Serotonin Reuptake Inhibitors (SSRIs) converge to a common final, perhaps genetic, destination. It is also possible that Inositol actives a cascade of events (as do other antidepressants), but at a later point or a different cascade that eventually interacts of converges with the events related to other antidepressant drugs.) Inositol is a key intermediate of the phosphatidyl-inositol (PI) cycle - a second messenger system used by several noradrenergic alpha, several types of serotonergic and cholinergic nerve receptors and is a rate-limiting step in the synthesis of PI - considered a saturated system. No changes in mono-aminergic systems follow acute or chronic Inositol administration. Inositol is responsible for the production of second messengers Inositol triphospahte3 (IP3) and DAG and regulation of phospholipase C. Inositol functions as cell growth factor by stimulating fat used to construct myelinated nerve materials. In animal models, chronic dietary inositol significantly elevates cellular Inositol levels in the cortex (36%) and hippocampus (27%) but not in the striatum or cerebellum. Regional differences in inositol uptake by the brain may shed light on the mechanism of action of lithium in different brain regions. Cerebellar granule cells in culture, which do not accumulate high levels of inositol, are also less susceptible to inositol-induced reversal of the biochemical effects of lithium. (Introcerebroventricular replenishment of lithium-induced depletion of inositol reverses lithium’s effects on behavior.) Inositol also reverses desensitization of serotonin receptors.
Indications and Usage: Epi-inositol appears to be more potent than myo-inositol, but all studies referenced in this document relate to the use of Myo-Inositol. Animal and human studies have shown Inositol to have efficacy in treating: Mild-Moderate Anxiety; Panic Attacks; Obsessive Compulsive Disorder (OCD); Agoraphobia; Simple Phobias; Social Phobia; Sensory Nerve Problems; Post-Traumatic Stress Disorder, Mild-Moderate Depression. Inositol is significantly effective for approximately 60-70% of patients depending on condition. Inositol has been found to be ineffective in treating Bipolar Disorder, Schizophrenia, Autism, Alzheimer patients, and to worsen Attention Deficit Disorder. Benefit from Inositol appears to increase with severity of disorder. Inositol also reverses desensitization of serotonin receptors so it may have some use in combination with serotonergic medications to prevent receptor desensitization with long-term use. Inositol Nicotinate (Hexopal) has been used to abolish the increased vascular spasm found in Raynaud’s phenomenon.
Contraindications: Do not use this product if you are pregnant or lactating without first seeking advice from your physician. Diabetics may wish to consult their physician before use as Inositol is an isomer of glucose. Persons with a personal or family history bleeding problems, blood clotting disorders, high blood pressure or who ware taking a prescription, over the counter or herbal vasodilator should consult their physician before use. Persons with Alzheimer’s Disease, other memory impairing diseases, Autism, or Schizophrenia will likely find no effect with Inositol use. Persons with Attention Deficit Disorder may experience a worsening of symptoms with chronic Inositol use.
Dosage and Administration: Inositol administered orally in high enough doses crosses the blood-brain barrier. Administration of 3 grams of inositol will triple blood levels of inositol and 12 grams will increase human cerebral spinal fluid (CSF) inositol levels by as much as 70%. Range - 6 to 18 grams taken in powdered form. Begin with 4 grams per day taken in two divided doses a.m. and p.m. dissolved in juice. The second week increase to 8 grams per day in three divided doses. The third week take 12g per day in divided doses. Maintain this level for milder depression and anxiety disorders. Continue to increase to 18 grams for OCD and more moderate depression and anxiety over the next two weeks. Can also supplement morning and evening powered doses with chewable tablets during the day whenever symptoms arise but amount taken must be written down to calculate daily target total..
Clinical Effect In: Results after two weeks are comparable to placebo. After 4 weeks significant results have been reported. In Obsessive Compulsive Disorder clinical effect may be delayed in similar fashion to serotonin reuptake inhibitor treatment.
Adverse Reactions: Inositol appears quite safe. It has been administered without untoward effects to adult diabetics in doses up to 12g/day and to newborns with acute respiratory distress syndrome in doses of 80 mg/Kg. (As Inositol is an isomer of glucose persons with diabetes should discuss the use of Inositol with their physicians.) Persons with Inositol Hexaphospate, Nicotinate and Trisphosphate have been found to act as a vasodilator - increasing arterial blood flow. The clinical significance of this for Inositol has not been determined, but it is recommend that persons with a personal or family history of vascular disease consult their physician before initiating Inositol use. Side Effects include: Early stimulation of anxiety and insomnia is common and clears within two weeks. Gastrointestinal upset such as loose stools, nausea and flatulence are sometimes seen and tend to disappear within two weeks. No changes have been found in studies of hematology, kidney, or liver function. If you suspect that an herb or other supplement is making you sick, call the FDA’s MedWatch hotline at 800-332-1088 or contact the agency via it’s website at www.fda.gov/medwatch.
Known Interactive Effects: Inositol (18 grams/day) has been administered in combination with SSRI medications for periods up to 6 weeks. While small studies conducted to date found no augmentation effect or additional benefit from combining inositol with serotonergic drugs (probably because the site of action of the two drugs is different) the combination was well tolerated with no adverse effects.
Additional Considerations: Inositol is about 4 calories per gram. Attempt discontinue in 6 months but 50% of subjects in studies relapsed to pre-treatment condition after discontinuation of Inositol. NOW brand powered inositol appears to be subjected to the greatest quality control standards on the market and can be ordered in quantity from: Health Research Institute Pharmacy 800-505-2842.
Warnings: The information above is provided for educational purposes and may not be construed as a medical prescription or as a substitute for the advice of your physician. Do not use this product without first consulting your physician especially if you are pregnant or lactating. Be advised that some herbs and dietary supplements can cause severe allergic reactions in some individuals and may also have an adverse result in conjunction with other medications, or treatments. You should regularly consult your physician in matters regarding your health and particularly in respect to symptoms and conditions, which may require diagnosis or medical attention. Reevaluate use of this product after 6 months.

21 patients with panic disorder (some of whom also had agoraphobia) were given 12 g per day of inositol for 4 weeks in a randomized, double-blind placebo-controlled trial. Compared with placebo, inositol significantly decreased the frequency and severity of panic attacks and the severity of agoraphobia. There was no significant side effects. Benjamin J et al: Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152(7):1084-6, 1995.

Inositol is a B vitamin that has been found to be quite effective treating panic disorder. Inositol works by regulating the action serotonin, a calming neurotransmitter, within the nerve cells. Its safety has been noted up to twenty grams per day. At HRC we find it a powerful brain chemical in reducing anxiety.
In addition to the amino acids discussed above, certain B vitamins are crucial to reducing anxiety, Indeed, the textbook description of anxiety neurosis exactly matches the symptoms of vitamin B3 (niacin) deficiency: hyperactivity, depression, fatigue, apprehension, headache, and insomnia. A deficiency of vitamin B6 (pyridoxine) causes extreme anxiety, nervousness, confusion, and melancholy. Vitamin B6 is easily destroyed by heavy use of alcohol, drugs, and refined sugars.
Can B vitamins relieve anxiety? An interesting new study showed significantly decreased levels of anxiety among a group of alcoholics treated with megavitamins. Over a twenty-one-day period, the group took approximately three grams of vitamin C, three grams of niacin, six hundred milligrams of B6, and six hundred international units (IU) of vitamin E per day. A comparison group received only inert gelatin capsules. None of the subjects in either group took antidepressants or antianxiety drugs. Anxiety levels among both groups were measured three times over the twenty-one days. They fell dramatically only in the group on megavitamin therapy.

 

[GaryWary]

Inositol

A sugar-like water-soluble substance, inositol is classified as a member of the B-complex vitamin group; found in the heart muscle, kidney, liver and skeletal muscle, and in the leaves and seeds of most plants; similar to choline, inositol is an essential component of phospholipids (phosphatidyl inositols, or "PI") in cellular membranes; phosphatidyl inositols function as cell membrane components and as regulators of cell membrane transport by acting as a calcium-mobilizing system (the "PI" effect) - thus, inositol interacts with a wide variety of hormonal and regulatory events within the cells; lipotropic activity (reduction of blood or tissue lipid levels) of inositol centers around the role of phosphatidyl inositol in lipoproteins; facilitates the production of arachadonic acid (a specialized fatty acid); needed for the proper function of the gallbladder , kidneys and liver; contributes to energy metabolism; enhances brain function due to its importance in transmitting nerve impulses and memory; and is essential for the health of the myelin sheath (the protective coating of the nervous system).

An inositol deficiency could be a contributing cause of abnormal platelet aggregation, alcoholism, heart disease (along with B-vitamin deficiencies), liver disease, memory loss, panic/anxiety attacks, and tardive dyskinesia. Pharmaceutical drugs that can cause an inositol deficiency include aminoglycosides, cephalosporins, chlortetracycline, demeclocycline, doxycycline, fluoroquinolones, macrolides, minocycline, oxytetracycline, penicillins, sulfonamides, tetracyclines and trimethoprim.

Dietary sources richest in inositol (per serving) include cantaloupe, citrus fruits, nutritional supplements, nuts, organ meats, seeds and whole grains and grain products.

 

[GaryWary]

Inositol ­ Clinical Applications for Exogenous Use

Lisa Colodny, Pharm D. and Ronald L. Hoffman, M.D.



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Abstract

Recent advances in nutritional and biochemical research have documented inositol as an important dietary and cellular constituent. The processes involved in inositol metabolism and its derivatives in the tissues of mammals have been characterized in vivo as well as at the enzymatic level. Biochemical functions defined for phosphatidylinositol in biological membranes include the regulation of cellular responses to external stimuli and/or nerve transmission as well as the mediation of enzyme activity through interactions with various specific proteins. Altered production of inositol has been documented in patients with diabetes mellitus, chronic renal failure, galactosemia, and multiple sclerosis. Inositol has been reported to be effective in treating central nervous system disorders such as depression, Alzheimer's disease, panic disorder, and obsessive-compulsive disorder. It has documented benefit for use in pediatric respiratory depression syndrome. In addition, recent studies have evaluated its usefulness as an analgesic. Inositol has been studied extensively as potential treatment to alleviate some negative effects associated with lithium therapy. The use of inositol in pregnant women remains controversial. Although its benefit in preventing neural tube defects in embryonic mice is documented, the risk of inducing uterine contractions limits its usefulness in pregnancy. (Altern Med Rev 1998;3(6):432-447)



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Introduction

Inositol has been identified as an important dietary and cellular constituent. Biochemical functions of phosphoinositol (PI) in cell membranes include regulation of cellular responses to external stimuli as well as mediation of enzyme activity.

In mammals, inositol exists as phosphorylated derivatives, various phosphoinositides, and in its free form. These membranous bound phosphatidylinositols are cleaved by phospholipase C to form diacylglycerol (DAG) and the inositol phosphates. Subsequent enzymatic processes produce a variety of mono-, bi-, tri-, and tetraphosphate inositols depending on specific substrate and the enzyme as described in the diagram that follows. For example, the Ins-1,4,5-P3 kinase is stimulated by calcium. Therefore, the conversion of Ins-1,4,5-P3 to the Ins-1,3,4,5-P4 is facilitated when cytosolic concentrations are increased due to any agonistic action at the cell membrane site. Likewise, the action of the enzyme, polyphosphate 1-phosphomonoesterase is inhibited by lithium and also by calcium in the physiologic range (Figure 1).1

The end product of each pathway eventually is inositol, which is recycled back as a component of the original PI precursor. In addition, this parent compound, phosphatidylinositol, can moderate the activity of numerous membrane enzymes.

Glycosyl-phosphatidylinositol (GPI) structures covalently anchor several enzymes (acetylcholinesterase, alkaline phosphatase, membrane dipeptidase, and 5-nucleotidase) to the outer surface of the plasma membrane.2 In addition, these GPI anchors may provide the protein with other properties, such as phospholipase cleavage susceptibility and the ability to cluster in detergent insoluble domains. These anchors can also act as signalers both intracellularly and transmembranously to regulate metabolic processes of the cells. This allows for enzymes to be activated when agonist activity is high, thereby decreasing further mobilization of calcium. Inactive enzymes remain attached to the membrane and allow agonist stimulation when calcium demand is decreased.

The inositols are ubiquitous, cyclic carbohydrates with a basic 6-carbon ring structure. There are actually nine isomers of inositol, of which myo-inositol is the most abundant isomer in the central nervous system of mammals (Figure 2). Myo-inositol is unique in that it has a single axial hydroxyl group at the number 2 carbon.1



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Physiology

Because amines, polypeptides, and glycoproteins cannot penetrate the lipid layer of target cell membranes, an alternative activator is required. It is known that most hormones act as a "second messenger" by binding to these cell membrane receptors and beginning a cascade of reactions that produces a "messenger" to actually potentiate the intended action.3

This "second messenger" concept is not unique to hormones. The original "second messenger" to be discovered was cyclic adenosine monophosphate (cAMP). For this reason, cAMP is also the best understood. For example, the hormonal effects of epinephrine and norepinephrine are regulated by cAMP. The neurotransmitters released at nerve endings are also regulated by cAMP.

When the agonist binds to the cell membrane receptor, ATP is converted to cAMP which in turn activates a kinase enzyme. The kinase becomes the "second messenger" as it continues in the cycle to promote the original agonistic effect (Figure 3).

Phosphoinositide composition of the central nervous system cell membranes are fatty-acid enriched and consist primarily of phosphatidylinositol (PI), phospha-tidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-biphosphate (PIP2). Once the membrane is stimulated, phospholipase C is activated and consequently inositol triphosphate along with diacylglycerol is produced. PI is used as a precursor for phosphatidylinositol-3-phosphate [PI(3)P] and 3,4,5-triphosphate (Figure 4).1

Cytoplasmic calcium concentration is kept very low by active transport carriers, calcium pumps in the cell membrane itself, and in the endoplasmic reticulum. Usually the calcium concentration inside the cytoplasm is 5,000-10,000 times less than the concentration in the extracellular fluid.

This endoplasmic store of calcium can be accessed upon stimulation by inositol. Inositol triphosphate is released from the cell membrane and travels through the cytoplasm until it reaches the endoplasmic reticulum. This inositol then releases the sequestered calcium, which can go on to mediate the release of neurotransmitters in response to depolarization (Figure 5).4

In addition to releasing endoplasmic reticulum calcium, myo-inositol functions as the major central nervous system non-nitro-genous osmoregulator. Modulation of this inositol pool is regulated in response to states of high or low osmolalities. The inositol pool is supplied via a sodium/inositol transporter, a sodium dependent active transport system, and a passive low affinity transporter.

Hypo- or hyperfunctioning occurs in different areas of the brain depending on the concentration of a specific myo-inositol pool.1 Regulation of the brain inositol system is maintained exclusively by the production of intrinsic myo-inositol. Levels of intrinsic myo-inositol must be closely regulated, as an increase or decrease in the concentration can directly affect cellular signaling. IMPase, a magnesium dependent enzyme that hydrolyzes myo-inositol monophosphate into intracellular myo-inositol, accomplishes this regulation.5

Using rats as models, Kitamura et al proposed modulation of osmolality by inositol occurs in the renal medulla, especially the ascending limb of Henle.6 During this study, acute renal failure was induced by injection of MMI (2-0, C methylene-myo-inositol), a sodium transport inhibitor, producing a significant increase in serum creatinine and urea nitrogen 12 hours after the dose was administered. The subsequent administration of myo-inositol prevented acute renal failure and improved tubular injury after MMI injection.6 This may suggest a future role for inositol supplementation to improve renal function in compromised patient populations.

The specificity of the IP3 receptors as well as the identification of other inositol receptors may play an important role in the development of newer inositol agents that can be directed to a specific receptor or enzyme. Recently, the work of Monkawa et al identified three different types of inositol-1,4,5-triphosphate receptors in the rat kidney.7 Type 1 inositol triphosphate receptors were most commonly located in the glomerular mesangial cells and in vascular smooth muscle cells. Receptors of type 2 specificity were located in the collecting ducts from the cortex to the inner medulla. Type 3 inositol triphosphate receptors can be found at all sites.6

Although receptor differences in the human model are not as clearly understood, calcium may have the potential to inhibit IP3 binding to types 1 and 3 triphosphate receptors. Calcium binding to type 3 receptors may be stimulated at intermediate concentrations of calcium. As a result of these differences, type 3 receptors are more sensitive to IP3 than type 1 receptors when the cytosolic calcium concentration is within normal range.8 However, as the cytosolic calcium concentrations increase, type 1 receptors become more sensitive to IP3 compared to type 3 receptors.

In addition to the IP3 receptors, numerous non-inositol receptors have been identified in the central nervous system that can potentially interact with the inositol signaling system. The receptors listed in Table 1 are linked to the G proteins and produce DAG and inositol-1,4,5-triphosphate as second messengers.1 The receptors listed can be found in nearly every human organ system. The potential interactions between these receptors and their agonists are responsible for regulation of the body on a day-to-day basis. In view of the intricacy of these systems and their actions, a perfect balance is required for regulation of the signaling systems.

Theoretically, an imbalance of inositol concentration could potentially affect the development and function of one or all of these receptors. Therefore, any organ system that houses these receptors could also be potentially affected. Cholinergic receptors are located in the liver, heart, stomach, and lungs. Serotonin and glutamine receptors are found mostly in the CNS tissues. Adrenergic receptors are present in various tissues including CNS, vascular tissues, and heart. Histaminergic receptors are predominantly found in the lungs and stomach. Given the omnipresence of inositol or inositol related entities, maintaining a state of euinositolism may be a promising objective for regulation of functions required for development and/or maintenance of organ systems.

Under normal conditions the average dietary intake of inositol is only about one gram per day. Fortunately, oral intake of inositol accounts for only one of three pathways for inositol production. Inositol monophosphate can be produced as a result of a receptor mediated salvage system and from glucose-6-phosphate. Inositol from either of these two pathways is metabolized by a lithium sensitive enzyme, polyphosphate-1-phospho-monoesterase. These two pathways account for the majority of inositol produced (Figure 6). Inositol accumulation from the third pathway, attained as a result of dietary uptake, is considered a minor pathway.



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Potential Clinical Applications

A change in CNS availability of inositol may produce altered brain signaling and eventually lead to the development of neurological disorders. Studies evaluating the effectiveness of inositol indicate it may be effective in the treatment of depression, Alzheimer's disease, panic disorder, obsessive compulsive disorder, autism, post-traumatic stress disorder, and pain control.

Depression: 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 etiology for depression is believed to be linked to a deficiency of neurotransmitters at post-synaptic receptor sites. In the catechol-amine theory the deficiency is norepinephrine; in the indolamine theory the deficiency is serotonin. Receptors linked to the inositol signaling system include serotonin (5HT2a and 5HT2b) and norepinephrine (alpha 1a, 1b, and 1d). Therefore, inositol may be an important participant in this neurological arena.

Presently, serotonin reuptake inhibitors (SSRIs) are the primary class of agents utilized for depressed patients. Kavoussi et al reported bupropion (a semi-serotonin agent) and sertraline (an SSRI) equally effective for the treatment of depression.9 However, orgasm dysfunction, nausea, vomiting, somnolence, and sweating were frequently reported side-effects in the sertraline group.10 Lydiard et al reported amitriptyline not superior to placebo for several subjective assessments of depression.11 Van Houdenhave et al reported 23 percent of study patients experienced mild to moderate gastrointestinal effects for sertraline treated patients and a withdrawal rate of eight percent.12 Venlafaxine was evaluated by Dunner et al and a dropout rate of 11.5 percent due to side-effects associated with therapy was reported.13 Presently, the SSRIs as a class are probably the best tolerated antidepressants currently available for use in patients with depression. They are commonly selected over the anticholinergic agents due to their effectiveness and lack of anticholinergic side-effects.

Anticholinergic effects of antidepressants include dry mouth, blurred vision, constipation, and urinary hesitancy. Autonomic effects include sweating, impotence and ejaculation dysfunction. At normal doses cardiac adverse effects include tachycardia and EKG changes. Other effects include: orthostatic hypotension, sedation, restlessness, insomnia, weight gain, anorexia, nausea, vomiting, tremor, and confusion.

In 1978, Barkai et al demonstrated depressed patients had significantly decreased CSF levels of inositol as compared to healthy patients.14 In 1993 this theory was expanded to conclude that administration of high-dose inositol could increase CSF levels by as much as 70 percent.15 This led to the study of inositol for treatment of depression.16,17

In 1995 Levine et al completed a, double-blind study for treatment of depression using inositol at a dose of 12 grams daily compared to placebo.18 Patients receiving inositol showed significant improvement in depression as ranked by the Hamilton Depression Rating Scale (33.4 +/- 6 versups 21.6 +/- 10). 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 twelve 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.18

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.19

It can be concluded that inositol at a dose of 12 grams daily may be effective in treating the clinical manifestations of depression and should be considered a treatment alternative. In addition to the possible clinical responses relative to symptom resolution, therapy with inositol may be advantageous since potential side-effects of the more conventional therapy can be avoided.

Panic Disorder: Panic disorder begins as an acute or spontaneous attack of anxiety that involves an intense, terrifying fear. The attack seems to peak in about ten minutes and lasts approximately 20-30 minutes. 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. Conventional therapy includes SSRIs, the serotonergic agent clomipramine, tricyclic antidepressants such as imipramine or desipramine, MAOIs (especially phenelzine), alprazolam, and clonazepam. However, treatment with these medications continues to produce a significant number of adverse reactions.

Papp et al concluded clomipramine at therapeutic doses produced a significant number of adverse drug reactions and a high drop rate.20 Paroxetine for panic disorder was evaluated by Ballenger et al who reported adverse drug reactions consistent with those most commonly reported for the class as a whole.21 The most compelling adverse drug reaction information was reported by Cowly et al, who found 27 percent of the clinical trials reporting intolerable side-effects as the most common reason for treatment failures, especially with tricyclic antidepressants.22 Rosenbaum et al concluded clonazepam in higher doses was more likely to cause somnolence and ataxia, while normal maintenance doses were more likely to be associated with depression, dizziness, fatigue, and irritability.23

Benjamin et al expanded the clinical use of inositol by evaluating its effectiveness in panic disorder.24 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 Marks-Matthews 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 a potentially attractive therapeutic agent for panic disorder.

Obsessive Compulsive Disorder (OCD): OCD is the fourth most common psychiatric disorder. It is estimated 2.5 percent of adults and one percent of children meet the DSM-IV classification for OCD. It usually first appears late in adolescence or early adulthood. OCD incidence is higher in females than in males. The age of onset is usually earlier in males than in females, 6-15 years compared to 20-29 years, respectively.25

Although OCD can occur following a brain injury, there is usually no neurological precipitant. Most compelling for the evidence suggesting a biological cause is the successful treatment using SSRIs. Currently the medication of choice for treating OCD is the benzodiazepine agent, clomipramine. Flament et al reported a 26-percent discontinuation rate for OCD treated with clomipramine and 11 percent for those treated with the serotonin agent, sertraline. In addition, there is poor tolerance for long-term use of clomipramine.26 Nausea, vomiting, and decreased sleep were the most commonly reported side-effects in a study of citalopram for OCD.27 Patients also reported decreased sexual desire and orgasmic dysfunction.

Since the phosphatidylinositol cycle as a second messenger is known to affect several neurotransmitters, including serotonin receptors, inositol at 18 grams daily was studied for treatment in OCD in a double-blind, placebo controlled, crossover trial. Thirteen patients were treated for six weeks. There was a significant improvement at week six during the inositol period when compared to placebo period. There were no side-effects reported during the study period.28 The improvement noted with inositol in this study was comparable to that reported for fluvoxamine and fluoxetine.28 Longer periods of inositol therapy may produce even more significant results.

Alzheimer's Disease: Alzheimer's Disease (AD) is a degenerative brain disorder that affects approximately four million people in the United States.29 This number is anticipated to increase to nearly nine million by the year 2040. It is estimated that currently more than 10 percent of the U.S. population aged 65 or older and 48 percent of those aged 85 or older have AD.30

Annually, the national cost of AD is estimated at 110 billion dollars. This includes the direct costs of medical care and social services, informal costs, and costs due to lost productivity. First characterized in 1907 by Alois Alzheimer, AD is a dementia of insidious onset, with deterioration of intellectual ability occurring gradually. Clinically, it is a progressive brain failure that results from neuronal dysfunction and ultimately cell death. Multiple neuronal pathways are destroyed in AD. This destruction is believed to be caused by accumulation of neuritic plaques and neurofibrillary tangles (NFT).

NFTs are located intracellularly within the cytoplasm of neurons. The neuritic plaques are extracellularly located (brain and cerebral vasculature). Both the plaques and NFTs significantly interfere with neuronal transmission.

Although the role of aluminum in AD is still speculative at best, the presence of aluminosilicates at the core of senile plaques in diseased neurons is a consistent feature found in the CNS of AD patients during autopsy.31 It is known that aluminum inhibits the incorporation of inositol into phospholipids and the hydrolysis of the phosphoinositides by binding to one of two specific phosphate groups. This copulation of phosphate and aluminum affects the calcium releasing effects of the cell. The resulting profound disturbance of the phosphatidylinositol second messenger system may account for neuronal malfunction and eventual cell death.31

Currently all medications for AD are palliative. Even with newer agents like tacrine, the prognosis for AD is not improved. The newer agents do not affect the underlying disease processes, although progression of the disease may be retarded. Table 2 lists the currently approved agents and those currently being studied for Alzheimer's disease.30,32-39

Since the potential role of aluminum as a causative agent for cell death may be affected by the deregulation of calcium concentration, possibly due to inositol depletion, supplementation with inositol may produce positive CNS effects. Recent data suggests the loss of PI second messenger system target sites and IP3 receptors may add to cognitive impairment and the failure of conventional therapies in AD. Therefore, supplementation of inositol to replenish the diminished PI system may be beneficial in the treatment of AD.

In 1996 Barak et al completed a double-blind, controlled, crossover study of six grams inositol daily compared to placebo for 30 days in 11 Alzheimer's patients.40 Patients in the study were diagnosed with dementia of the AD type as classified by DSM - IIIR and aged 65 years or older. The Cambridge Mental Disorder of the Elderly Examination (CAMDEX) was used as the basic assessment parameter and was administered upon admission into the study. Included in CAMDEX is part A: patient's present physical and mental state, part B: Cognitive Subscale of CAMDEX (CAMCOG), part C: interviewers observations, and part D: physical examination. CAMCOG was repeated at two, four, six, and eight weeks. Participants scored 80 or less on the CAMCOG examination and their symptoms of depression were not severe.

Patients were excluded from the study if they had a history of psychiatric, alcohol, and/or drug addiction disorders, or abnormalities in baseline laboratory values (blood count, electrolytes, liver or kidney functions, VDRL, or CT scan) not consistent with AD. Patients with additional neurologic, metabolic, endocrinologic disorders, or presence of internal disease that grossly impaired brain functioning were also excluded.

Subjects were given either three grams inositol or placebo in the morning and again in the evening. After four weeks patients were crossed over into the other arm (inositol or placebo) for an additional four weeks. Only benzodiazepines were allowed during the study period (15 mg of oxazepam or equivalent), provided the patient was receiving it on study entry.

Analysis of the improvement scores of all patients who completed the study showed inositol increased the total CAMCOG score from a baseline of 31.36 +/- 20.90 to 40.09 +/- 24.54, while the placebo group increased from baseline of 35.9 +/- 25.96 to 39.27 +/- 25.10. The authors concluded only two of the eight subscales (language and orientation) showed significant improvement with inositol. Adverse effects of the inositol treated group were considered mild and transient (insomnia and flatus).

Further studies targeting orientation and/or improvement in language skills are warranted. The relatively small number of patients enrolled in the study may have lacked the statistical power to identify other significant differences that may have existed. It is also questionable why the researchers decided to use inositol at a dose of six grams when it is known relatively larger doses (12 grams or more) are generally required. Thirdly, the length of time inositol was administered may have been too short since studies in which patients were treated for three to five months produced more favorable results.

Recent advances in AD neurobiology have provided evidence for development of more effective and less toxic strategies for disease management. Of most significance is the realization that muscarinic receptors (M1) post-synaptically are relatively preserved in AD patients, whereas the number of pre-synaptic receptors (M2) are reduced (Figure 7).41 Therefore, stimulation of intact post-synaptic membranes by M1 receptor agonists may theoretically be more efficacious in treatment of AD than treatment with conventional therapies like acetylcholinesterase inhibitors that predominantly act on dysfunctional pre-synaptic membrane receptors.

Inositol's proposed mechanism of action in the CNS does not include direct manipulation with either pre- or post-receptors. However, it may indirectly affect the relationship between receptor and agonist. By mediating the physiochemical characteristics of the M1 pre-synaptic receptor (solubility, osmolality, etc.), inositol may alter the binding site and influence the signaling that occurs as a result.

The development of a diagnostic test to confirm the existence of an "Alzheimer's protein" may also provide beneficial early therapy for patients predisposed to AD. In December 1997 the discovery of a protein called AD7c-NTP in nerve cells that may cause Alzheimer-like changes, including cell death, was announced.42 This might enable physicians to identify patients with the AD protein and begin appropriate therapy, which can include inositol given its benign adverse reaction profile. Presently, the debilitating neurological signs on presentation are often the initial prognosticators of AD. By this time, however, the damage that has occurred is usually severe and untreatable. Physicians may opt to include inositol in addition to one of the other agents for AD before neurological deterioration is severe.

Post Traumatic Stress Disorder (PTSD): PTSD is a pathological reaction to a psychologically traumatic experience. Symptoms may be acute or delayed, and are characterized by nightmares and flashbacks where the event is re-experienced.

Resistance to drug therapy may best be explained by Adamac who reported the traumatic event may actually produce a "photograph" of the occurrence in the CNS. This permanent emotional memory may be triggered exogenously and the event is relived continually upon exposure to agonists.43

Only about 50 percent of PSTD patients reported significant improvement in depressive symptoms at one month when compliant with medications. SSRIs produced better outcomes than norepinephrine inhibitors.

In 1996 the effects of inositol in patients suffering from PSTD were evaluated by Kaplan et al. Patients were given 12 grams daily or placebo for four weeks, then crossed over into the other study group for an additional four weeks. There were no significant differences in improvement between the treated group as compared to the placebo group.44

Autism: The use of inositol at 200 mg/kg was evaluated in nine children for the treatment of autism.45 The investigators concluded there was benefit for its use in this patient population. Studies on a larger population seem warranted.

Respiratory Distress Syndrome Disorder (RDSD): One of the oldest documented uses of inositol is for use in neonatal RDSD.46 It is known that inositol administration to immature animals increases pulmonary surfactant levels. Administration of inositol at 80 mg/kg parenterally to premature infants may decrease the likelihood of respiratory distress syndrome. Hallman et al concluded parenteral inositol therapy during the early neonatal period may also decrease the incidence of severe, chronic injury of the retina.47

Analgesia: Given the success of inositol for some central nervous system disorders, its use for pain control was recently evaluated. Tarnow et al reported an analgesic effect for inositol-1,2,6-triphosphate in a double-blind, randomized study of 24 patients undergoing cholecystectomy.48 Opioid analgesia requirements were significantly reduced when patients received a bolus inositol dose of 240 mg followed by 90 mg/hr for 24 hours. There were no side-effects reported with the bolus or maintenance infusions.

The analgesic relationship between inositol and pain was also investigated by Raffa et al who reported the phosphoinositide pathway may play an important role in opioid efficacy and in the development of morphine tolerance.49

The recent work of Ferrara et al proposed an anti-edematous action of alpha-trinositol when used to treat canine scald injuries, reportedly through a decrease of the transmembrane flux.50

Lithium-Induced Adverse Reactions: It is believed lithium inhibits inositol monophosphatase which in turn depletes brain stores of inositol. In fact, this may be the mechanism for lithium's effectiveness in treating manic-depressive disorder.

Concern is therefore warranted over the concept of treating lithium induced side-effects with inositol, since administration of inositol may cause the concentration of inositol to rise and subsequently reintroduce manic or depressive episodes. However, the exogenous administration of inositol does not appear to alter the manic-depressive control at all.

It is theorized inositol derived from inositol phosphate breakdown is recycled for use in membranous phosphatidylinositol. Hyperactivated systems would be affected by lithium's depletion of the recyclable inositol pool, whereas isosystems would not be affected.51 A similar finding was reported by Berridge et al who concluded lithium inhibits phosphoinositide derived second messengers of activated systems only.52

Johnson et al concluded inositol depletion induced by lithium can be bypassed by introduction of exogenous inositol.53 They administered inositol at 1500 mg daily (500 mg three times daily) to 11 patients who experienced polyuria-polydipsia as a result of lithium treatment. Forty-five percent of the patients experienced dramatic improvement in polyuria-polydipsia complaints; another 36 percent reported mild improvement. This improvement may be more related to the osmoregulatory effect of inositol than its function as a second messenger. Improvement was also noted in lithium-induced psoriasis.



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Possible Clinical Contraindications for Inositol Supplementation

Attention Deficit Hyperactivity Disorder (ADHD): ADHD is a disorder of early childhood which can be symptomatic well into adulthood. These patients are inattentive, impulsive, quick-tempered, unable to tolerate stress, and are restless since childhood. ADHD is most commonly treated with methylphenidate, but propranolol and tricyclic antidepressants are also alternatives.

Evaluation of inositol in 11 children with attention deficit hyperactivity disorder was reported in 1995 by Levine et al in a double-blind, crossover study.54 There were no therapeutic advantages observed in the inositol group. In fact, there was a trend toward the worsening of the disorder in the inositol treated group. Therefore, inositol appears to have no clinical advantages for the treatment of ADHD and may even antagonize the condition.

Schizophrenia: Schizophrenia accounts for 7-20 percent of all psychiatric hospital admissions. It is estimated that 0.5-1.0 percent of the worldwide population will experience a schizophrenic episode at some point in life. Schizophrenia usually begins in adolescence and early childhood, only rarely beginning before adolescence or after the age of 40. It affects the sexes equally and usually becomes more pronounced at approximately age 20. Males tend to have an earlier onset than females (15-24 years versus 25-34 years, respectively).

The most accepted and well-supported biochemical etiology for the development of schizophrenia involves the neurotransmitter, dopamine. It is believed excessive concentrations of dopamine may induce psychotic/schizophrenic episodes.

Although anti-psychotics drugs are effective in treating the disorder, the adverse reactions associated with them can be severe. The side-effects can range from Parkinsonian-like symptoms to anticholinergic effects (dry mouth, constipation, urinary retention, drowsiness, etc) depending on the pharmacological class of the agent. Therefore, noncompliance with anti-psychotic medications is a pivotal problem for patients and caregivers.

In 1993, Levine et al performed the first study utilizing inositol as an agent for schizophrenia. This study found no significant benefit of inositol supplementation.55,56 However, the authors concluded the dose of six grams daily was probably not sufficient to produce a significant clinical effect. Large exogenous doses are usually required since inositol absorption from the periphery into the CNS is poor. In addition, losses of seven to eight grams daily can result from degradation by renal enzymes.57

Another theory for the lack of efficacy of inositol may be explained by the recent work of Jope et al who reported schizophrenia may be associated with an increased, rather than decreased, activity of the phosphoinositol signaling system.58 Therefore, it may be contra-indicated in schizophrenia.

Pregnancy: Inositol may stimulate uterine contractions. Oxytocin is a potent uterine stimulator whose clinical use in labor and delivery is well documented. Phaneuf et al reported oxytocin's clinical effectiveness is due to the activation of phospholipase C to produce inositol-1,4,5-triphosphate which releases calcium from intracellular stores and stimulates uterine contractions.59 The activation of the phosphatidylinositol signaling system by calcium agonists is also supported by the work of Chien et al who noted dose-related myometrial contractions when laboratory mice were injected with a calcium agonist.60

Reece et al reported inositol supplementation of 0.08 mg/kg/day significantly decreased embryonic neural tube defects from 20.4 percent to 9.5 percent in diabetic rats. They concluded the incidence of diabetic embryopathy and congenital malformations may be reduced by supplementation with inositol.61 Similarly, Greene et al stated about 30 percent of all neural tube defects are resistant to supplementation with folic acid alone. However, addition of inositol significantly decreased the incidence of spinal neural tube defects in mice by increasing protein kinase activity and delaying the closure of the neuropore. They concluded that combination therapy of folic acid and inositol may prevent neural tube defects like spina bifida in humans.62 Therefore, while inositol may prevent neural tube defects, its use during pregnancy may be contraindicated due to the potential for uterine stimulation.



--------------------------------------------------------------------------------


Conclusion

Propelled by incredible advances in the understanding of the pathological etiologies and characteristics of psychiatric disorders, prospects for treatment have brightened considerably in the last 10 years. It is known that a change in the CNS concentration of inositol may lead to modified brain cell signaling pathways, and possibly to the development of a psychiatric disorder. Recent evidence indicates inositol has psychoactive effects by interacting with the second messenger system and ulti-mately regulating the cytosolic concentration of calcium.

The signaling by calcium is known to mediate an array of cellular functions (secretion, contraction, and conduction). Due to the role calcium plays, its regulation intracellularly is known to be a complex phenomenon 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 CNS disorders like Alzheimer's disease, depression, panic disorder, obsessive compulsive disorder, and as an analgesic for pain control. Likewise, its use to alleviate lithium-induced adverse reactions is also promising.

The benefit of inositol therapy in post traumatic stress disorder and autism has yet to be established. To date most studies have been characteristically small in number. In addition, studies have not consistently approached rea-listic doses of inositol for therapeutic effect to be evaluated. There is a need for additional studies to be performed utilizing large numbers of patients and increased supplemental doses of inositol.

At this time inositol supplementation for the treatment of schizophrenia and attention deficit hyperactivity disorder is not believed to be effective. In fact, it may be contraindicated as it might exacerbate these conditions. The risk of premature labor induction versus benefit for prevention of embryonic defects should be considered thoroughly before initiation of inositol therapy during pregnancy.

As new clinical studies involving inositol are concluded and the research is evaluated, the understanding of inositol's role in intracellular and extracellular signaling may provide even better insight into the therapeutic applications of inositol and inositol-based products.



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References

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2. Hooper N. Glycosyl-phosphatidylinositol anchored membrane enzymes. Clin Chim Acta 1997;266:3-12.

3. Kalant H, Roschlau W. Principles of Medical Pharmacology 5th edition. Burlington, Ontario and Philadelphia, PA: BC Decker, Inc; 1989.

4. Gill DL, Ghosh TK, Mullaney JM. Calcium signaling mechanisms in endoplasmic reticulum activated by inositol 1,4,5 triphosphate and GTP. Cell Calcium 1989;10:363-374.

5. Parthasarathy L, Vadnal R, Parthasarathy R, et al. Biochemical and molecular properties of lithium-sensitive myo-inositol monophosphatase. Life Sci 1994;54:1127-1142.

6. Kitamura H, Yamauchi A, Sugiura T, et al. Inhibition of myo-inositol transport causes acute renal failure with selective medullary injury in the rat. Kidney Int 1998;53:146-153.

7. Monkawa T, Hayashi M, Miyawaki A, et al. Localization of inositol-1,4,5-triphosphate receptors in the rat kidney. Kidney Int 1998;53:296-301.

8. Cardy T, Traynor D, Taylor C. Differential regulation of types-1 and -3 inositol triphosphate receptors by cytosolic calcium. Biochem J 1997;328:785-793.

9. Dow B, Kline N. Antidepressant treatment of post traumatic stress disorder and major depression in veterans. Ann Clin Psychiatry 1997;9:1-5.

10. Kavoussi R, Segraves R, Hughes A, et al. Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. J Clin Psychiatry 1997;58:532-537.

11. Lydiard R, Stahl S, Hertzman M, et al. A double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. J Clin Psychiatry 1997;58:484-491.

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15. Levine J, Rapaport A, Lev L, et al. Inositol treatment raises CSF inositol levels. Brain Research 1993;627:168-169.

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19. Levine J, Barak Y, Kofman O, et al. Follow-up and relapse of an inositol study of depression. Isr J Psychiatry Relat Sci 1995;32:14-21.

20. Papp L, Schneider F, Fyer A, et al. Clomipramine treatment of panic disorder: pros and cons. J Clin Psychiatry 1997;58:423-425.

21. Ballenger J, Wheadon D, Steiner M, et al. Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry 1998;155:36-42.

22. Cowley D, Ha E, Roy-Byrne P. Determinants of pharmacologic treatment failure in panic disorder. J Clin Psychiatry 1997;58:555-561.

23. Rosenbaum J, Moroz G, Bowden C. Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic Disorder Dose Response Study Group. J Clin Psychopharmacol 1997;17:390-400.

24. Benjamin J, Levine J, Fux M, et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 1995;15:1084-1086.

25. Wells B, Hayes P. Obsessive Compulsive Disorder. Pharmacotherapy, A Pathophysiologic Approach. 3rd ed. Stamford, CT: Appleton & Lange; 1997:1463-1473.

26. Fux M, Levine J, Aviv A, et al. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 1996;153:1219-1221.

27. Flament M, Bisserbe J. Pharmacologic treatment of obsessive-compulsive disorder: comparative studies. J Clin Psychiatry 1997;58:18-22.

28. Koponen H, Lepola U, Leinonen E, et al. Citalopram in the treatment of obsessive-compulsive disorder; an open pilot study. Acta Psychiatr Scand 1997;96:343-346.

29. Eggert A, Crismon L, Ereshefsky L. Alzheimer's disease. Pharmacotherapy, A Pathophysiologic Approach. 3rd ed. Stamford, CT: Appleton & Lange; 1997:1325-1341.

30. Lacy C. Update on treatment of Alzheimer's disease. Pharmaguide to Hospital Medicine 1998;10:1-11.

31. Birchall J, Chappell J. Aluminum, chemical physiology, and Alzheimer's disease. Lancet 1988;29;1008-1010.

32. Bodick N, Offen W, Shannon H, et al. The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11:S16-S22.

33. Cheng D, Ren H, Tang X. Huperzine A. A novel promising acetylcholinesterase inhibitor. Neuroreport 1996;8:97-101.

34. Kawakami Y, Inoue A, Kawai T, et al. The rationale for E2020 as a potent acetylcholinesterase inhibitor. Bioorg Med Chem 1996;4:1429-1446.

35. Knopman D, Schneider L, Davis K, et al. Long term tacrine (Cognex) treatment: effects on nursing home placement and mortality, tacrine study group. Neurology 1996;47:166-167.

36. Mohr E, Nair N, Sampson M, et al. Treatment of Alzheimer's disease with sabeluzole: functional and structural correlates. Clin Neuropharmacol 1997;20:338-345.

37. Rogers S, Friedhoff L. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The donepezil study group. Dementia 1996;7:293-303.

38. Schneider L, Farlow M, Pogoda J. Potential role for estrogen replacement in the treatment of Alzheimer's dementia. Am J Med 1997;103:46S-50S.

39. Van Dyck C, Lin C, Robinson R, et al. The acetylcholine releaser linopiridine increases pariental regional cerebral blood flow in Alzheimer's disease. Psychopharmacology 1997;132:217-226.

40. Barak Y, Levine J, Glasman A, et al. Inositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:729-735.

41. Avery E, Baker L, Asthana S. Potential role of muscarinic agonists in Alzheimer's disease. Drugs Aging 1997;11:450-459.

42. De la Monte S, Ghanbari K, Frey W, et al. Characterization of the AD7C-NTP c DNA expression in Alzheimer's disease and measurement of a 41-kD protein in cerebrospinal fluid. J Clin Invest 1997;100:3093-3104.

43. Adamec R. Transmitter systems involved in neural plasticity underlying increased anxiety and defense - implications for understanding anxiety following traumatic stress. Neurosci Biobehav Rev 1997;21:755-765.

44. Kaplan Z, Amir M, Swartz M, et al. Inositol treatment of post traumatic stress disorder. Anxiety 1996;2:51-52.

45. Levine J, Aviram A, Holan A, et al. Inositol treatment of autism. J Neural Transm 1997;104:307-310.

46. Thompson G, Kalid N. Inositol therapy of neonatal respiratory distress syndrome. Micromedix 1997:97. (on-line drug information service)

47. Hallman M, Bry K, Hoppu K, et al. Inositol supplementation in premature infants with respiratory distress syndrome. N Engl J Med 1992;326:1233-1239.

48. Tarnow P, Cassuto J, Jonsson A, et al. Postoperative analgesia by D-myo-inositol-1,2,6-triphosphate in patients undergoing cholecystectomy. Anesth Analg 1998;86:107-110.

49. Raffa R, Connelly C, Martinez R. Opioid efficacy is linked to the LiCl-sensitive inositol-1,4,5-triphosphate-restorable pathway. Eur J Pharmacol 1992;21:221-223.

50. Ferrara J, Kukuy E, Gilman D, et al. Alpha-trinositol reduces edema formation at the site of scald injury. Surgery 1998;123:36-45.

51. Belmaker R, Bersudsky Y, Agam G, et al. How does lithium work on manic depression? Clinical and psychological correlates of the inositol theory. Annu Rev Med 1996;47:47-56.

52. Berridge M. Regulation of ion channels by inositol triphosphate and diacylglycerol. J Exp Biol 1986;124:323-335.

53. Johnson E, Gray-Keller M. Rescue of excitation by inositol following Li(+)-induced block in Limulus ventral photoreceptors. Vis Neurosci 1998;15:105-112.

54. Levine J, Ring A, Barak Y, et al. Inositol may worsen attention deficient disorder with hyperactivity. Hum Psychpharmacol 1995;10:481-484.

55. Levine J, Goldberger I, Rapaport A, et al. CSF inositol in schizophrenia and high dose inositol treatment if schizophrenia. Eur Neuropsychopharmacol 1994;4:487-490.

56. Levine J, Umansky R, Ezrielev G, et al. Lack of effect of inositol treatment in chronic schizophrenia. Biol Psychiatry 1993;33:673-675.

57. Holub BJ. The nutritional significance, metabolism, and function of myo-inositol and phosphatidylinositol in health and disease. Adv Nut Res 1982:4:107-141.

58. Jope R, Song L, Grimes C, 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.

59. Phaneuf S, Europe-Finner G, Carrasco M, et al. Oxytocin signalling in human myometrium. Adv Exp Med Biol 1995;395:453-467.

60. Chien E, Saunders T, Phillippe M. The mechanisms underlying Bay K 8644-stimulated phasic myometrial contractions. J Soc Gynecol Investig 1996;3:106-112.

61. Reece E, 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.

62. Greene N, Copp A. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med 1997;3:60-66.

 

[GaryWary]

Myo-inositol:

Can it help to regenerate nerves?

A study published in Diabet Med found that myo-inositol levels are positively correlated with signs of nerve regeneration. The study compared sorbitol and myo-inositol levels and morphology of sural nerve with nerve function and clinical neuropathy in men with:

diabetic glucose tolerance

impaired glucose tolerance

and normal glucose tolerance

Nerve degeneration correlated with clinical neuropathy but not with glucose tolerance status. However, nerve myo-inositol levels positively correlated with signs of nerve regeneration (i.e. increased cluster density) (1).

Infants of diabetic mothers exhibit congenital anomalies about two to three times as often as in normal population. Multiple etiologic factors have been proposed regarding the mechanism of diabetes related birth defects. The metabolic alterations associated with hyperglycemia include myo-inositol and arachidonic acid deficiency. These deficiencies result in a disturbed metabolism of prostaglandins. Recent studies provide evidence that a prostaglandin deficiency adversely affects membranogenesis (the formation of new membranes) and membrane function. These changes in membrane function permit the influx of high levels of glucose into the cells, inducing the generation of free oxygen radicals that cause morphologic damage of the embryo. It was determined that a deficiency of prostaglandins at a critical time of fetal development can cause embryonic malformations (2).

Myo-inositol is found in vegetables, fruits, grains, and nuts

1. Sundkvist G, Dahlin LB, Nilsson H, Eriksson KF, Lindgarde F, Rosen I, Lattimer SA, Sima AA, Sullivan K, Greene DA Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance. Diabet Med 2000 Apr;17(4):259-68

2. Wiznitzer A, Furman B, Mazor M, Reece EAThe role of prostanoids in the development of diabetic embryopathy. Semin Reprod Endocrinol 1999;17(2):175

 

[GaryWary]

PHARAMACOLOGY AND ACTION

Inositol hexaphosphoric acid (phytic acid, INN Fytine acid Roempps Chemie Lexicon, 1983) serves as a phosphate depot in the body and is broken down by phytase to myo-inositol. The human body contains about 40 g of myo-inositol. It also plays the role of a growth factor and is identical in action to the formerly designated as "bios I" factor, necessary for optimal growth. Based on its mode of action, myo-inositol can be classified to the vitamin complex of ht B-group (Roempps Chemie Lexicon, 1983). In the body, myo-inositol can be synthesized from glucose-6-phosphate, but human requirements are chiefly covered through consumption of fruit and cereals, where it occurs in the form of inositol-hexaphosphate (phytic acid).

By competitive chelate formation phytic acid participates in the process of intestinal absorption of calcium, magnesium and iron ions. The formation of insoluble chelate complexes of phytic acid accounts for some of its extremely important properties, such as its anticancer and antiviral activity.

Myo-inositol increases the oxygen transporting capacity of hemoglobin in red blood cells, improves and regulates cellular metabolism, especially in conditions of phosphorus deficiency in the body, stimulates hemopoiesis and bone tissue formation, and improves the tone of the nervous system.

The overall complex effect of Phytin is expressed in a general tonic action which, combined with its involvement in the regulatory metabolic processes, improves the intensity and stability of attention, increases performance and work capacity, removes the feeling of fatigue, and stimulates the organism's defenses through yet not entirely clear mechanisms (Torre et al., 1991).

Phytin as a food supplement is very good for prophylaxis in conditions of physical and mental strain, and for increasing general endurance during active exercise and sports. Phytin can also be included in the complex therapy of such conditions of the nervous system that are associated with phosphorous deficiency. For bone diseases, in combination with calcium preparations, it can be used rickets, osteomalacia, and bone fractures. In combination with iron preparations, it can be used for anemia in adults and children. It is recommended for insomnia and loss of appetite, either alone or in combination with various prescription drugs.

The inhibitory effect of phytic acid on the proliferation of human immune deficiency viruses (HIV), implicated as causative agents of the acquired immune deficiency syndrome (AIDS), has been tested in vitro by Japanese scientists (Otaka et al., 1989). They found that phytic acid, at a concentration of 1.67 mg/ml, inhibits the cytotoxic effect of the immune deficiency virus and the specific antigenic reaction in the effected cells.

Several studies (Nicoletti F. et al. 1989) have demonstrated an increase of calcium ion influx in cerebellar neurons. They provide evidence for a direct activating effect of phytic acid and its salts on the functional activity of the central nervous system. These data are further confirmed by other authors, who established an important role of phytic acid in the regulation of cell metabolism.

Various studies (Shamsuddin A. M. et al., 1989; Ullah A. et al. 1990) in recent years investigated the anticancer effect of phytic acid and its salts. Interesting results were obtained on experimental intestinal tumors in mice and rats. The antineoplastic effect was tested in physiologic pH. The reported anticancer activity in test animals, expressed in significant tumor reduction, suggests a likely prophylactic use for phytic acid and its salts in humans who are predisposed to intestinal and pancreatic tumors.

Repeated dose administration of Phytin has revealed no changes in the body mass and electrolytic balance, and no signs of toxicity in the test animals, even at higher doses.

The inclusion of inositol-hexaphosphate (InsP6 or IP6) as an active ingredient of fiber-rich diets is being discussed in literature. The anti-carcinogenic activity of inositol-hexaphosphate has been confirmed on in vitro and in vivo models (Shamsuddin A. M. 1996). The investigation of Graf (1993) on the inhibitory effect of phytic acid containing dietetic foods also corroborated that activity.

According to most recent studies of phytic acid as a major component of cereal grains and beans is considered an important antioxidant and is increasingly used in various therapeutic diets for its protective effect on cancer of the colon and rectum (Owen R.W. et al. 1996).

Rao P.S. et al (1991) studied the antioxidation properties of phytic acid at oral doses of up to 15 mg/100g body mass in rats for its protective effect on ischemic heart disease and found improved perfusion in the ischemic myocardial region.


PHARAMACOLOGY AND ACTION

Inositol hexaphosphoric acid (phytic acid, INN Fytine acid Roempps Chemie Lexicon, 1983) serves as a phosphate depot in the body and is broken down by phytase to myo-inositol. The human body contains about 40 g of myo-inositol. It also plays the role of a growth factor and is identical in action to the formerly designated as "bios I" factor, necessary for optimal growth. Based on its mode of action, myo-inositol can be classified to the vitamin complex of ht B-group (Roempps Chemie Lexicon, 1983). In the body, myo-inositol can be synthesized from glucose-6-phosphate, but human requirements are chiefly covered through consumption of fruit and cereals, where it occurs in the form of inositol-hexaphosphate (phytic acid).

By competitive chelate formation phytic acid participates in the process of intestinal absorption of calcium, magnesium and iron ions. The formation of insoluble chelate complexes of phytic acid accounts for some of its extremely important properties, such as its anticancer and antiviral activity.

Myo-inositol increases the oxygen transporting capacity of hemoglobin in red blood cells, improves and regulates cellular metabolism, especially in conditions of phosphorus deficiency in the body, stimulates hemopoiesis and bone tissue formation, and improves the tone of the nervous system.

The overall complex effect of Phytin is expressed in a general tonic action which, combined with its involvement in the regulatory metabolic processes, improves the intensity and stability of attention, increases performance and work capacity, removes the feeling of fatigue, and stimulates the organism's defenses through yet not entirely clear mechanisms (Torre et al., 1991).

Phytin as a food supplement is very good for prophylaxis in conditions of physical and mental strain, and for increasing general endurance during active exercise and sports. Phytin can also be included in the complex therapy of such conditions of the nervous system that are associated with phosphorous deficiency. For bone diseases, in combination with calcium preparations, it can be used rickets, osteomalacia, and bone fractures. In combination with iron preparations, it can be used for anemia in adults and children. It is recommended for insomnia and loss of appetite, either alone or in combination with various prescription drugs.

The inhibitory effect of phytic acid on the proliferation of human immune deficiency viruses (HIV), implicated as causative agents of the acquired immune deficiency syndrome (AIDS), has been tested in vitro by Japanese scientists (Otaka et al., 1989). They found that phytic acid, at a concentration of 1.67 mg/ml, inhibits the cytotoxic effect of the immune deficiency virus and the specific antigenic reaction in the effected cells.

Several studies (Nicoletti F. et al. 1989) have demonstrated an increase of calcium ion influx in cerebellar neurons. They provide evidence for a direct activating effect of phytic acid and its salts on the functional activity of the central nervous system. These data are further confirmed by other authors, who established an important role of phytic acid in the regulation of cell metabolism.

Various studies (Shamsuddin A. M. et al., 1989; Ullah A. et al. 1990) in recent years investigated the anticancer effect of phytic acid and its salts. Interesting results were obtained on experimental intestinal tumors in mice and rats. The antineoplastic effect was tested in physiologic pH. The reported anticancer activity in test animals, expressed in significant tumor reduction, suggests a likely prophylactic use for phytic acid and its salts in humans who are predisposed to intestinal and pancreatic tumors.

Repeated dose administration of Phytin has revealed no changes in the body mass and electrolytic balance, and no signs of toxicity in the test animals, even at higher doses.

The inclusion of inositol-hexaphosphate (InsP6 or IP6) as an active ingredient of fiber-rich diets is being discussed in literature. The anti-carcinogenic activity of inositol-hexaphosphate has been confirmed on in vitro and in vivo models (Shamsuddin A. M. 1996). The investigation of Graf (1993) on the inhibitory effect of phytic acid containing dietetic foods also corroborated that activity.

According to most recent studies of phytic acid as a major component of cereal grains and beans is considered an important antioxidant and is increasingly used in various therapeutic diets for its protective effect on cancer of the colon and rectum (Owen R.W. et al. 1996).

Rao P.S. et al (1991) studied the antioxidation properties of phytic acid at oral doses of up to 15 mg/100g body mass in rats for its protective effect on ischemic heart disease and found improved perfusion in the ischemic myocardial region.

 

[GaryWary]

and finally... myo-inositol is inositol-mono-phosphate. myo-inositol is the form that shows promise for dep and anxiety. inositol-hex-phosphate (IP6) converts eventually into myo-inositol (and other inositols) as it loses its phosphates.... IP6 is considered to be the better anti-cancer agent.. a combination of inositol and IP6 apparently allows for a long period of phosphate swapping.. hence Inositol-tri-phosphate IP3 is formed. IP3 is also believed to exert potent anti-cancer activity. Both IP6 and inositol are effective in treating anxiety and depression. But inositol is obviously better for this purpose.

The END. I aint posting anything else inositol related.

Probably would have been a good idea to spell inositol properly in the subject field....

inositol = myo-inositol

 

[GaryWary]

IP6 protects against hair loss and prostate cancer.

 

[GaryWary]

http://www.standardprocess.com/lit/monographs/StJohnsWortL9000.pdf

 

[GaryWary]

http://www.antidepressantsfacts.com/inositol-depr.htm

 

[FullCircle]

Big Bump for the info Gary.

This is some good shit, 2 months of inositol and psychotherapy did hundreds of times more for me than therapy alone, SSRI's, SRI's or any of the minor tranquilizers such as Xanax, Ativan, Valium, or Buspar.

To anyone considering taking these things. Do some reading of the author Peter Breggin. Toxic Psychiatry is the reason I pulled myself from all anti anxiety and depression drugs. Withdrawls are a bitch, and the drugs are nothing but a band-aid. Seek treatment of the problem, not the symptoms. Inositol is a great beginning to getting on the 'drug free' (meaning psychiatric drugs) road.

nearly all psychiatric drugs have been proven to cause everything from tardive dyskinsea, permament brain damage, cerebral ventricular enlargement (brain shrinkage), INCREASED anxiety and despair....just to name a couple.

Everyone here is obviously somewhat concerned for thier body... and the brain is the key. Don't go fucking with brain chemicals.

-FC