Beating Attention Deficit Disorder (or Nutrition and Nootropics For Focus & Attention) By James South MA
"Concentration" denotes the ability to sustain focused attention on a given object, external (such as people or rocks or colors), or internal (such as thoughts, feelings or sensations). The power of concentration also involves the ability to screen out irrelevant distractions that might divert or disrupt sustained, focused attention. Although animals can concentrate to some extent (e.g. a lion focusing on the animal chosen for its dinner), concentration as a volitional power reaches its zenith only in humans. Only humans can concentrate on things that do not yet exist (such as a building that exists only in the mind of its architect), or on such abstract notions as "infinity," "justice", or "eternity."
Yet concentration for humans is a very practical, mundane necessity of life. Psychiatrist Daniel Amen reports that adults who come to his clinic suffering from ADD (attention deficit disorder), a serious disorder of concentration, typically are concerned with poor school or work performance caused by such concentration-related symptoms as difficulty sustaining attention to reading or paperwork; tendency to being easily bored by tedious material; poor planning and organization; chronic procrastination; restlessness and non-phobic difficulty staying in confined spaces; difficulty listening carefully to directions; frequent lateness for work or appointments; and tendency to misplace things. They also frequently complain of difficulty thinking clearly; poor self-discipline, mood problems, anxiety, restlessness, drug abuse, temper problems, marital problems, insomnia, over impulsiveness, and money problems. And all of these problems in turn relate to their difficulty with sustaining attention and resisting distractions. (1)
ADD and ADHD
Amen notes that ADD has been present in some form in all four of the editions of the Diagnostic and Statistical Manual of the American Psychiatric Association, although the condition's name has changed in each edition. ADD is therefore not just some recent "fad" diagnosis. It is currently labelled "Attention Deficit /Hyperactivity Disorder" (ADHD), although many children and adults lack the hyperactivity component of the attention deficit syndrome. (2)
There is a core group of symptoms common to those who have ADD. These include difficulty focusing attention; difficulty organizing tasks, space and time; difficulty following tasks through to completion; easy distractibility; poor self-supervision; forgetfulness; and poor attention to detail and careless mistakes. (3,4)
Psychiatrist Amen diagnoses AD(H)D based in part on careful symptom questionnaires, as well as medical and family history. However, his clinic specializes in using a neuro-imaging technology called SPECT to more definitively establish the diagnosis. "SPECT" is Single Photon Emission Computed Tomography. It involves injecting a mildly radioactive substance into the patient's bloodstream which is easily taken up by brain cells. Then, either at rest or during a concentration session, a special gamma ray camera photographs the brain from multiple angles over a 15 minute period. A supercomputer then reconstructs 3-dimensional images of brain blood flow levels. (5) Clarke and Sokoloff report that neuro-imaging studies "... establish that local energy metabolism in the brain is coupled to social functional activity and confirm the local cerebral blood flow is adjusted to metabolic demand in local tissue." (6) Through the SPECT maps, physicians have been able to identify certain patterns of brain activity that correlate with psychological and neurological illnesses. (7) Amen is probably the current leading expert on SPECT imaging, having conducted about 10,000 patient SPECT studies. (8)
ADD: The 6 Types
Through his extensive clinical research conducted over the past dozen years, involving 10,000 SPECT studies and 15,000 patient evaluations, Amen has been able to subdivide ADD into 6 subtypes. (8A) Type 1, or "classic" ADD, involves a normal resting brain, but during concentration there are decreases in metabolic activity in the underside (orbito-frontal) and topside (dorsolateral) prefronal cortex. (9) It should be noted that the "lion's share" of brain metabolic activity - about 40%-goes to operating the membrane sodium-potassium pumps that make the brain electrical activity possible. (10) Thus, reduced brain metabolic activity necessarily equals reduced brain electrical activity. And since brain electrical activity drives neurotransmitter release (11), reduced brain metabolic activity also equals reduced brain neurotransmitter activity. Amen has defined the primary symptoms of "classic" ADD (really ADHD) as inattentiveness, distractibility, disorganization, hyperactivity, restlessness and impulsiveness. (12)
Type 2, or inattentive ADD, involves a normal resting brain, with reduced metabolic activity in the dorsolateral prefrontal cortex during concentration. Primary symptoms include inattentiveness, sluggishness, slow-moving, low-motivation, frequent boredom, with sufferers frequently described as spacecadets, daydreamers, or couch potatoes. (13)
Amen's Type 3 is called "overfocused ADD." SPECT findings show increased metabolic activity at rest and during concentration in the anterior cingulate gyrus, (a brain region connecting the prefrontal cortex and limbic system). During concentration there is also reduced metabolic activity in the orbitofrontal and dorsolateral prefrontal cortex. Over-focused ADD people have trouble shifting attention and frequently get stuck in negative thought or behavior patterns. They are also obsessive and worry excessively. They tend to be inflexible and are frequently argumentative and oppositional. (14)
Type 4 is temporal lobe ADD. At rest and during concentration there is decreased (occasionally increased) temporal lobe activity. During concentration there is typically reduced activity in the orbitofrontal and dorsolateral prefrontal cortex. Temporal lobe ADD symptoms include inattentiveness, impulsiveness, learning difficulties, unstable moods, irritability, dark thoughts, and aggressiveness. (15)
Type 5 is limbic ADD. SPECT findings include increased deep limbic activity (thalamus and hypothalamus) both at rest and during concentration, and decreased activity in orbitofrontal and dorsolateral prefrontal cortex. Symptoms include inattentiveness, low-grade depression, low energy, feelings of hopelessness, chronic negativity, and perceiving situations in the worst possible light. (16)
Amen's Type 6 is called "ring of fire" ADD. SPECT findings include, both at rest and during concentration, patchy increased activity across the cerebral cortex, with focal areas of increased activity, especially in the parietal lobes, temporal lobes, and prefrontal cortex. Symptoms are inattentiveness with extreme distractibility, anger/irritability, moodiness, verbosity, and extremely oppositional. (17)
Amen's book contains a 71 question questionnaire to help the reader decide if he might possibly suffer from one of the 6 ADD types. He also provides many case histories of each ADD type, with before and after treatment SPECT photographs, that are very helpful in seeing the psychological/behavioral and neurological differences among the types.
Amen's treatment regimen is extremely broad, involving biological, psychological and social interventions. (18) His biological treatments focus on eliminating toxins, including caffeine and nicotine because they decrease brain blood flow; avoiding activities with high risk of head injury; dietary changes - a high protein, low sugar diet for all except over-focused ADD; intense aerobic exercise; avoiding prolonged exposure to video and computer games; medication - including Ritalin ® or amphetamines; and nutritional supplements, including a complete multivitamin/mineral supplement, as well as St. John's Wort, 5-HTP, DL-phenylanine, tyrosine, GABA, and fish oils, with the specific supplements varying depending on the type. The interested reader is referred to Dr. Amen's book for more detail. (1)
To Ritalin ® Or Not To Ritalin ®?
Perhaps the most controversial, (at least to orthomolecular nutritionists, naturopaths, and "holistic' physicians) part of Dr. Amen's treatment regimen is his frequent use of Ritalin ® (methyl-phenidate-MPH) and amphetamines (AMP). Actually, among "mainstream" practitioners of ADD medicine, MPH and AMP are not controversial - they are routinely used to treat presumed AD(H)D cases. Yet a growing movement, led by Dr. Peter Breggin, challenges the need, safety and efficacy of MPH/AMP use in children or adults. (19) Breggin points out that the effects of MPH and AMP are almost identical, and that neither are safe. (20) Breggin quotes a 1995 DEA report that "The potential adverse effects of methylphenidate and d-amphetamine are almost identical." (21) These potential side effects include heart palpitations, increased heart rate, increased blood pressure, excessive CNS stimulation (including convulsions), toxic or organic psychosis, depression, dizziness, headache, insomnia, nervousness, irritability, tic syndromes, appetite loss, nausea, vomiting, stomach pain, weight loss, growth suppression, blurred vision, low white blood cell count, anemia and hypersensitivity reactions. (22) Breggin also provides evidence that MPH/AMP may cause gross brain malfunction/brain damage, especially in children, whose brains and synaptic connections are still developing. (23) Breggin also cites extensive evidence that MPH/AMP may promote what he calls "the zombie effect," snuffing out enthusiasm, curiosity, initiative, spontaneity, and exploration, while making children obsessed with meaningless, robotic activities, and turning them into compliant, docile "robots." (24) Anyone who is on, or who has a child on MPH/AMP, or who is considering MPH/AMP for their child or themselves, should definitely read Breggin's book before making a final decision on MPH/AMP use, especially since there are many non-toxic nutritional/nootropic treatments that may work well in improving concentration and focus.
The Neurobiology Of Attention 101
In order to understand the rationale for the nutritional/nootropic treatments offered later in this article, it may be helpful to gain at least a brief overview of the neurobiology of attention. Over the past 50 years, neuroscience has identified four distinct components that make up the brain's attention system: arousal, motor orientation, novelty detection and reward, and executive command. "At the lowest level, the brainstem maintains our vigilance - our general degree of arousal. At the next level, the brain's motor centers allow us to physically reorient our bodies so that we can redirect our senses [as needed]. Then, the limbic system accomplishes both novelty detection and reward. Finally, the cortex-especially the frontal lobes - commands action and reaction and integrates our attention with short - and long-term goals." (25)
Arousal is mediated through circuits which connect the brain stem reticular activating system (especially the noradrenaline-using locus coeruleus [LC] and the dopamine-using ventral tegmental area [VTA] with the prefrontal cortex, posterior cortex, limbic system (including thalamus and nucleus accumbens) and sense organs. (26,27) The LC and VTA are essential in activating the frontal lobes - the most distinctively human brain structures. Under-activity of the LC or VTA may in turn lead to underactive frontal lobes (28,29) - a routine finding in Amen's SPECT studies.
The brain's motor centers help us focus/refocus attention in three steps. First, the posterior parietal cortex helps us disengage from a stimulus. Then, the basal garglia and frontal parietal attention circuits shift the focus of attention to something new. Finally, neurons in the thalamus engage attention by focusing the brain on the new stimulus while inhibiting other distracting signals. (30) Once we are aroused and oriented, the brain's novelty/reward system is activated, governed by VTA dopamine neurons. The VTA-limbic system (hippocampus) circuit takes note of novelty, while the nucleus accumbens in the limbic system is a key part of the reward system. The nucleus accumbens is well-connected to the VTA dopamine system, as well as other parts of the limbic system. (27,31)
Damage to or under-activity of the reward system leads to difficulty sustaining attention to matters that don't provide instant gratification. (32) People with "reward deficiency syndrome" are often impulsive, lack inhibitions, and are quick to act because they are "hooked" on immediate positive feedback. Monkeys with lesions in the nucleus accumbens are unable to sustain attention. (33)
The fourth system of attention-executive command - directs our actions and integrates attention with our goals, and is centred in the frontal lobes, especially the prefrontal cortex. The frontal lobes also interact with the posterior (sensory) cortex, inhibiting the posterior cortex from raising irrelevant, distracting stimuli to focal awareness. (28) "The frontal lobes ... are linked to intentionally, purposefulness and complex decision making .... They co-ordinate and lead other neural structure in concerted action. The frontal lobes are the brain's command post .... even subtle damage to the frontal lobes produces apathy, inertia, and indifference ....
ADD and ADHD are caused by subtle dysfunctions of the frontal lobes and the pathways connecting them to other parts of the brain .... True to its 'executive' functions, the prefrontal cortex is probably the best connected part of the brain. The prefrontal cortex is directly interconnected with every distinct functional unit of the brain.... Of all the structures in the brain, only the prefrontal cortex is embedded in such a richly networked pattern of neural pathways." (34) From this brief description of the neurobiology of attention, several things should be obvious.
1) Concentration (focused attention) is a whole-brain activity. Virtually every part of the brain is involved in mediating attention. 2) While almost every brain structure is essential to making concentration possible, the prefrontal cortex is "first among equals." Under-activity (or over-activity, in "ring of fire" ADD) of the prefrontal cortex is the common denominator of all 6 ADD types described by Amen.
The Brain Is Easily Wounded
Neurologist/neuropsychiatrist Elkhonen Goldberg emphasizes repeatedly in his book The Executive Brain that the frontal lobes are easily wounded. Thus he notes "The frontal lobes are exceptionally fragile .... When neurological illness affects the frontal lobes, the ability to stay on track becomes lost, and the patient is completely at the mercy of incidental environmental stimuli and tangential internal associations.... attention deficit hyperactivity disorder (ADHD), with its extreme distractibility, is usually linked to frontal lobe dysfunction.... deficit of attention is among the most common consequences of brain damage .... In most such [ADHD] cases biochemical disorder affecting the frontal lobe connections is present, but there is no structural damage to the frontal lobes .... Damage to the frontal lobes produces wide ripple effects through the whole brain. At the same time, damage anywhere in the brain sets off ripple effects interfering with frontal lobe function." (36)
Optimizing Brain Function To Enhance Concentration
Concentration is not an all-or-nothing state. There are gradations in concentration, from none (in coma) to the extremely high level of a chess grandmaster focusing on 20 moves ahead of his current move on the chessboard. ADD represents a significant impairment of attention, but even in ADD it's not all-or-nothing. Both Amen and Goldberg note that attention deficit in ADD is often selective. (37, 38) Things that are novel, stimulating, interesting or frightening provide enough stimulation (through adrenaline release) to help ADD people pay attention in these contexts. It is the routine, mundane, boring, trivial, rote activities that fail to stimulate ADD brains to concentrate. Similarly, attention is not at a fixed level in "normal" people, either. The more healthy overall brain function is (especially frontal lobe function), the more effective and effortless concentration becomes. Thus, both ADD sufferers and "normal" people can improve their concentration abilities through optimizing their brain function. Various nutritional strategies and nootropic drugs can synergistically improve neural function, often dramatically.
Glucose is the principal brain fuel. Most other cells and organs of the body are able to "burn" fat as well as glucose to produce ATP bioenergy, but brain neurons can only burn glucose under normal, non-starvation conditions. (39) The brain is only 2% of the body mass, yet typically consumes 15-20% of total body ATP energy. (40) The brain is dependent on a second-by-second delivery of glucose from the bloodstream, as neurons can only store about a 2-minute supply of glucose (as glycogen) at any given time. (39) The brain must routinely have access to a large portion of the glucose flowing through the bloodstream.
Yet the modern high sugar, high refined carbohydrate (CHO) lifestyle creates serious potential problems for the brain. Unlike most other body tissues, the brain does not require insulin to absorb glucose from the blood. (39) Thus, the optimal blood status for the brain to acquire its disproportionately large share of blood sugar is a normal blood sugar level (70-100 mg %) combined with low blood insulin. When insulin is low or absent in the bloodstream, the rest of the body will ignore the blood sugar and burn fat or amino acids for their fuel.
The chief stimulant for insulin release is CHO. (41) A surge in blood sugar (glucose) from rapidly absorbed dietary sugar/refined starch may increase insulin levels 10-fold within minutes, and keep on increasing insulin to even higher levels for 2-3 hours. (41) This will cause a rapid glucose uptake by almost all body tissues, leaving far less than optimal supplies for the brain. (42)
The modern Western diet typically contains 50% or more of its calories as CHOs, mostly as simple sugars and refined (de-fibered) starches. Many ADD sufferers (and "normal" people, as well) start their day with a super-CHO breakfast. Cereal with sugar or fruit, toast or muffin and jam, waffles or pancakes with sugar syrup, doughnuts, pastries, "pop-tarts," etc. are "normal" breakfast foods in much of Europe and America. Many people consume mid-morning snacks of doughnuts, pastries or croissants with sugar-laced coffee. Many people routinely eat lunches rich in bread, pasta, potatoes, rice, corn/potato chips, etc. topped with sugary desserts. Dinners are also often CHO-rich: pizza. pasta, potatoes, bread, chips, sugary dessert, etc. And these high-CHO meals are often washed down with sugar-rich soft drinks. The typical Western diet is a virtual recipe to promote hyperinsulinism, with consequent reactive hypoglycaemia (low blood sugar following CHO-rich meals).
Hypoglycaemia & Attention
Dr. Stephen Gyland was an American physician in the 1950s who studied 1307 cases of hypoglycaemia from his clinical practice. (43) Among his hypoglycaemia patients, 89% suffered from irritability, 67% forgetfulness, 57% mental confusion, 50% indecisiveness, 43% in-coordination, and 42% lack of concentration. (44) These are all signs of hypoglycaemia's negative effects on the brain. Goldberg notes that indecisiveness is a classic indicator of poor frontal lobe function. (45)
Bonnie Spring and colleagues reported an experiment that compared high protein and high CHO meals. They observed that among older (40 or above) subjects eating a high CHO lunch, attention was significantly impaired in performance tests. (46) Gibson and Blass state that "... a high carbohydrate diet (78%) low in fat (12%) and low in protein (10%) markedly decreases brain glucose utilization.... even marginal protein dietary deficiency when coupled with a carbohydrate-rich diet suppresses cerebral glucose utilization to a degree often seen in metabolic encephalopathies [brain diseases]." (47)
Amen reports that he has found a high simple CHO diet makes concentration problems worse for most people, especially those prone to ADD. He has found that most ADD children and adults function better on a high protein, low simple CHO (sugar) diet. (48)
Thus, the simplest method of enhancing focus and attention is to adopt a high protein, low simple CHO diet. Reduce or eliminate sugar-and-flour-rich foods, and derive CHOs mainly from nuts, seeds, beans, and peas (moderate quantities) and low-CHO vegetables, Avoid sugar-laden soft drinks and sugar-laced coffee.
As noted earlier, the brain must use 15-20% of the body's total ATP energy supply. Neurons cannot borrow this ATP from other cells - it must all be produced within the brain from the metabolism of glucose. The conversion of glucose to ATP energy occurs in 3 stages inside each neuron. The 3 interlocking phases of glucose metabolism are glycolysis, the Kreb's or citric acid cycle, and the electron transport chain (ETC). The Kreb's cycle and ETC both occur inside the mitochondria, the tiny "power plants" of the cell, and produce most of the cell's ATP. Various enzymes gradually convert glucose to ATP. These enzymes require an activating partner, a "coenzyme" to function properly. The coenzymes are all active forms of various B vitamins. The vitamins used in the 3 interlocking ATP cycles are vitamins B1 (thiamin), B2 (riboflavin), B3 (niacinamide), B5 (pantothenate), biotin, and the B-vitamin-like substance alpha-lipoic acid, as well as coenzyme Q10. Other B vitamins, such as B6 (pyridoxine), B12 (cobalamin) and folic acid are used to transform various amino acids into forms that allow small quantities of them to be "burned" in the Kreb's cycle. (49) These vitamins must be converted to their active, or coenzyme, forms to become functional. E.g., B1 becomes thiamin pyrophosphate, B3 becomes nictinamide adenine dinucleotide, etc.
It was Linus Pauling, in 1968, who first observed that dietary and blood levels of various B vitamins that are adequate to feed all the other cells of the body, may not be adequate to nourish the brain. This is due to the blood-brain barrier (BBB). (50) The BBB serves to protect the vulnerable brain from many toxins, but it is primarily water-soluble substances that the BBB excludes. (40) All the B vitamins are water-soluble, and are only poorly transported across the BBB. Thus, Pauling noted that many people (especially those with any form of brain malfunction), may require much higher than RDA (recommended dietary allowance) levels of vitamins to achieve high enough blood levels to "push" adequate amounts of B vitamins through the BBB. (50)
As one clinical example of this phenomenon, Lonsdale and Shamberger reported in 1980 that 20 patients consuming a "junk food" diet showed biochemical evidence of a serious thiamin deficiency, and presented with symptoms similar to ADHD. When supplemented with 150-300 mg thiamin/day, their behavioral problems improved - yet the 1980 RDA for thiamin was only 1.7mg. (51) In his classic book Nutrition and Vitamin Therapy, psychiatrist M. Lesser reported inability to concentrate, poor memory, apathy and slowing of intellectual processes as consequences of deficiency in vitamins B1, B3, B6, B12 and folic acid. (52) Lesser also routinely recommends B vitamin supplementation at higher-than-RDA levels for optimal mental health and functioning. (52)
A simple nutritional method to improve mental energy and concentration is the routine supplementation of B vitamins, alpha-lipoic acid, and CoQ10 (or its improved analogue, idebenone). Lipoic acid and idebenone also provide important antioxidant benefits to the brain, as well. Lipoic acid, and its inter-convertible reduced form, dihydrolipoic acid (DHLA), scavenge a broad range of free radicals and oxidants, including hydroxyl/radicals, peroxynitrite, hydrogen peroxide, singlet oxygen, superoxide radical, and peroxyl radical. (65)
DHLA also recycles the major cell antioxidants vitamin E, vitamin C, glutathione and CoQ10. (65) Idebenone reduces oxygen radical formation, and is a far more effective antioxidant than CoQ10. (66,67) These benefits are especially important to the brain, as it has relatively poor antioxidant defences, and increasing brain mitochondrial energy production will also increase free radical formation. (65)
Typical daily doses would be 10-100mg B1 and B2, 50-250 mg B3; 50-200 mg B5; 25-100 mg B6; 1-5 mg B12; 0.5-10 mg biotin; 0.8-5 mg folic acid; 50-200 mg alpha-lipoic acid; 50-100 mg CoQ10 or 45-90 mg idebenone. For those wishing a "hi-tech" approach, a sublingual coenzyme B formula with CoQ10 is available. I formulated this product for Source Naturals in the early 1990s. It contains coenzyme B1, B2, B3, B6 and B12. It also contains pantetheine, a form of B5 that is more easily converted to coenzyme form than B5, as well as folic acid, biotin, and CoQ10. The sublingual form is best, because the coenzyme will be absorbed directly into blood vessels in the mouth. When coenzyme Bs are swallowed, they are broken down by intestinal lining enzymes during digestive absorption. Methylcobalamin is the "neuro-active" form of B12. It is also now available in 1 and 5 mg sublingual tablets.
For more detailed information on energy metabolism, B vitamins, the RDA vs. optimal vitamin levels, etc., the reader is referred to my article "Tired of Being Tired?" in the Winter 1999 IAS Anti-Aging Bulletin.
Magnesium: Mineral For The Mind
Magnesium (Mg) is the activator mineral for over 300 different enzymes - more than any other mineral. (53) Mg serves as the mineral activator for most of the enzymes of the glycolytic and Krebs' cycles. (54) Once ATP is produced, it is normally complexed with Mg for stable storage. (55) Mg activates sodium potassium ATPase, the membrane pump which transfers sodium and potassium across neural membranes to allow repeated bursts of electrical nerve activity (56), and which consumes up to 40% of neural ATP. (10) Mg regulates the activity of NMDA glutamate receptors, and thus glutamate nerve activity. (57) Glutamate nerves are the chief excitatory nerves, and are the primary neurons, along with the GABA nerves, in the brain areas connected with attention: the frontal cortex, hippocampus, striatum, thalamus, hypothalamus, and posterior cortex. (58)
Given Mg's myriad roles in human physiology, it is perhaps not surprising that cellular Mg deficiency leads to a wide variety of symptoms: anxiety, fear, restlessness, poor attention, confusion, memory loss, mood changes including depression, lack of co-ordination, appetite loss, weakness, insomnia, muscle tremors, disorientation, learning disability, apathy, fatigue, heart disturbances, problems in nerve conduction and muscle contraction, muscle cramps, and predisposition to stress, to name just a few! (59 - 62) Note that many of these symptoms are common to ADHD.
Is Mg deficiency common enough to think that it might play a role in difficulties with attention, memory, learning abilities, restlessness, etc.? Actually, most people in the Western world are probably at least marginally Mg deficient. Dietary surveys show women on typical Western diets to average 175-225mg Mg/day, men 225-275mg Mg/day. A typical modern "junk food" diet, consisting primarily of soft drinks, hot dogs, hamburgers, white bread, French fries, cheese, pastries, candy, pizza, snack chips, etc. might fail to provide even 200mg Mg/day. The RDA for Mg has been set at 300-400mg/day. Yet Mg "guru" Mildred Seelig, M.D., has done extensive research which indicates that 8mg/kg body weight is probably a more optimal intake level. (63) This would be a 560mg/day requirement for a 70kg (154 pound) person.
In addition, there are many factors that impair intestinal absorption of Mg. High intake of phosphate (common in meat, soft drinks and baked goods) calcium, fat, phytate (found in unleavened bread and wheat bran), lactose (milk sugar), oxalate (found in spinach, rhubarb, chocolate), and alcohol, as well as laxative abuse, all inhibit intestinal Mg absorption. (53, 59, 60) Healthy kidneys may reabsorb up to 95% of Mg before it is lost in the urine, yet many factors promote Mg urinary loss: the stress hormones adrenaline and cortisol, diuretics (including caffeine), some antibiotics, digoxin, alcohol, high sodium/calcium/sugar intake (i.e. the typical western diet) and birth control pills, among others. (53, 59, 64) Thus anyone who lives the typical modern high stress/ high fat and sugar/ high soft drink/ high coffee and alcohol lifestyle may be an appropriate candidate for Mg supplementation, with increased focus, attention, stress resistance, memory and learning powers as possible benefits. However, Mg repletion at the cellular level is a slow process, and may take weeks to months to achieve maximum benefit. Most people can safely and beneficially take 100 - 200mg Mg 2 - 3 times daily (with some at bedtime for insomniacs). If diarrhoea develops, reduce dosage and /or frequency. Anyone with serious kidney disease should check with a nutritionally knowledgeable physician before adding Mg. Best supplement forms are Mg malate, orotate, succinate, taurinate, glycinate and chloride.
Nootropics For Alertness & Attention
Nootropic drugs are one of the premier classes of proven anti-aging drugs. They are especially effective at enhancing memory, alertness and attention. The concept and definition of a nootropic drug was first proposed by Giurgea in 1973. The characteristics of a nootropic drug include:
enhancement of learning and memory (and concentration is the gateway to learning and memory);
enhancing the resistance of learning and memory to conditions which tend to disrupt them (e.g. electroconvulsive shock, poor brain blood flow);
protection of the brain against various physical and chemical injuries (e.g. barbiturates, scopalamine);
lack of the usual pharmacology of other psychotropic drugs (e.g. sedation, stimulation, restlessness, etc.) and possessing very few and only minimal side effects and very low toxicity. (68) Considering that concentration is a whole-brain activity, that decreased brain blood flow and energy metabolism (especially in the frontal lobes) is a key element in decreased attention, and that "deficit of attention is among the most common consequences of brain damage" (36) the following nootropics are excellent aids to enhanced focus and attention.
Vinpocetine (VPC) is a slightly altered form of vincamine (VCM), an alkaloid extracted from the Periwinkle plant, vinca minor. In use for almost 30 years, research has gradually shown VPC to be the superior vinca alkaloid, having few and minor if any side effects, with a greater range of metabolic and clinical benefits than VCM. VPC has been shown to be a cerebral metabolic enhancer and a selective cerebral vasodilator (i.e. one which increases blood flow only to brain regions where it is compromised). (69, 70) VPC has been shown to enhance oxygen and glucose uptake from blood by brain neurons, and to increase neuronal ATP energy production, even under hypoxic (low oxygen) conditions. (71, 72) Both animal and human research has shown VPC to restore impaired brain carbohydrate/energy metabolism. (69, 73)
An important objective measurement of impaired concentration and alertness is the EEG (electroencephalogram) record. In 1991 J. Lubar published his results of 15 years of EEG research on ADD subjects. Comparing ADD children to normal controls, he discovered that ADD children "...produce excessive theta activity in the 4-8 Hz [cycles/second] range and were particularly deficient in beta [14 Hz and above] production .... Specifically, increased theta activity was obtained in many [brain regions] particularly frontal and centrally .... Decreased beta activity was found in many frontal and temporal locations." (74) EEG is a measure of brain electrical activity. Theta (slow wave activity) is typical of deeply sedated mental states, while beta is associated with concentration and focused mental activity. Saletu and Grunberger report that "Human brain function as measured by ... [EEG] shows significant alterations in normal and pathological aging characterised by an increase of [slow wave] delta and theta activity and a decrease of alpha and ... beta [fast wave] activity.... These changes are indicative of deficits in the vigilance regulatory systems. By the term vigilance we [mean] the ...dynamic state of total neural activity [remember - concentration is a whole brain activity] .... Elderly subjects with bad memory exhibit slower [EEG] activity and less ... beta activity than those with good memory .... nootropic drugs such as ... vincamine alkaloids [VPC & VCM] induce interestingly just oppositional changes [to the age-related slowing of EEG waves] in human brain function, thereby improving vigilance [and attention]." (75) Two things follow from this:
1) both the normal and pathological aging brain become more and more like an ADD child's brain; and 2) VPC can reverse these ADD-like brain states to more normal alert and attentive brain states!
VPC has very few side effects and is extremely non-toxic (76), although some experts caution against its use in pregnant women. (76) Gastric upset, increased heart rate, and skin rash are the main (rarely occurring) reported side effects. A dose of 2.5 - 5mg 2 to 3 times daily is generally safe and effective. Taking VPC right after a meal reduces chance of gastric upset.
Piracetam (PIR) is the original nootropic drug, for which the category was first defined. (68) PIR is one of the least toxic drugs ever discovered: "Piracetam is apparently virtually non-toxic .... Rats treated chronically with 100 to 1,000 mg/kg orally for 6 months and dogs treated with as much as 10 gm/kg orally for one year did not show any toxic effect." (77) For a human equivalent, 10 gm/kg would be 700 gm (11Ú2 pounds!) for a 70 kg (154 pound) person. PIR has been shown to improve memory, EEG, alertness and mental performance in a wide variety of human clinical studies. PIR restored normal EEG and state of consciousness in people suffering acute and chronic cerebral ischaemia (decreased brain blood flow). (78, 79) PIR has improved alertness and IQ in elderly psychiatric patients suffering from "mild diffuse cerebral impairment." (80) PIR increased memory and verbal learning in dyslexic children, as well as speed and accuracy of reading, writing and spelling. (81,82) PIR has improved mental performance in "aging, non-deteriorated individuals" suffering only from "middle-aged forgetfulness." (83) Elderly outpatients suffering from "age-associated memory impairment" given PIR showed significant improvement in memory consolidation and recall (84), and as Smith and Lowrey note in a study on concentration in elderly subjects, "Concentration is intimately involved in the process of reception, storage, and recall [of memories]." (85) Like VPC, PIR reversed typical EEG slowing (which mimics the EEG of the ADD brain state) associated with normal and pathological human aging, increasing beta (fast) EEG activity, while simultaneously increasing vigilance, attention and memory. (86) In a 1987 study, Grau and co-workers fed rats i.v. radioactive deoxyglucose to help measure brain metabolism. Compared to saline controls, PIR rats had a 22% increase in whole brain glucose metabolism, while the increase in 12 specific brain regions ranged from 16 to 28%. The increase in brain energy metabolism occurred under normal oxygen conditions. (87) And remember - decreased brain energy metabolism equals reduced focus and attention, while increased brain energy metabolism equals enhanced focus and attention.
Typical PIR dosages range from 800 - 1600 mg 2 to 4 times daily. PIR may (very rarely) cause headache, insomnia, over-stimulation or irritability. This is most likely to occur in heavy caffeine-users, or those taking high doses of other nootropics. I have personally used PIR continually for 12 years and have never noticed any side effects from it. Along with VPC, it is one of my favorite concentration-enhancing drugs.
Deprenyl, (DPR), also called selegiline, is a popular anti-aging drug.
It is a potent neuroprotector. (88) It is also a selective MAO-B inhibitor. (88) MAO-B is the neuro-enzyme that breaks down the neurotransmitter dopamine (DA) and the neuromodulator phenylethylamine (PEA). DPR and its "cousin" PEA are catecholamine activity enhancers (CAE). (88) Catecholamines include DA, noradrenaline (NA) and adrenaline. DA and NA are the neurotransmitters for the key activating brain circuits: the mesolimbic-cortical (MLC) circuit and the locus coeruleus (LC). The MLC and LC both activate the frontal lobes, and are critical for maintaining focus, alertness, concentration, and effortful attention. (89)
The pioneering research of Dr. Joseph Knoll has shown DPR and PEA serve to more effectively couple the release of DA/NA to the electrical impulse that triggers their release, thus enhancing the activity of the MLC and LC attention circuits. (88) DPR also increases brain levels of PEA dramatically. (88) Baker and colleagues presented evidence in 1991 that a deficiency of brain PEA may play a role in ADD, and that this may result in part from a deficiency of the amino acid phenylalanine, the precursor of PEA. (90) A 1984 study showed a unique synergy between DPR and phenylalanine in treating anti-depressant drug-resistant depression patients. (91) Thus a combination of 1.5 - 5mg DPR daily plus 250 mg phenylalanine may prove helpful to those who suffer impaired concentration and attention connected with a "spacey," "foggy," under-aroused state of consciousness. DPR has been shown to increase attention, alertness and memory in various Alzheimer disease studies. (89, 92) In some cases, DPR, with or without phenylalanine, may lead to over-stimulation, irritability, or insomnia. Reduce dosage or discontinue if this occurs.
DMAE & Lucidril
Centrophenoxine (CPH), also known as Lucidril and meclofenoxate, is one of the oldest nootropic drugs - it was developed in 1959. (93) Imre. Zs.-Nagy, M.D. the world's most prolific CPH researcher, has called CPH a "brain metabolic stimulant" and a "neuroenergeticum" - i.e. a neuroenergizer. (93)
CPH "stimulates glucose uptake, oxygen consumption, and carbon dioxide production in vivo [in the living organism] ...." (94) "...centrophenoxine can stimulate cerebral electrical activity in the aging brain." (93) Increased brain metabolic and electrical activity are the basis for improved attention and alertness. "Clinical studies with [CPH] in geriatric patients with such symptoms as confusion ... and disturbances of memory and intellectual concentration revealed marked improvement after several weeks of treatment .... Clinical studies in European literature have reported a significant improvement of such symptoms as fatigue, irritability, confusional states [the opposite of alert, focused attention] and improvement of memory in the geriatric patients treated with centrophenoxine." (95)
CPH is a combination of two other biochemicals - DMAE (dimethylaminoethanol) and PCPA (paarachlorophenoxyacetic acid). DMAE is a natural brain constituent, closely related to choline. (93) CPH is, in effect, a super-DMAE: "Pharmacokinetic studies of CPH revealed that ... much higher levels of DMAE were found in the brain after CPH treatment, as compared to DMAE, alone, since apparently the esterified form of DMAE with PCPA penetrates much easier the blood-brain barrier." (94) This is significant, because DMAE was used successfully to treat children suffering form "minimal brain dysfunction" (the earlier name for ADHD) during the 1958 - 75 period, with increased attention span as the result. (96 - 98) Thus CPH can be expected to provide even better results in improving attention.
CPH is considered an extremely non-toxic drug. (93) Doses used in human clinical studies are typically 250 - 1,000 mg twice daily (breakfast and lunch). (93) For use in enhancing focus and attention span, where no major brain pathology is present (that would increase dosage), 250 mg once or twice daily is a generally safe and useful dose. Although CPH is generally safe and non-toxic, there are a few precautions to its use. CPH is a powerful enhancer of brain acetylcholine (ACh) levels. (93) Excessive brain/peripheral nervous system levels of ACh can lead to headaches, neck/jaw/shoulder muscle tension, insomnia, irritability, agitation and depression. This is NOT a toxicity reaction - it is simply too much of a good thing, ACh. If any of these symptoms occur, simply discontinue CPH for several days, then try a reduced dosage. Those especially sensitive to CPH may need to take it only on alternate days to avoid ACh excess. Any persons suffering from major depression, mania, seizure disorders or Parkinson's disease should avoid CPH, as too much ACh may worsen these conditions. Also, pregnant women should avoid CPH.
Pyritinol (PYR) is a nootropic that had been in use over 40 years. PYR is closely related to pyridoxine (vitamin B6), but it has no B6 activity. (99) PYR is a compound of 2 pyridoxine molecules which are joined together by 2 sulphur atoms. (99) "[PYR] has been shown to increase glucose uptake and utilisation, tending to normalize or increase transport across the blood-brain barrier. Oxygen consumption ... and cortical acetylcholine release are ... improved by the drug. Nerve cells may be protected in cerebral deficiencies, with cell membrane structures and functions undergoing improvement after damage, and regional blood flow increases [after damage]. Pyritinol has also been shown to produce a vigilance [alertness] response, both behaviourally and electrophysiologically (EEG recordings) in animals and healthy human volunteers ....
Clinical research has shown that pyritinol 600 - 800 mg per day is effective in improving ... activity, alertness, mental power, interest and emotional stability in individuals suffering from mental insufficiency and clinical dementia. (99) In a South African study on PYR with hyperkinetic and learning-disabled children, it was noticed during the placebo-controlled trial that "... 8 children in one of the [test] groups were making great strides in many ways: drive, alertness and concentration were improving .... These 8 pupils were all in the [PYR} group." (100) In a study of PYR in senile dementia (Alzheimer and stroke dementia), "... EEG mapping demonstrated significant differences between placebo and pyritinol, with the latter decreasing slow [theta/delta] and increasing fast alpha and beta activity, which reflects improvement of vigilance [attention]." (101) PYR is generally a very safe nootropic, with few and mild side-effects. (101, 103) However, in a study of those suffering severe rheumatoid arthritis and taking high dose (600 mg/day) long term (1 year) PYR, there was a 2% incidence of serious side-effects. (102) For those wishing to use PYR to enhance general brain function and improve concentration, 100 mg once or twice daily (breakfast and lunch) is a reasonable dosage regimen.
As this article has indicated, concentration is a function of whole-brain activity and health, and impaired attention is a natural consequence of any brain damage - structural or functional. For most people not suffering any major brain damage or pathology, simply adopting a high protein/ low sugar and refined carbohydrate diet, combined with a good B complex vitamin, Mg, CoQ10 or idebenone, and lipoic acid, will promote improved focus, alertness and attention span.
For those wishing to "go the extra mile," adding one or more of the nootropics discussed above will usually provide even further benefit. I have personally interviewed many (more or less) healthy people who use one or more of these nootropics in their health regimens, who have found noticeably enhanced alertness, concentration and memory.
I have used nootropics for many years to aid in the intense concentration and focus I need to get through the dense, technical, tedious and often boring books and papers I have to read to write my many anti-aging/ nootropic / nutritional articles. They do work!
1. D. G. Amen, (2001) Healing ADD N.Y.: G.P. Putnam's, p.38.
2. Amen, p.12
3. Amen, p. 77
4. D. Miller & K. Blum (1996) Overload: Attention Deficit Disorder and the Addictive Brain Kansas City: Andrews & McNeel, pp. 21-25.
5. Amen, pp.44-58 6. G.J. Siegal et al (ed.) (1999) Basic Neurochemistry Philidelphia: Lippincott Williams & Wilkins, p.656.
7. Amen, p.47
8. Amen, p. 58 8A. Amen, p.67
9. Amen, p.61
10. Siegel, p.100
11. Siegel, pp.192-206.
12. Amen, p.62
13. Amen, p.63
14. Amen, pp62-63.
15. Amen, p.63
16. Amen, p.65
17. Amen, pp.65-66
18. Amen, pp.209-379.
19. P.R. Breggin (1998) Talking Back To Ritalin Monroe, ME: Common Courage Press.
20. Breggin, pp.6-65.
21. Breggin, p.11.
22. Breggin, pp.11-20.
23. Breggin, pp.38-55.
24. Breggin, pp.56-65.
25. J.J. Ratey (2001) A User's Guide to the Brain N.Y.: Vintage Books, p.115.
26. Ratey, p.115.
27. Pliszka, S.R. et al (1996) "Catecholamines in Attention Deficit Hyperactivity Disorder: Current Perspectives J Am Acad Child Adolesc Psychiatry 35, 264-72.
28. Arnsten, A.F. et al (1996) "The Contribution of alpha2-Noradrenergic Mechanisms to Prefrontal Cortical Cognitive Function" Arch Gen Psychiatry 53, 448-55.
29. Heilman, K.M. et al, (1991) "A Possible Pathophysiologic Substrate of Attention Deficit Hyperactivity Disorder" J Child Neurol 6(suppl), s74 - s79.
30. Ratey, p.116.
31. Ratey, p.117.
32. Miller & Blum, pp.55 - 67.
33. Ratey, p.117.
34. E. Goldberg (2001) The Executive Brain: Frontal Lobes and the Civilized Mind N.Y.: Oxford Univ. Press, pp.2 - 4, 35 - 36. 35. Amen, p.101. 36. Goldberg, pp.4, 129, 172, 114.
37. Amen, p.13.
38. Goldberg, p.173. 3
9. A.C. Guyton & J.E. Hall (2000) Textbook of Medical Physiology Philadelphia: W.B. Saunders, p.715.
40. Guyton & Hall, p.174.
41. Guyton & Hall, pp.890-91.
42. Guyton & Hall, p.886.
43. R.C. Wunderlich, Jr. (1982) Sugar and Your Health St Petersburg, FL: Good Health Publications, pp.291-92.
44. C. Fredericks (1985) New Low Blood Sugar and You N.Y.: Perigee Books, p.40.
45. Goldberg, p.79.
46. Spring, B. et al (1982/83) "Effects of Protein and Carbohydrate Meals on Mood and Performance: Interactions with Sex and Age" J Psychiat Res 17, 155-67.
47. Siegel, p.694.
48. Amen, p.25.
49. R.L. Pike & M.L. Brown (1984) Nutrition: An Integrated Approach N.Y.: Macmillan Pub., pp.423-27, 463-78.
50. Pauling, L. (1968) "Orthomolecular Pschiatry" Science 160, 265-71.
51. Lonsdale, D. & Shamberger, R. (1980) "Red Cell Transketolase as an Indicator of Nutritional Deficiency" Am J Clin. Nutr 33, 205-11.
54. R. Garrison & E. Somer (1995) The Nutrition Desk Reference New Canaan: Keats, p.159.
55. C. Mathews & K.van Holde (1990) Biochemistry Redwood City CA: Benjamin/Cummings Pub., p.84.
56. M.H. Stipanuk (2000) Biochemical and Physiological Aspects of Human Nutrition Philadelphia: W.B. Saunders, p.679
57. South, J. (2001) "Excitotoxins: the Ultimate Brainslayer IAS Anti-Aging Bulletin, 4(10) 14-27.
58. Greenamyre, J. & Porter, R. (1994) "Anatomy and Physiology of Glutamate in the CNS" Neurol 44 (suppl), s7-s13.
59. A.R. Gaby (1994) Magnesium New Canaan: Keats, p.13.
60. Garrison & Somer, p.160.
61. R.A. Passwater & E.M. Cranton (1983) Trace Elements, Hair Analysis and Nutrition New Canaan: Keats, p.68.
62. M.T. Murray (1996) Encyclopedia Of Nutritional Supplements Rocklin CA: Prima Pub., pp.159-61.
63. Seelig, M.S. (1981) "Magnesium Requirements in Human Nutrition" Mag Bull 3, 26-41.
64. Lesser, pp.112-13.
65. Packer, L. et al (1997) "Neuroprotection by the Antioxidant alpha-Lipoic Acid" Free Rad Biol Med 22, 359-78.
66. Weiland, E. et al (1995) "Idebenone Protects Hepatic Microsomes against Oxygen Radical-Mediated Damage in Organ Preservation Solutions" Transplantation 60, 444-51.
67. Sugiyama, Y. & Fujita, T. (1985) "Stimulation of the Respiratory and Phosphorylating Activities in Rat Brain Mitochondrin by Idebenone (CV - 2619), a New Agent Improving Cerebral Metabolism" FEBS Letters 184, 48-51.
68. Giurgea, C. (1973) "The 'Nootropic' Approach to the Pharmacology of the Integrative Activity of the Brain" Cond Reflex 8, 108-15.
69. Vamosi B. et al (1976) "Comparative Study of the Effect of Ethyl Apovincaminate and Xanthinol Nicotinate in Cerebrovascular Diseases" Arzneim Forsch (Drug Research) 28, 1980-84.
70. Solti, F. et al (1976) "Effect of Ethyl Apovincaminate on the Cerebral Circulation" Arzneim Forsch (Drug Research) 28, 1945.
71. Karpaty, E. & Szporny, L. (1976) "General and Cerebral Haemodynamic Activity of Ethyl Apovincaminate" Arzneim Forsch (Drug Research) 28, 1908 - 12
72. Szobor, A. & Klein, M. (1976) "Ethyl Apovincaminate Therapy in Neurovascular Disease" Arzneim Forsch (Drug Research) 28, 1984-89.
73. Biro, K. et al (1976) "Protective Activity of Ethyl Apovincaminate on Ischaemic Anoxia of the Brain" Arzneim Forsch (Drug Research) 28, 1918 - 20.
74. Lubar, J.F. (1991) "Discourse on the Development of EEG Diagnostics and Biofeedback for Attention-Deficit/ Hyperactivity Disorders" Biofeedback and Self-Regulation 16, 201-25.
75. Saletu, B. & Grunberger, J. (1985) "Memory dysfunction and Vigilance: Neurophysiological and Psychopharmalogical Aspects" Ann NY Acad Sci 444, 406-27.
76. Cholnoky, E. & Domok, L. (1976) "Summary of Safety Tests of Ethyl Apovincaminate" Arzneim Forsch, 28, 1938-44.
77. Tacconi, M. & Wurtman, R. (1986) "Piracetam: Physiological Disposition and Mechanism of Action" in Advance in Neurology vol.43 S.Fahn et al, ed. N.Y.: Raven Press.
78. Herrschaft, H. (1989) "Effects and Therapeutic Efficacy of Nootropic Drugs in Acute and Chronic Cerebral Ischaemia in Man" in Pharmacology of Cerebral Ischaemia J. Kriegelstein, ed. Boca Raton FL: CRC Press.
79. Platt, D. et al (1993) "On the Efficacy of Piracetam in Geriatric Patients with Acute Cerebral Ischaemia: A Clinically Controlled Double Blind Study" Arch Gerontal Geriatr 16, 149-64.
80. Chouinard, G. et al (1983) "Piracetam in Elderly Psychiatric Patients with Mild Diffuse Cerebral Impairment" Psychopharmacol 81, 100-106.
81. Tallal, P. et al (1986) "Evaluation of the Efficacy of Piracetam in Treating Information Processing, Reading and Writing Disorders in Dyslexic Children" Int J Psychophysiol 4, 41-52.
82. Wilsher, C. (1986) "Effects of Piracetam on Development Dyslexia" Int J Psychophysiol 4, 29-39.
83. Mindus, P. et al (1976) "Piracetam-Induced Improvement of Mental Performance" Acta Psychiat Scand 54, 150-60.
84. DeBerdt, W. (1994) "Interaction between Psychological and Pharmacological Treatment in Cognitive Impairment" Life Sci 55, 2057-66.
85. Smith, W.L. & Lowrey, J.B. (1975) "Effects of Diphenylhydantoin on Mental Abilities in the Elderly" J Am Geriat Soc 23, 207-11.
86. Saleto and Grunberger, op.cit.
87. Grau, M. et al (1987) "Effect of Piracetam on Electrocortigram and Local Cerebral Glucose Utilization in the Rat" Gen Pharmacol 18, 205-11.
88. South, J. (2001) "Deprenyl - The Anti-Aging Psychoenergizer IAS Anti-Aging Bulletin 4(9), 3-19.
89. Finali, G. et al (1991) "L-deprenyl Therapy Improves Verbal Memory in Amnesic Alzheimer Patients" Clin Neuropharmacol 14, 523-36.
90. Baker, G.B. et al (1991) "Phenylethylaminergic Mechanism in Attention Deficit Disorder" Biol Psychiatry 29, 15-22.
91. Birkmeyer, W. et al (1984) "L-deprenyl plus L-phenylalanine in the Treatment of Depression" J Neural Transm 59, 81-87.
92. Tolbert, S.R. & Fuller, M.A. (1996) "Selegiline in Treatment of Behavioral and Cognitive Symptoms of Alzheimer Disease" Ann Pharmacother 30, 1122-29.
93. South, J. (2001) "Lucidril- The Anti-Aging Neuro-Energizer" IAS Anti-Aging Bulletin 4(9), 31-39.
94. Zs.-Nagy, I. (1994) "A Survey of the Available Data on a New Nootropic Drug, BCE-001" Ann NY Acad Sci 717, 102-14.
95. Nandy, K. (1978) "Centrophenoxine: Effects on Aging Mammalian Brain" J Am Ger Soc 26, 74-81.
96. Oettinger, L. (1958) "The Use of Deanol in the Treatment of the Disorders of Behavior in Children" J Pediat 53, 761-75.
97. Geller, S.J. (1960) "Comparison of a Tranquilizer and a Psychic Energizer" JAMA 174, 89-92.
98. Coleman, N. et al (1976) "Deanol in the Treatment of Hyperkinetic Children" Psychosomatics 17, 68-72.
99. Hindmarch, I. et al (1990-91) "Psychopharmacological Effects of Pyritinol in Normal Volunteers" Neuropsychobiol 24, 159-64.
100. Logue, G. et al (1974) "The Effects of Pyrithioxine on the Behaviour and Intellectual Functioning of Learning-Disabled Children" S Afr Med 48, 2245-46.
101. Fischoff, K. et al (1992) "Therapeutic Efficacy of Pyritinol in Patients with Senile Dementia of the Alzheimer Type (SDAT) and Multi-Infarct Dementia (MID)" Neuropsychobiol 26, 65-70.
102. Lemmel, E.-M (1993) "Comparison of Pyritinol and Auranofin in the Treatment of Rheumatoid Arthritis" Br J Rheumatol 32, 375-82.
103. Lane O'Kelly, D.J. (1975) "Pyritinol in the Treatment of Chronic Alcoholics" J Int Med Res 3, 323-27.