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The average American consumes somewhere between two to three pounds of sugar each week. Over the last twenty years, our national sugar consumption exploded from 26 pounds to 135 pounds of sugar—per person—annually. Compare that to sugar consumption in the late 1800s, when the average consumption was five pounds per person-per year. A time, incidentally, when heart disease and cancer were virtually unknown.

While your brain requires a pretty constant supply of the blood sugar product glucose in order to function properly, constantly eating refined sugars and slurping down sodas does not provide the best route for sugar intake. On the contrary, researchers at the Salk Institute in California found that high glucose levels resulting from quick, easy sugar intake slowly but surely damage cells everywhere in the body, especially those in the brain.

Unfortunately, having too little glucose and having too much glucose are both problematic. When your blood sugar levels drop, your hypothalamus sends out a distress signal that leads to the release of adrenaline to your liver, ordering it to turn excess fat into glucose.

When you consume too much sugar, your pancreas secretes insulin to nudge that extra sugar into your cells, and too much insulin can deplete your normal glucose levels, depress your immune system, and lead to kidney disease.

Plus, excess insulin also promotes fat storage, which sets up a vicious cycle. Either extreme can leave you feeling woozy, nervous, fatigued, and shaky.

Two additional reasons why excess refined sugar is detrimental to your brain:

A research group at the University of Wisconsin found that the brain may react to excess refined sugars found in food as if they were a virus or bacteria. The resulting immune response may cause cognitive deficits such as those associated with Alzheimer’s disease.
High blood sugar coupled with performing a mentally challenging task is associated with high levels of cortisol—a stress hormone known to impair memory.

In other words, that second piece of cake at the company birthday party might stress out you, your body, and your brain . . . and affect your afternoon work efficiency!

Your Brain on Sugar

It’s pretty clear—excessive glucose in the form of refined sugar can be very detrimental to your brain, ultimately affecting your attention span, your short-term memory, and your mood stability. Excessive refined sugar can:

Block membranes and thereby slow down neural communication.
Increase free radical inflammatory stress on your brain. Free radicals can rupture cells.
Interfere with synaptic communication.
Cause neurons to misfire and send erroneous messages that take time and energy to sort out.
Increase delta, alpha, and theta brain waves, which make it harder to think clearly.
Can eventually damage your neurons.

Is There Such a Thing as Healthy Sugar?

Not really . . . a simple sugar is a simple sugar. However, those occurring in real food, such as fructose in fruit and lactose in milk, also provide other nutrients so are slightly more healthy than any other sugar. And even though health food stores love to promote honey, molasses, maple syrup, or agave as natural sweeteners, they are still simple sugars, with the same fattening calories and little nutritive value as refined white sugar. They do, however, tend to be a tad sweeter, so maybe you’ll be happier with a smaller amount, but don’t kid yourself about them being healthier. Sugar is sugar, and you need to limit how much you consume on a daily basis.

Go Light on the Honey, Honey

Although honey is a natural sweetener, 96 percent of honey consists of the simple sugars fructose, glucose, and sucrose. Honey also has the highest calorie content of all sugars with 65 calories per tablespoon, compared to the 48 calories per tablespoon found in table sugar. The increased calories are bound to cause increased blood serum fatty acids, as well as weight gain, on top of the risk of more cavities.

Why Soda Crashes and Burns Your System

Your brain uses 65 percent of your body’s glucose, but too much or too little glucose can have a detrimental effect on brain function. One can of soda contains 10 teaspoons of table sugar, all of which floods into a blood stream that typically contains a total of 4 teaspoons of blood sugar. The rush alerts your pancreas to release a lot of insulin. Some sugar is quickly ushered into the cells, including brain cells, and the rest goes into storage or into fat cells. An hour later, your blood sugar may fall dramatically, creating low blood sugar, and these rapid swings produce symptoms of impaired memory and clouded thinking.

Actually we have studies dating back to the 1970’s and even earlier showing that the entire cycle of sugar and carbohydrate addiction is induced by a deficiency of serotonin. Serotonin is known to be the “happy” neurotransmitter and it can only be made in the brain from protein. Because sugar does nothing to replenish depleted serotonin, it’s hard to break the addiction cycle.

The natural food supplements L-tryptophan and 5HTP provide the brain with more of the raw material it needs to make serotonin. The same studies mentioned above also showed that when people take these supplements in appropriate doses their cravings abate and their consumption of carbohydrates and overall calories decrease. (J Pharm Pharmacol 1975 Jan; 27 (1): 31-7; Brain Res Bull 1986 Nov; 17 (5): 681-9; Pharmacol Biochem Behav 1986 Oct; 25 (4): 711-6; J Neurol Transm 1989; 76 (2): 109-17).

Armed with this knowledge, physician Marty Hinz, MD, has built a large and successful practice focused entirely on treating weight problems with these types of supplements. Dr. Hinz has also stated repeatedly that in his experience – spanning more than a decade and thousands of patients – these amino acid (protein) supplements work better for appetite control than any medication, including the ill-fated phen-fen combination. For more on Dr. Hinz and his work visit www.neuroreplete.com.

Effects of Nutrients on Neurotransmitter Release¹

Richard J.Wurtman ²

Contrary to earlier expectations, it has now become well established that the amounts of neurotransmitter released when certain neurons fire normally vary over a broad range. One process that generates such variations involves receptors on the neurons’ own presynaptic terminals: when activated by the neurotransmitter molecules that the neuron has released into the synapse, by concurrently released neuromodulators such as adenosine, or by other transmitters (e.g., the enkephalins) released at axoaxonal synapses, these receptors initiate intracellular events that diminish the number of neurotransmitter molecules released subsequently.

Another type of process that particularly affects the release of amine neurotransmitters depends on changes in the composition of the blood plasma induced by eating or by prolonged physical activity. Changes in plasma levels of choline or of certain amino acids lead to changes in brain levels of the precursors for these neurotransmitters—choline for acetylcholine, tryptophan for serotonin, and tyrosine for the catecholamines. These, in turn, regulate the rates at which the transmitters are synthesized, their concentrations within nerve terminals, and ultimately, the quantities released each time the neurons fire. For one transmitter—serotonin—the relevant variations in plasma composition probably affect most, if not all, of the neurons that release it. For other transmitters (e.g., the catecholamines), individual nerve cells can become more or less precursor dependent at any time, depending on the rates at which they happen to be firing.

Unlike the receptor-mediated presynaptic modulation of transmitter release, precursor-dependent modulation depends primarily on metabolic events occurring outside the brain and arising from a particular type of voluntary behavior, such as eating or exercise. Indeed, the primary physiological role of this dependency may be sensory (i.e., to provide the omnivore’s brain with information about what has been eaten or about important changes in macronutrient requirements, so that the individual can better decide what to eat next). However, because precursor-dependent neurotransmitters are involved in a wide variety of normal (and pathological) brain mechanisms besides those controlling food intake, this relationship may have broad physiological and medical implications. It also provides benign ways of influencing neurotransmission, and thus mental and physical performance.

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FOOD CONSUMPTION, TRYPTOPHAN AVAILABILITY, AND BRAIN SEROTONIN SYNTHESIS

The initial observation that physiological changes in precursor availability (i.e., after food consumption) could affect neurotransmitter synthesis was made in studies on rats performed in 1971 (Fernstrom and Wurtman, 1971). Animals were allowed to eat a test diet that contained carbohydrates and fat but that lacked protein. Soon after the start of the meal, brain levels of the essential (and scarce) amino acid tryptophan were found to have risen, thus increasing the substrate saturation of the enzyme that controls serotonin synthesis, tryptophan hydroxylase. The resulting increase in brain serotonin levels was associated with an increase in brain levels of serotonin’s metabolite, 5-hydroxyindole acetic acid, thus suggesting that serotonin release had also been enhanced. (Direct evidence that physiological variations in brain tryptophan concentrations affect serotonin release was not obtained until 1987 [Schaechter and Wurtman, 1989].)

The rise in brain tryptophan levels after consumption of this test diet was accompanied by either a small increase (rats) or no change (humans) in plasma tryptophan levels. Both of these changes had been unanticipated, since the insulin secretion elicited by dietary carbohydrates was known to lower plasma levels of most of the other amino acids. However, the unusual response of plasma tryptophan to insulin was soon recognized as resulting from the amino acid’s unusual propensity to bind loosely to circulating albumin. Insulin causes nonesterified fatty acid molecules to dissociate from albumin and to enter adipocytes. This dissociation increases the protein’s capacity to bind circulating tryptophan; hence, whatever reduction insulin causes in free plasma tryptophan levels is compensated for by a rise in the tryptophan bound to albumin, yielding no net change in total plasma tryptophan levels in humans (Madras et al., 1974). Because this binding is of low affinity, the albumin-bound tryptophan is almost as able as free tryptophan to be taken up into the brain.

Considerably more difficult to explain were the data then obtained on what happens to brain tryptophan and serotonin levels after rats consume a meal rich in protein. Although plasma tryptophan levels were found to rise, reflecting the contribution of some of the tryptophan molecules in the protein, brain tryptophan and serotonin levels either failed to rise or, if the meal contained sufficient protein, actually fell (Fernstrom and Wurtman, 1972). The explanation for this paradox was found to lie in the transport systems that carry tryptophan across the blood-brain barrier (Pardridge, 1977) and into neurons. The endothelial cells that line central nervous system capillaries contain various macromolecules that shuttle specific nutrients or their metabolites between the blood and the brain’s extracellular space. One such macromolecule mediates the transcapillary flux (by facilitated diffusion) of tryptophan and other large neutral amino acids (LNAAs) such as tyrosine; others move choline, basic or acidic amino acids, hexoses, monocarboxylic acids, adenosine, adenine, and various vitamins. The amount of any LNAA transported by the macromolecule depends on its ability to compete with the other circulating LNAAs for binding sites. Thus, the ability of circulating tryptophan molecules to enter the brain is increased when plasma levels of the other LNAAs fall (as occurs after insulin is secreted) and is diminished when the plasma levels of the other LNAAs rise, even if plasma tryptophan levels remain unchanged. Since all dietary proteins are considerably richer in the other LNAAs than in tryptophan (only 1.0–1.5 percent of most proteins), consumption of a protein-rich meal decreases the plasma/tryptophan ratio (the ratio of the plasma tryptophan concentration to the summed concentrations of its major circulating competitors for brain uptake, principally, tyrosine; phenylalanine; the branched-chain amino acids leucine, isoleucine, and valine; and methionine). This, in turn, decreases tryptophan’s transport into the brain and slows its conversion to serotonin. (Similar plasma ratios predict brain levels of each of the other LNAAs—including drugs such as levodopa (L-dopa)—following meals or other treatments that modify plasma amino acid patterns (Wurtman et al., 1980). This is why a high-protein meal interferes with levodopa’s therapeutic effect, whereas a high-carbohydrate, protein-free meal can lead to abnormal movements caused by too much levodopa suddenly entering the brain (Wurtman et al., 1988).

The fact that administration of pure tryptophan could increase brain serotonin synthesis, thereby affecting various serotonin-dependent brain functions (e.g., sleepiness and mood), has been known since at least 1968. What was novel and perhaps surprising about the above findings was their demonstration that brain tryptophan levels—and serotonin synthesis—normally undergo important variations in response, for example, to the decision to eat a carbohydrate-rich (as opposed to a protein-rich) breakfast or in response to the administration of a very low dose of tryptophan (Fernstrom and Wurtman, 1971).

It remained possible, however, that mechanisms external to the serotonin-releasing neuron might exist. These mechanisms kept such food-induced increases in serotonin’s synthesis from causing parallel changes in the amounts released into synapses. Indeed, it was known that if rats were given very large doses of tryptophan that were sufficient to raise brain tryptophan levels well beyond their normal range, the firing frequencies of their serotonin-releasing raphe neurons decreased markedly; this was interpreted as reflecting the operation of a feedback system designed to keep serotonin release within a physiological range. Similar decreases in raphe firing had also been observed in animals given drugs, such as monoamine oxidase (MAO) inhibitors or serotonin-reuptake blockers, which cause persistent increases in intrasynaptic serotonin levels. Indeed, the administration of serotonin uptake inhibitors such as fluoxetine can cause the prolonged inhibition of serotonin release (Gardier and Wurtman, 1991). However, when rats were given small doses of tryptophan that were sufficient to raise brain tryptophan levels but not beyond their normal peaks or when they consumed a carbohydrate-rich meal, which raised brain tryptophan levels physiologically, no decreases in raphe firing occurred. Hence, food-induced changes in serotonin synthesis were found to affect the amounts of serotonin released per firing without slowing the neuron’s firing frequencies, thus “allowing” modulation of the net output of information from serotonergic neurons.

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BRAIN SEROTONIN, NUTRIENT CHOICE, AND CARBOHYDRATE CRAVING

If rats are allowed to pick from foods in two pans presented concurrently and containing differing proportions of protein and carbohydrate, they choose among the two so as to obtain fairly constant (for each animal) amounts of these macronutrients.

However, if before “dinner” they receive either a carbohydrate-based snack or a drug that facilitates serotonergic neurotransmission, they quickly modify their food choice, selectively diminishing their intake of carbohydrates (Wurtman and Wurtman, 1979).

These observations support the hypothesis that the responses of serotonergic neurons to food-induced changes in the relative concentrations of plasma amino acids allow these neurons to serve a special function as sensors in the brain’s mechanisms governing nutrient choice (Wurtman, 1983, 1988).

Perhaps these neurons participate in a feedback loop through which the composition of breakfast (i.e., its proportions of protein and carbohydrate) can, by increasing or decreasing brain serotonin levels, influence the choice of lunch.

The ability of serotonin-containing neurons to distinguish between two foods (or the net compositions of two meals or snacks) depends upon the extent to which the foods produce significantly different plasma tryptophan/LNAA ratios.

Thus, a food (e.g., berries for rats or popcorn for people) which contains carbohydrates but little or no protein is easily distinguished from one (e.g., meat or eggs) that is rich in protein. Less easily distinguished would be one containing, say, 10 percent protein from one containing 15 percent protein, unless one of the foods happens to lack carbohydrates entirely (Yokogoshi and Wurtman, 1986). Perhaps the food-plasma-serotonin connection evolved because certain carbohydrates taste too good; to maintain its muscle mass, the bear must eventually stop eating honey and go catch a fish.

A similar mechanism may operate in humans and may underlie the tendency of people in all known cultures to eat about 13 percent of their total calories as protein and about four to five times as much carbohydrate as protein.

Subjects housed in a research hospital were allowed to choose from six different isocaloric foods (containing varying proportions of protein and carbohydrate but constant amounts of fat) at each meal, taking as many small portions as they liked; they also had continuous access to a computer-driven vending machine stocked with mixed carbohydrate-rich and protein-rich isocaloric snacks.

It was observed (Wurtman and Wurtman, 1989) that the basic parameters of each person’s food intake (total number of calories, grams of carbohydrate and protein, and number and composition of snacks) tended to vary only within a narrow range on a day-to-day basis and to be unaffected by placebo administration.

To assay the involvement of brain serotonin in maintaining this constancy of nutrient intake, pharmacological studies were undertaken in individuals in whom the feedback mechanism might be impaired.

These were obese people who claimed to suffer from carbohydrate craving, manifested as their tendency to consume large quantities of carbohydrate-rich snacks, usually at a characteristic time of day or evening (Wurtman et al, 1985). (Too few protein-rich snacks were consumed by the subjects to allow assessment of drug effects on this source of calories.)

Administration of dexfenfluramine, an antiobesity drug that increases intrasynaptic serotonin levels by releasing the transmitter and then blocking its reuptake, suppressed this carbohydrate craving. Other drugs thought to enhance serotonin-mediated neurotransmission selectively (e.g., the antidepressants zymelidine, fluvoxamine, and fluoxetine) have also been found to cause weight loss over the short term and may also selectively suppress carbohydrate intake. This contrasts with the weight gain (and carbohydrate craving) often associated with less chemically specific antidepressants such as amitriptyline.

Severe carbohydrate craving is also characteristic of patients suffering from seasonal affective disorder syndrome (SADS), a variant of bipolar clinical depression associated with a fall onset, a higher frequency in populations living far from the equator, and concurrent hypersomnia and weight gain (O’Rourke et al., 1989). A reciprocal tendency of many obese people to suffer from affective disorders (usually depression) has also been noted. Since serotonergic neurons apparently are involved in the actions of both appetite-reducing and antidepressant drugs, they might constitute the link between a patient’s appetitive and affective symptoms. Some patients with disturbed serotonergic neurotransmission might present themselves to their physicians with problems of obesity, reflecting their overuse of dietary carbohydrates to treat their dysphoria.

(The carbohydrates, by increasing intrasynaptic serotonin, would mimic the neurochemical actions of bona fide antidepressant drugs, such as the MAO inhibitors and tricyclic compounds [Wurtman, 1983].)

Other patients might complain of depression, and their carbohydrate craving and weight gain would be perceived as secondary problems. Another group might include women suffering from premenstrual syndrome (PMS) who experience late-luteal-phase mood disturbances, weight gain, carbohydrate craving (Brzezinski et al., 1990), and sometimes bloating and fluid retention. Yet another group includes people attempting to withdraw from nicotine (Spring et al., 1991), a drug that releases serotonin (Ribeiro et al., submitted for publication).

The participation of serotonergic neurons in a large number of brain functions besides nutrient choice regulation might have the effect of making such functions hostages to eating (seen in the sleepiness that can, for example, follow carbohydrate intake), just as it could cause mood-disturbed individuals to consume large amounts of carbohydrates for reasons related to neither the nutritional value nor the taste of these foods. In support of this view, it was observed that the serotonergic drug dexfenfluramine can be an effective treatment for both the affective and the appetitive symptoms of SADS (O’Rourke et al., 1989), PMS (Brzezinski et al., 1990), and smoking withdrawal (Spring et al., 1991).

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UNDER WHAT CIRCUMSTANCES WILL NUTRIENT INTAKE AFFECT NEUROTRANSMISSION?

On the basis of the tryptophan-serotonin relationship, one can formulate a sequence of biochemical processes that would have to occur in order for any nutrient precursor to affect the synthesis and release of its neurotransmitter product.

First, plasma levels of the precursor (and of other circulating compounds, such as the LNAAs, that affect tryptophan’s availability to the brain) must be allowed to increase after its administration (or after its consumption as a constituent of foods). In other words, plasma levels of tryptophan, the other LNAAs, or choline cannot be under tight homeostatic control comparable to, for example, that of plasma calcium or osmolarity. In actuality, plasma levels of tryptophan, tyrosine, and choline do vary severalfold after the consumption of normal foods, and those of the branched-chain amino acids may vary by as much as five- or sixfold.

Second, the brain level of the precursor must be dependent on its plasma level (i.e., there must not be an absolute blood-brain barrier for circulating tryptophan, tyrosine, or choline).

In fact, such absolute barriers do not exist for these nutrients; rather, facilitated diffusion mechanisms that allow these compounds to enter the brain at rates that depend on the plasma levels of these ligands are in operation.

Third, the rate-limiting enzyme within presynaptic nerve terminals that initiates the conversion of the precursor to its neurotransmitter product must, similarly, be unsaturated with this substrate so that when presented with more tryptophan, tyrosine, or choline it can accelerate synthesis of the neurotransmitter. (Tryptophan hydroxylase and choline acetyltransferase [CAT] do indeed have very poor affinities for their substrates tryptophan and choline.)

As discussed below, tyrosine hydroxylase activity becomes tyrosine-limited when neurons containing the enzyme have been activated and the enzyme has been phosphorylated (Wurtman, 1988; Wurtman et al., 1980).

Available evidence suggests that only some of the neurotransmitters present in the human brain are subject to such precursor control, principally, the monoamines mentioned above (serotonin; the catecholamines dopamine, norepinephrine, and epinephrine; and acetylcholine) and, possibly, histidine and glycine.

Pharmacological doses of the amino acid histidine do elevate histamine levels within nerve terminals, and the administration of threonine, a substrate for the enzyme that normally forms glycine from serine, can elevate glycine levels within spinal cord neurons (and, probably, thereby ameliorate some of the clinical manifestations of spasticity [Growdon et al., 1991]).

One large family of neurotransmitters, the peptides, is almost certainly not subject to precursor control.

Brain levels of these compounds have never been shown to change with variations in brain amino acid levels; moreover, there are sound theoretical reasons why it is unlikely that brain peptide synthesis would respond.

The immediate precursor for a brain protein or peptide is not an amino acid per se, as is the case for some of the monoamine neurotransmitters, but the amino acid molecule attached to its particular species of transfer RNA (tRNA).

In brain tissue, the known enzymes that catalyze the coupling of an amino acid to its tRNA have very high affinities for their amino acid substrates, such that their ability to operate at full capacity in vivo is probably unaffected by amino acid levels (except possibly in pathological states that are associated with major disruptions in brain amino acid patterns, such as phenylketonuria).

Little information is available concerning the possible precursor control of the nonessential amino acids, such as glutamate, aspartate, and γ-aminobutyric acid (GABA), even though these are probably the most abundant neurotransmitters in the brain. It is difficult to do experiments on these relationships; the precise biochemical pathways that synthesize glutamate and aspartate within nerve terminals are not well established, and for GABA, although it is well established that its precursor is glutamate, brain levels of that amino acid cannot be raised experimentally without sorely disrupting normal brain functions.

The macromolecule that transports acidic amino acids such as glutamate and aspartate across the blood-brain barrier is unidirectional and secretes these compounds from the brain into the blood by an active transport mechanism (Pardridge, 1977). Hence, administration of even an enormous dose of monosodium glutamate will not affect brain glutamate levels unless it elevates plasma osmolarity to the point of disrupting the blood-brain barrier.

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TYROSINE EFFECT ON DOPAMINE AND NOREPINEPHRINE SYNTHESIS

Because tyrosine administration had not been shown to increase brain dopamine or norepinephrine levels in otherwise untreated animals, it was initially assumed that the catecholamine neurotransmitters were not under precursor control, even though (1) plasma tyrosine levels do increase severalfold after protein intake or tyrosine administration; (2) the LNAA transport system does ferry tyrosine, like tryptophan, across the blood-brain barrier; and (3) tyrosine hydroxylase, which catalyzes the rate-limiting step in catecholamine synthesis, is unsaturated in vivo (Wurtman et al., 1980).

It did seem possible, however, that a pool of neuronal dopamine or norepinephrine might exist for which synthesis did depend on tyrosine levels, but which was of too small a size in relation to the total catecholamine mass to be detected.

Hence, studies were performed to determine whether catecholamine synthesis or release could be affected by changes in brain tyrosine concentrations. At first, catecholamine synthesis was estimated by following the rate at which dopa, the product of tyrosine’s hydroxylation, accumulated in the brains of rats treated acutely with a drug that blocks the next enzyme in catecholamine formation (aromatic l-amino acid decarboxylase). Tyrosine administration did increase dopa accumulation, whereas other LNAAs decreased both dopa accumulation and brain tyrosine levels. Catecholamine release was then estimated by measuring the brain levels of metabolites of dopamine (homovanillic acid [HVA], dihydroxyphenylacetic acid [DOPAC]) or norepinephrine (methoxyhydroxyphenylglycol sulfate [MHPH-SO₄]). Administration of even large doses of tyrosine had no consistent effect on these metabolites. However, if the experimental animals were given an additional treatment designed to accelerate the firing of dopaminergic or noradrenergic tracts (e.g., dopamine receptor blockers, cold exposure, partial lesions of dopaminergic tracts, and reserpine), the supplemental tyrosine caused a marked augmentation of catecholamine release (Wurtman, 1988; Wurtman et al., 1980). These initial observations formed the basis for the hypothesis that catecholaminergic neurons become tyrosine sensitive when they are physiologically active and lose this capacity when they are quiescent.

The biochemical mechanism that couples a neuron’s firing frequency to its ability to respond to supplemental tyrosine involves phosphorylation of the tyrosine hydroxylase enzyme protein, a process that occurs when the neurons fire.

High tyrosine foods:

Spirulina: Spirulina is a seaweed, which is rich in tyrosine and other nutrients as well
Soy Foods
Eggs: The trusty egg is a powerhouse of nourishing vitamins
Cheese
Fish And WILD Salmon
Poultry
Meat
Beans And Grains

This phosphorylation, which is short-lived, enhances the enzyme’s affinity for its cofactor (tetrahydrobiopterin) and makes the enzyme insensitive to end product inhibition by catechols; these changes allow its net activity to depend on the extent to which it is saturated with tyrosine.

An additional mechanism underlying this coupling may be an actual depletion of tyrosine within nerve terminals as a consequence of its accelerated conversion to catecholamines (Milner et al., 1987).

If slices of rat caudate nucleus are superfused with a standard Krebs-Ringer solution (which lacks amino acids) and are depolarized repeatedly, they are unable to sustain their release of dopamine; concurrently, their contents of tyrosine, but not of other LNAAs, decline markedly.

The addition of tyrosine to the superfusion solution enables the tissue to continue releasing dopamine at initial rates and also protects it against depletion of its tyrosine. The concentrations of tyrosine needed for these effects are proportional to the number of times the neurons are depolarized. (Of course, the intact brain is continuously perfused with tyrosine-containing blood, making it highly unlikely that tyrosine levels fall to a similar extent, even in continuously active brain neurons. However, they might decline somewhat, since tyrosine is poorly soluble in aqueous media and diffuses relatively slowly.)

More recently, in vivo dialysis techniques have been used to assess tyrosine’s effects on brain dopamine release. When otherwise untreated animals receive the amino acid systemically, there is, after 20–40 min, a substantial increase in dopamine output from nigrostriatal neurons unaccompanied by detectable increases in dopamine’s metabolites DOPAC or HVA. However, this effect is short-lived, and dopamine release returns to basal levels after 20–30 min. This latter response probably reflects receptor-mediated decreases in the firing frequencies of the striatal neurons (to compensate for the increase in dopamine release that occurs with each firing) and, perhaps, local presynaptic inhibition. If animals are given haloperidol, a dopamine receptor-blocking agent, before—or along with—the tyrosine, the supplemental tyrosine continues to amplify dopamine output for prolonged periods (During et al., 1989).

Tyrosine has now been shown to enhance the production and release of dopamine or norepinephrine in a variety of circumstances. This amino acid may ultimately have considerable utility in treating catecholamine-related diseases or conditions; it may also prove useful in promoting performance— particularly in high-stress situations.

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EFFECTS OF CHOLINE ON SYNTHESIS OF ACETYLCHOLINE AND PHOSPHATIDYLCHOLINE

The amounts of acetylcholine released by physiologically active cholinergic neurons depend on the concentrations of choline available. In the absence of supplemental free choline, the neurons will continue to release constant quantities of the transmitter, especially when stimulated (Maire and Wurtman, 1985). However, when choline is available (in concentrations bracketing the physiological range), a clear dose relationship is observed between its concentration and acetylcholine release (Blusztajn and Wurtman, 1983; Marie and Wurtman, 1985). When no free choline is available, the source of the choline used for acetylcholine synthesis is the cells’ own membranes (Blusztajn et al., 1987).

Membranes are very rich in endogenous phosphatidylcholine (PC), and this phospholipid serves as a reservoir of free choline, much as bone and albumin serve as reservoirs for calcium and essential amino acids.

It has been suggested that a prolonged imbalance between the amounts of free choline available to a cholinergic neuron and the amounts needed for acetylcholine synthesis might alter the dynamics of membrane phospholipids to the point of interfering with normal neuronal functioning (“autocannibalism”) (Blusztajn and Wurtman, 1983; Nitsch et al., 1992a), for example, in patients with Alzheimer’s disease.

PPC

In that event, providing the brain with supplemental choline would serve two purposes: it would enhance acetylcholine release from physiologically active neurons and it would replenish the choline-containing phospholipids in their membranes (Wurtman, 1985).

Neurons can draw on three sources of free choline for acetylcholine synthesis: that stored as PC in their own membranes, that formed intrasynaptically from the hydrolysis of acetylcholine (and taken back up into the presynaptic terminal by a high-affinity process estimated to be 30–50 percent efficient in the brain), and that present in the bloodstream (and taken into the brain by a specific blood-brain barrier transport system). The PC in foods (e.g., liver and eggs) is rapidly hydrolyzed to free choline in the intestinal mucosa (or is broken down more slowly after passage into the lymphatic circulation). Consumption of adequate quantities of PC can lead to severalfold elevations in plasma choline levels, thereby increasing brain choline levels and the substrate saturation of CAT.

The PC molecules consumed in the diet, as well as those formed endogenously in neuronal membranes, are very heterogeneous with respect to their fatty acid compositions. Some PCs (e.g., those in soybeans and nerve terminals) are relatively rich in polyunsaturated fatty acids; others (e.g., those in eggs) are highly saturated. PCs are also heterogeneous with reference to their mode of synthesis. Brain neurons produce PC by three distinct biochemical pathways: the sequential methylation of phosphatidylethanolamine (PE), the incorporation of preexisting free choline via the CDP-choline cycle, or the incorporation of free choline via the base exchange pathway (in which a choline molecule substitutes for the ethanolamine in PE or the serine in phosphatidylserine [PS]). Quite possibly, the different varieties of PC may subserve distinct functions; for example, one type of PC, distinguished by its fatty acid composition or its mode of synthesis, could be preferentially utilized to provide a choline source for acetylcholine synthesis or could be formed preferentially during the processes of cell division or synaptic remodeling. Similarly, one particular species might be especially involved in the pathogenesis of particular degenerative diseases afflicting cholinergic neurons (e.g., Alzheimer’s disease).

Supplemental choline or PC has been used with some success in the treatment of tardive dyskinesia. A summary of related publications (Nasrallah et al., 1984) concluded that choline and the cholinesterase inhibitor physostigmine were about equally efficacious and that choline was less toxic. Most patients exhibited some reduction in the frequency of abnormal movement, but in only a few cases was there complete cessation of the movements. Choline sources have also been tried in the treatment of Alzheimer’s disease. Most well-controlled studies have treated subjects for relatively short intervals (6–8 weeks) and have focused on younger subjects, with little or no success. A single double-blind study administered the PC for 6 months (Little et al., 1985).

Improvement was noted in about one-third of the subjects; the average age of the responders was 83 years and that of nonresponders was 73 years, a relationship thought to be compatible with evidence that Alzheimer’s disease may be more restricted to cholinergic neurons in subjects who become symptomatic at a later age.

Occasional reports have also described the useful effects of choline or PC in treating mania, ataxia, myasthenic syndromes, and Tourette’s syndrome.

Very recently it has been observed (Nitsch et al., 1992a) that the brains of people dying of Alzheimer’s disease (but not Down’s Syndrome) contain reduced levels of PC and free choline (and PE and free ethanolamine) but major increases in those of the PC metabolite glycerophosphocholine and the PE metabolite glycerophosphoethanolamine.

CHOLINE

These changes were not restricted to regions containing plaques, tangles, or amyloid.

Since low brain choline levels both impair acetylcholine synthesis and accelerate the breakdown of membrane PC and since adequate acetylcholine may be needed to prevent the formation of the amyloid protein of Alzheimer’s disease (Nitsch et al., 1992b), supplemental choline and ethanolamine could have a role in the prevention of this disease.

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CONCLUSIONS

The design of experiments to display the potentially useful effects of foods and nutrients on the ability to perform well, particularly under stressful circumstances, will require considerable sophistication. These chemicals are not nearly as potent as drugs and, in fact, lack intrinsic potency, having first to be converted to a neurotransmitter within a nerve terminal and then to be released from that terminal. (Of course, they are also likely to be significantly less toxic than drugs; this is perhaps their major advantage.) Such experimental design should be entrusted to people who are well trained in studying human behavior and who also fully understand the ground rules that determine when the food or nutrient is most likely to be effective (e.g., for tyrosine, when particular catecholamine-releasing neurons are firing frequently for long periods).
At this point, too few adequate experiments have been done with human subjects to begin to assess the utilities of neurotransmitter precursors such as tyrosine or choline in increasing or sustaining performance; in fact, a number of poorly designed studies muddy the waters.
Tyrosine’s effect on performance must be examined in situations in which subjects are under real stress. Choline’s effects on memory must be studied in experiments in which the nutrient is given for a sufficiently long period of time (i.e., one compatible with what is known about the dynamics of the choline-phosphatidylcholine interaction).
The peripheral actions of the neurotransmitter precursors may turn out to be very useful (e.g., tyrosine’s ability to normalize blood pressure when it is both too high and too low [Wurtman et al., 1980] and choline’s ability to sustain exercise tolerance in subjects whose plasma choline levels have been reduced by, for example, long-distance running [Conlay et al., 1986; Sandage et al., 1992]).
The development of foods or nutrients used to sustain performance—or otherwise to improve normal behaviors—requires guidance by the U.S. Food and Drug Administration, and perhaps other agencies as well, regarding how these compounds will be regulated. It is absolutely mandatory that all such preparations be safe and of adequate purity; it is also essential that they be adequately labeled, providing the user with full information about their indications, dosages, contraindications, and side effects. However, if and when it can be shown that their use is largely nutritional (i.e., to meet the body’s needs for more of the particular nutrient because environmental circumstances have increased those needs), then perhaps they can be designated as foods.
Considerable additional research should be done to identify special populations with unusual responses to foods or nutrients that affect neurotransmitters (e.g., the carbohydrate cravers who overconsume carbohydrate-rich snacks in order to relieve depressive symptoms). Heterogeneity of response will doubtless also exist among people in the military (e.g., those with mild seasonal depression or premenstrual syndrome and those giving up smoking).

Go to:

ACKNOWLEDGMENTS

Some of these studies were supported by National Institute of Mental Health grant MH-28783, U.S. Air Force grant AFOSR-830366, National Aeronautics and Space Administration grant NAG-2–210, and National Institutes of Health grant RR00088–24 to the Clinical Research Center, Massachusetts Institute of Technology.

How Neurons Talk to Each Other

Summary: A new study challenges conventional thinking about how neurons that release dopamine communicate. The findings could have vital implications for dopamine related diseases such as Parkinson’s.

Source: University of Pittsburgh.

Researchers at the University of Pittsburgh have uncovered the mechanism by which neurons keep up with the demands of repeatedly sending signals to other neurons. The new findings, made in fruit flies and mice, challenge the existing dogma about how neurons that release the chemical signal dopamine communicate, and may have important implications for many dopamine-related diseases, including schizophrenia, Parkinson’s disease and addiction.

The research conducted at Pitt and Columbia University was published online today in the journal Neuron.

Neurons communicate with one another by releasing chemicals called neurotransmitters, such as dopamine and glutamate, into the small space between two neurons that is known as a synapse. Inside neurons, neurotransmitters awaiting release are housed in small sacs called synaptic vesicles.

“Our findings demonstrate, for the first time, that neurons can change how much dopamine they release as a function of their overall activity. When this mechanism doesn’t work properly, it could lead to profound effects on health,” explained the study’s senior author Zachary Freyberg, M.D., Ph.D., who recently joined Pitt as an assistant professor of psychiatry and cell biology. Freyberg initiated the research while at Columbia University.

When the researchers triggered the dopamine neurons to fire, the neurons’ vesicles began to release dopamine as expected. But then the team noticed something surprising: additional content was loaded into the vesicles before they had the opportunity to empty. Subsequent experiments showed that this activity-induced vesicle loading was due to an increase in acidity levels inside the vesicles.

“Our findings were completely unexpected,” said Freyberg. “They contradict the existing dogma that a finite amount of chemical signal is loaded into a vesicle at any given time, and that vesicle acidity is fixed.”

The team then demonstrated that the increase in acidity was driven by a transport channel in the cell’s surface, which allowed an influx of negatively charged glutamate ions to enter the neuron, thus increasing its acidity. Genetically removing the transporter in fruit flies and mice made the animals less responsive to amphetamine, a drug that exerts its effect by stimulating dopamine release from neurons.

“In this case, glutamate is not acting as a neurotransmitter. Instead it is functioning primarily as a source of negative charge, which is being used by these vesicles in a really clever way to manipulate vesicle acidity and therefore change their dopamine content,” Freyberg said. “This calls into question the whole textbook model of vesicles as having fixed amounts of single neurotransmitters. It appears that these vesicles contain both dopamine and glutamate, and dynamically modify their content to match the conditions of the cell as needed.”

In the future, the team plans to look more closely at how increases in vesicle acidification affect health. A number of brain diseases are characterized by abnormal dopamine neuron signaling and altered levels of the neurotransmitter.

“Since we have demonstrated that the balance between glutamate and dopamine is important for controlling the amount of dopamine that a neuron releases, it stands to reason that an imbalance between the two neurotransmitters could be contributing to symptoms in these diseases,” said Freyberg.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: Funding was provided by National Institutes of Health grants GM007628, DA031241, DA022413, DA12408, DA007418, DA010154, MH086545, MH108186, NS075222, NS075572, AG08702, DA040443, MH076900, ES015747 and ES016732; Louis V. Gerstner, Jr., Scholars Program; Leon Levy Foundation; John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation; Lieber Center for Schizophrenia Research and Treatment; JPB and Parkinson’s Disease Foundations; Harold & Leila Y. Mathers Charitable Foundation; Dana Foundation; Gatsby Initiative in Brain Circuitry; New York Presbyterian Seizure Disorders Fund; Brain and Behavior Research Foundation; and the UCLA Brain Research Institute

Additional authors on the study are: co-lead authors Jenny Aguilar, B.A., of Vanderbilt University, and Matthew Dunn, Ph.D., of Columbia University; Zachary Farino, and Robin Freyberg, Ph.D., of Pitt; Susana Mingote, Ph.D., Caline Karam, Ph.D., Mark Sonders, Ph.D., Se Joon Choi, Ph.D., Yuchao Zhang, Ben Choi, Ph.D., Jorge Flores, Eugene Mosharov, Ph.D., Jonathan Javitch, M.D., Ph.D., David Sulzer, Ph.D., Stephen Rayport, M.D., Ph.D., Dalibor Sames, Ph.D., all of Columbia University; Anna Grygoruk, Ph.D., and David Krantz, M.D., Ph.D., both of the University of California, Los Angeles; and Carolina Cela, Ph.D., and Brian McCabe Ph.D., both of the École Polytechnique Fédérale de Lausanne, Switzerland.

Source: Arvind Suresh – University of Pittsburgh
Image Source: NeuroscienceNews.com image is credited to Center for Biologic Imaging/University of Pittsburgh.
Original Research: Abstract for “Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT” by Jenny I. Aguilar, Matthew Dunn, Susana Mingote, Caline S. Karam, Zachary J. Farino, Mark S. Sonders, Se Joon Choi, Anna Grygoruk, Yuchao Zhang, Carolina Cela, Ben Jiwon Choi, Jorge Flores, Robin J. Freyberg, Brian D. McCabe, Eugene V. Mosharov, David E. Krantz, Jonathan A. Javitch, David Sulzer, Dalibor Sames, Stephen Rayport, and Zachary Freyberg in Neuron. Published online August 17 2017 doi:10.1016/j.neuron.2017.07.038

University of Pittsburgh “How Neurons Talk to Each Other.” NeuroscienceNews. NeuroscienceNews, 17 August 2017.
<http://neurosciencenews.com/neural-communication-7326/>.

Abstract

Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT

Highlights
•Cell depolarization increases DA vesicular loading prior to release in flies
•Depolarization-induced SV hyperacidification drives increased DA vesicle loading
•VGLUT in DA SVs mediates depolarization-induced hyperacidification
•Depolarization-induced hyperacidification in DA SVs is conserved in mammals

Summary
The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content.

“Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT” by Jenny I. Aguilar, Matthew Dunn, Susana Mingote, Caline S. Karam, Zachary J. Farino, Mark S. Sonders, Se Joon Choi, Anna Grygoruk, Yuchao Zhang, Carolina Cela, Ben Jiwon Choi, Jorge Flores, Robin J. Freyberg, Brian D. McCabe, Eugene V. Mosharov, David E. Krantz, Jonathan A. Javitch, David Sulzer, Dalibor Sames, Stephen Rayport, and Zachary Freyberg in Neuron. Published online August 17 2017 doi:10.1016/j.neuron.2017.07.038

Do you APPROVE of the job Donald Trump is doing?

Huffington Post: President Trump's Average Approval Rating Dips To Just Below 40 Percent

We’re conducting a quick poll of our top supporters (that’s you Connie!).

Do you APPROVE of Donald Trump's performance?

Since becoming President, Donald Trump has tried to:

BAN Muslims from entering the country
REPEAL Obamacare
CUT taxes for the wealthy

And those are just a few.

Donald Trump’s uninformed and irresponsible agenda, and his chaotic and incompetent Administration, is harming Americans.

The majority of Americans don’t approve of Trump’s job performance or his agenda. But Connie, we want to hear from you.

Respond immediately and let us know if you APPROVE of Donald Trump:

http://go.ameripacfund.com/Trump-Approval-Poll

Thanks for your valuable input,

AMERIPAC

Donald Trump’s approval rating is PLUMMETING:

FP Editor’s picks 8-16-2017

Wednesday, August 16

Welcome to Editors’ Picks, FP’s round-up of the day’s best articles.

Today, we look at Berliners condemning the neo-Nazis who marched on Charlottesville, Virginia, accusations that the Saudi-led coalition in Yemen killed hundreds of children, and whether Germany’s car industry is deflating.

THE MADMAN’S DILEMMA: President Donald Trump may prize “unpredictability,” but history isn’t on his side, FP’s Stephen M. Walt writes: Read more

CONFIDENTIAL KILLINGS: A confidential U.N. report accuses the Saudi-led coalition of killing hundreds of children in the conflict in Yemen, FP’s Colum Lynch reports: Read more

BERLIN PROTESTS: Berliners gathered at Brandenburg Gate to denounce Charlottesville neo-Nazis, chanting “Nazi scum go away” and collecting donations for victims of the violence, Bethany Allen-Ebrahimian reports: Read more

DEFLATING INDUSTRY?: German car companies are driving the country off a cliff, Bernhard Rieger writes: Read more

SO FAR NOT SO GOOD: NAFTA negotiations, which began Wednesday, are off to a rocky start, FP’s Jesse Chase-Lubitz writes: Read more

California Attorney General Xavier Becerra took Donald Trump’s E.P.A.

California Attorney General Xavier Becerra is at the frontline of the fight for fairness and opportunity in the Trump era. To receive his most important email updates, click here. To unsubscribe, click here.

Donald Trump’s E.P.A. tried to END critical protections curbing harmful smog pollution.

So California Attorney General Xavier Becerra took them to court! And Connie — the Trump Administration backed down!

But now the Trump Administration refuses to disclose documents describing any conflict of interest standards at the agency despite an official request by Xavier that required a response.

Will you stand with Xavier as he fights further to protect our environment >>

THANK XAVIER FOR TAKING ACTION >>

Connie,

Donald Trump thought he could give Big Oil a pass by delaying a critical rule that would cut back on smog pollution.

But Connie, Xavier knows how critical these safeguards are for families in California to have access to clean air and water.

In California alone, this rule would save lives, cut back on hospital asthma visits, and prevent lost school days for children.

That’s why Xavier took a stand — and WON!

Xavier led a coalition of states and took Trump’s EPA head, Scott Pruitt, to court:

Look — when Donald Trump puts our clean air and water in jeopardy — you better believe Xavier will fight back.

Right now, Xavier’s at it again — on Friday, he sued the EPA for failing to disclose documents revealing its conflict of interest standards under the Trump Administration.

So Connie, please add your name to thank Xavier for standing up for our environment!

SIGN TO THANK XAVIER >>

Connie, Xavier knows that committing ourselves to these environmental standards will help save lives — period.

Please, add your name to thank Xavier for taking quick action to stop Trump:

http://go.xavierbecerra.com/EPA-Victory

-Team Xavier Becerra

Possible Roots of Schizophrenia Uncovered

Summary: Researchers report increased levels of methionine during pregnancy can alter the expression of genes linked to schizophrenia in offspring.

Source: UC Irvine.

Excess of methionine during pregnancy alters prenatal brain development related to the psychiatric disease.

An abundance of an amino acid called methionine, which is common in meat, cheese and beans, may provide new clues to the fetal brain development that can manifest in schizophrenia, University of California, Irvine pharmacology researchers report in the journal Molecular Psychiatry.

The findings point to the role methionine overload can play during pregnancy and suggest that targeting the effects of this amino acid may lead to new antipsychotic drugs.

The UCI study also provides detailed information on the neural developmental mechanisms of the methionine effect, which results in changes in the expression of several genes important to healthy brain growth and, in particular, to one linked to schizophrenia in humans.

Amal Alachkar and colleagues based their approach on studies from the 1960s and 1970s in which schizophrenic patients injected with methionine experienced worsened symptoms. Knowing that schizophrenia is a developmental disorder, the UCI team hypothesized that administering three times the normal daily input of methionine to pregnant mice may produce pups that have also schizophrenia-like deficits, which is what occurred.

The pups of the injected mothers displayed deficits in nine different tests encompassing the three schizophrenia-like symptoms behaviors – “positive” symptoms of overactivity and stereotypy, “negative” symptoms of human interaction deficits, and “cognitive impairments” memory loss.

The research team treated the mice with anti-schizophrenic drugs well used in therapy. A drug that in schizophrenics treats mostly the positive symptoms (haloperidol) did the same in the mice, and a drug that treat preferentially the negative symptoms and the cognitive impairments (clozapine) did the same.

Alachkar, an associate adjunct professor of pharmacology, said that the study is the first to present a mouse model based on methionine-influenced neural development that leads to schizophrenic-like behaviors.

“This mouse model provides much broader detail of biological processes of schizophrenia and thus reflect much better the disorder than in the animal models presently widely used in drug discovery,” said Olivier Civelli, chair and professor of pharmacology and an author on the paper.

“Our study also agrees with the saying, ‘we are what our mothers ate’,” Alachkar added. “Methionine is one of the building blocks of proteins. It is not synthesized by our bodies, and it needs to be ingested. Our study points at the very important role of excess dietary methionine during pregnancy in fetal development, which might have a long-lasting influence on the offspring. This is a very exciting area of research that we hope can be explored in greater depth.”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: The study received support from the National Institutes of Health (DA024746), the UCI’s Center for Autism Research & Translation, the Eric L and Lila D Nelson Chair of Neuropharmacology, and the Institute of International Education.

Source: Tom Vasich – UC Irvine
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research:Abstract for “Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits” by A Alachkar, L Wang, R Yoshimura, A R Hamzeh, Z Wang, N Sanathara, S M Lee, X Xu, G W Abbott and O Civelli in Molecular Psychiatry. Published online August 15 2017 doi:10.1038/mp.2017.164

UC Irvine “Possible Roots of Schizophrenia Uncovered.” NeuroscienceNews. NeuroscienceNews, 16 August 2017.
<http://neurosciencenews.com/schizophrenia-roots-brain-development-7315/>.

Abstract

Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits

The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny.

Pregnant mice were administered methionine equivalent to double their daily intake during the last week of gestation.

Their progeny (MET mice) exhibited schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis and synaptic plasticity, and abnormally reduced local excitatory synaptic connections in CA1 neurons.

Neural transcript expression of only one gene, encoding the Npas4 transcription factor, was >twofold altered (downregulated) in MET mice; strikingly, similar Npas4 downregulation occurred in the prefrontal cortex of human patients with schizophrenia.

Finally, therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked effects in human schizophrenia patients. Our data support the validity of MET mice as a model for schizophrenia, and uncover methionine metabolism as a potential preventive and/or therapeutic target.

“Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits” by A Alachkar, L Wang, R Yoshimura, A R Hamzeh, Z Wang, N Sanathara, S M Lee, X Xu, G W Abbott and O Civelli in Molecular Psychiatry. Published online August 15 2017 doi:10.1038/mp.2017.164

Toxicity of methionine in humans.

Garlick PJ¹.

Author information

Abstract

The literature has been searched to identify evidence relating to the possible toxicity of the amino acid methionine in human subjects.

Nutritional and metabolic studies have employed amounts of methionine, including the d and dl isomers, both below and above the requirement and have not reported adverse effects in adults and children.

Although methionine is known to exacerbate psychopathological symptoms in schizophrenic patients, there is no evidence of similar effects in healthy subjects. The role of methionine as a precursor of homocysteine is the most notable cause for concern.

A “loading dose” of methionine (0.1 g/kg) has been given, and the resultant acute increase in plasma homocysteine has been used as an index of the susceptibility to cardiovascular disease. Although this procedure results in vascular dysfunction, this is acute and unlikely to result in permanent damage.

However, a 10-fold larger dose, given mistakenly, resulted in death. Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, B-12, C, and folic acid. In infants, methionine intakes of 2-5 times normal resulted in impaired growth and extremely high plasma methionine levels, but no adverse long-term consequences were observed.

New York Times 8-17-2017

Trump Opens Breach With Party, Military and Industry

By MICHAEL D. SHEAR, GLENN THRUSH and MAGGIE HABERMAN

In the wake of his defense of white supremacists, President Trump was abandoned by executives, contradicted by military leaders and shunned by Republicans.
According to close aides, the president said he felt liberated by his news conference and viewed it as his latest retort to a political establishment trying to tame his impulses.

1100 Comments

Trump Says It Is ‘Foolish’ to Remove Civil War Statues

By EILEEN SULLIVAN 50 minutes ago

On Twitter, the president echoes a refrain of white supremacist groups that oppose the removal of Confederate monuments.

221 Comments

Pelosi Calls for Confederate Statues to Be Removed from Capitol 50 minutes ago

CreditJason Lappa for The New York Times

‘Our Home, Not Their Home’

By HAWES SPENCER and JONAH ENGEL BROMWICH 11:06 AM ET

People sang hymns, gospel songs and other anthems of belonging at a gathering in Charlottesville that was largely organized by word of mouth.

Bannon Mocks Colleagues and ‘Alt-Right’ in Interview

By MICHAEL D. SHEAR and MAGGIE HABERMAN

In an interview he said he believed was private, Stephen K. Bannon described the alt-right as a “collection of clowns” and lashed out at rivals in the Trump administration.

40 Comments

Confederate Symbols Being Taken Down

Our guide to the monuments of the Confederacy that have, or may, come down.

Robert E. Lee Statue Is Defaced at Duke University

DEVELOPING

Deaths in Barcelona After Driver Plows Into Pedestrians

By MARK A. WALSH, ANNE-SOPHIE BOLON and PALKO KARASZ 16 minutes ago

It was not immediately clear if the crash near the popular tourist areas of Plaza de Cataluña and Las Ramblas in the Spanish city was related to terrorism.

The Night the Oxygen Ran Out in an Indian Hospital

By JEFFREY GETTLEMAN and HARI KUMAR 9:08 AM ET

The Modi government of India has been criticized after children died when a vendor cut off oxygen supplies for lack of payment.

38 Comments

Texas Bathroom Bill Dies Again, but a Revival Is Inevitable

By DAVID MONTGOMERY and MANNY FERNANDEZ

A Texas version of a North Carolina-style bill to restrict transgender bathroom use failed for a second time, but the state’s lieutenant governor said it would return “because the people will demand it.”

86 Comments

Settlement Reached in Case on C.I.A. Torture Program

By SHERI FINK 12:33 PM ET

A lawsuit against two psychologists who helped devise the C.I.A.’s brutal interrogation program was an unusual effort to demand accountability for tactics adopted after Sept. 11.

12 Comments

MORE NEWS

THE DAILY 360

A 2:15 Alarm, 2 Trains and a Bus Get Her to Work by 7 A.M.

Like many in the housing-starved San Francisco region, Sheila James has moved far inland, gaining affordable space at the price of a brutal commute.

By CONOR DOUGHERTY and ANDREW BURTON

Your Thursday Briefing

By CHRIS STANFORD 10:38 AM ET

Here’s what you need to know to start your day.

New York Today: Dealing With Noisy Neighbors 6:00 AM

California Today: A Growing Threat on the Shoreline

By MIKE McPHATE 8:53 AM ET

Erosion continues to reshape the coast, the removal of Confederate symbols in Southern California, and another orca dies in San Diego.

1 Comment

AUDIO

Listen to ‘The Daily’

How the chief executives of the nation’s largest companies moved to cut ties with the president who rose to fame as a businessman.

Follow The Daily: Apple Podcasts Radio Public Stitcher

SMARTER LIVING

Chinese Film Beats Records (and Arrogant Westerners)

By CHRIS BUCKLEY

In “Wolf Warrior 2,” China’s top-grossing movie yet, a red-tinged Rambo named Leng Feng takes on a swaggering American soldier of fortune.

15 Comments

Confronting the Summer of Trump Onstage

By BEN BRANTLEY, JESSE GREEN and ALEXIS SOLOSKI

Theater has quickly taken on the Trump presidency. Whether what’s onstage can change minds or spark action is open to debate.

10 Comments

Earth in Suspension

By FERRIS JABR and GOLDEN COSMOS

A total solar eclipse is not just the momentary theft of day. It is a profound interruption of the world as we know it.

California Today

The news and stories that matter to Californians, delivered weekday mornings.

36 Hours in Cincinnati

Cincinnati is experiencing a boom, especially in the Over-the-Rhine district where rich cultural offerings and breweries thrive.

Cobblers: The Best Way to Let Summer Fruit Shine

The cobbler, a seasonal standby, can be made with pie crust, biscuits or cake — but its greatest versatility lies in the fruit you use.

A Personal, Breezy Tour of Classic Children’s Books

In “Wild Things,” Bruce Handy curates passages from his favorites, allowing readers both literary pleasure and a kind of time travel.

The Opinion Pages

EDITORIAL

After Racist Rage, Statues Fall Quietly

Trump’s response to Charlottesville has encouraged communities to settle the fate of Confederate monuments.

Climate Lessons from California

By NOAH S. DIFFENBAUGH

The state has been particularly ambitious in its efforts to reduce greenhouse gas emissions.

The A.C.L.U. Needs to Rethink Free Speech

By K-SUE PARK

Its conception of this right is unduly narrow.

35m

Toppling monuments, a visual history: From King George III to Saddam Hussein and beyond, world history has been littered with the remnants of shattered statues.
6h

The leader of Australia’s anti-immigrant One Nation party wore a burqa in Parliamentwhile advocating a ban. One lawmaker denounced her action as “appalling.”
7h

Malala Yousafzai, the Pakistani-born activist who is the world’s youngest Nobel laureate, said she would attend Oxford University to study philosophy, politics and economics.
August 16, 2017
11h

Mehdi Karroubi, a prominent opposition leader in Iran who has been under house arrest since 2011, began a hunger strike. He demanded a public trial in exchange for ending his fast.
11h

The U.K. wants to keep an open border with Ireland after Brexit. But the government is vague about how to do that while exiting the E.U. single market and customs union.
12h

Several of HBO’s Twitter accounts were hacked late Wednesday night, raising security concerns as the network deals with the sustained leaking of proprietary information.
15h

A homeless man who rushed to help victims of a deadly terrorist attack in Manchester this spring was charged with stealing from the people he had aided.
17h

“I am grateful for what Taylor Swift did.” We asked women to share their thoughts on Ms. Swift’s testimony about a former radio host who she said groped her.
20h

BRETT CARLSEN FOR THE NEW YORK TIMES

An alliance between Fiat Chrysler and BMW, which includes Intel and Mobileye, could help Fiat Chrysler catch up in the race to make self-driving cars.
20h

Zimbabwe’s first lady, Grace Mugabe, is said to be seeking diplomatic immunity from an assault charge. She’s accused of injuring a young model with an extension cord.
21h

The N.F.L. Players Association and the league have traded angry accusations over information related to the suspension of Dallas Cowboys running back Ezekiel Elliott.
1d

Dr. Marian C. Diamond, a neuroscientist who proved that environmental factors can change the structure of the brain and also studied the brain of Albert Einstein, is dead at 90.
1d

A comedian filed a lawsuit against the white supremacist website The Daily Stormer over an article claiming he was the mastermind of the Manchester attack.
1d

The renegotiation of the North American Free Trade Agreement is off to a rocky start, as the Trump administration lectured Canada and Mexico on the current agreement’s failures.
1d

A third woman has come forward to accuse Roman Polanski of sexual abuse, saying that the film director “sexually victimized” her in 1973, when she was 16.
1d

Giancarlo Stanton, the Miami Marlins slugger, is on pace to hit 60 home runs after hitting his 44th Tuesday. It was his sixth consecutive game with a homer; the record is eight games.
1d

CARLOS GONZALEZ FOR THE NEW YORK TIMES

As part of its campus extension, the University of Southern California made commitments to help its neighbors, in one of the state’s poorest areas.
1d

Barack Obama’s response to the violence in Charlottesville, with a quote from Nelson Mandela, quickly became the most-liked tweet ever.
1d

Hope Hicks, a longtime aide to President Trump, will be the interim White House director of communications, temporarily filling the spot left by Anthony Scaramucci.
1d

The sperm count of men in Western countries has been declining, according to research, bolstering a school of thought that male health in the modern world is at risk.
1d

A tech start-up is working to reduce health care costs while improving care. The results are on view at two medical practices in southeast Kansas.
1d

After months of feuding, Britain’s government said it wanted to remain — temporarily — in something similar to the European customs union after Brexit. Critics called it a “fantasy,” “contradictory” and “daft.”
August 15, 2017
2d

Michael Moore has targeted President Trump in his Broadway show, and now he is offering his audience more: a double-decker bus ride to Trump Tower to protest.
2d

Thirty immigrants became United States citizens on Tuesday in the first naturalization ceremony held on the 102nd floor of One World Trade Center in Manhattan.
2d

A 200-year-old tree crashed to the ground in Portugal, killing 13 people and injuring 49 others who had gathered for a religious celebration.
2d

“Groundhog Day,” the ambitious Broadway adaptation of the popular 1993 film, will close Sept. 17. Despite strong reviews, it failed to draw audiences to support its running costs.
2d

Dr. Ruth Pfau, a German-born medical missionary who was hailed as the “mother Teresa of Pakistan” for her role in fighting leprosy, is dead at 87.
2d

After days of torrential rain and flooding in Freetown, Sierra Leone, hundreds are still missing and coroners are struggling to find room for the dead.
2d

An age-old Spanish practice in which ranchers in the country’s northwest corral free-roaming, wild horses is now under threat from activists and regulation.
2d

A judge has ordered Costco to pay Tiffany & Co. over $19 million for selling generic diamond engagement rings that were marketed using Tiffany’s name.

Washington Post Today’s WorldView

BY ADAM TAYLOR

Trump’s Charlottesville response puts his foreign friends in an awkward position

President Trump’s defiant and seemingly sympathetic reaction to far-right violence during protests in Charlottesville last weekend has left his domestic allies scrambling. But don’t forget the foreign leaders who count Trump as an ally: Some had tried to overlook the president’s remarkable global unpopularity in the interest of shoring up strategic partnerships with the United States — and now find themselves tarred by association.

Case in point? Theresa May. The British prime minister rushed to Washington to meet the newly elected Trump in January. The pair sought to give the impression that, at a time when Britain and the United States were looking isolated among their Western allies, the “special relationship” was still strong. A photo of the two awkwardly holding hands as they toured the White House soon went viral.

Things haven’t gone well for May since then. The prime minister called a snap election for June, thinking she was all but guaranteed to boost her parliamentary majority. Instead, she only narrowly avoided a historically disastrous defeat. Much of the blame lies with May herself, a wooden politician who seems out of touch with the nation, but her association with Trump also seems to have jinxed her. The U.S. president was never popular in Britain, and his attacks on London Mayor Sadiq Khan after terrorist attacks in the capital made him positively toxic.

And now, just when it looked like Trump’s reputation couldn’t sink lower in Britain, Charlottesville happened.

Trump’s apparent sympathy for far-right protesters — who included neo-Nazis, the Ku Klux Klan and members of “alt-right” groups — played horribly in a country that still reveres the sacrifices made during World War II. Even among adamant right-wing “Brexiteers,” perhaps Britain’s most pro-Trump group, there is a unshakable pride in Britain’s role in defeating Nazi Germany. Paul Mason, a left-leaning journalist, summed up the feelings of many Britons when he directly addressed May on Twitter: “if you don’t condemn Trump’s support for white supremacists NOW why did our fathers fight [World War II]?”

On Wednesday, May told reporters that she saw “no equivalence between those who propound fascist views and those who oppose them,” but did not mention Trump by name. Critics, including many in her own party, concluded that it was too weak a statement — especially as May was spending a considerable amount of time condemning a decision to temporarily silence Big Ben, the giant clock in London’s Houses of Parliament, which is undergoing renovations.

For all her faults, May is not a far-right sympathizer. But she made the fateful decision to tie her leadership to Trump and his “America First” vision and seems to be too cautious now to criticize her ally.Other European leaders had been more circumspect: France’s Emmanuel Macron and Germany’s Angela Merkel courted Trump when needed but have also undermined Washington at other points.

Whoever leads Britain after May will almost certainly be a loud critic of Trump. Her popular Labour rival, Jeremy Corbyn, has frequently attacked Trump, as has Liberal Democrat leader Vince Cable. “Donald Trump should unequivocally condemn those who want to reverse the achievements of the civil rights movement and take us back to the days of Jim Crow,” said Corbyn to reporters on Wednesday. Members of May’s own Conservative part like Sajid Javid, a member of parliament have made their own thoughts clear as well.

May isn’t the only one in a bind. Across the world, it’s become increasingly clear that allying yourself with Trump presents a political liability. As The Post’s Isaac Stanley-Becker, James McAuley and Rick Noack noted on Wednesday, even those on Europe’s far right struggled to reconcile Trump’s comments with their own drive for mainstream legitimacy. “They don’t want to be tarnished by every scandal or misstep that rocks the Trump presidency,” said Thomas Greven, a political scientist at the Free University in Berlin to my colleagues.

The Trump toxicity can work the other way, too. After the president made military threats against Venezuela last week, other Latin American leaders — even ones who enjoy close and friendly relationships with Washington — were united in condemning Trump, the New York Times noted Wednesday. “The possibility of a military intervention shouldn’t even be considered,” said Juan Manuel Santos, Colombia’s president. Venezuela’s pariah president, Nicolás Maduro, also used Trump’s threat to rally his flagging support at home.

Vice President Pence is now touring the region as Trump’s “global translator” in a bid to soothe these relationships, The Post’s Philip Rucker reported — though Pence announced on Wednesday he was returning to Washington a day early amid this week’s furor.

Of course, there are still a number of world leaders Trump can count on as allies, although many are despots and autocrats. One of the few democratic leaders who has stuck by Trump is Israel’s Benjamin Netanyahu, but his reaction to events in Charlottesville has been muted despite the anti-Semitism on display. The Israeli prime minister took several days to offer a milquetoast condemnation of “anti-Semitism, neo-Nazism and racism,” although his 26-year-old son wrote on Facebook that he was more worried about left-wing violence than threats from the right.

As Today’s WorldView noted yesterday, most of Trump’s foreign policy is not radical. He has not followed through on the suggestions of true isolationism he made on the campaign trail, and his threats to the United States’ alliances remain unfulfilled for now. But own-goals like the one we’ve seen Trump spectacularly score this week are only making him more isolated on the world stage.

Why? Just ask Britain’s May. Allies may fear Trump’s wrath, but his embrace seems far more politically damaging.

• The New York Times’ Andrew Kramer and Andrew Higgins broke the news that a Ukrainian man thought to have unknowingly created malware used in alleged Russian hacking against the United States is now a witness for the FBI. As the Times notes, this new detail in the investigation seems to show that much of the harder work in the hack was outsourced to “private and often crime-tainted vendors.”

“It is the first known instance of a living witness emerging from the arid mass of technical detail that has so far shaped the investigation into the election hacking and the heated debate it has stirred,” the Times notes. And while the man, who goes by the alias “Profexer,” did not apparently work directly with Russia, the information he’s providing is giving U.S. officials critical new insight into how Russian hacking groups operate and develop their tools.

• Trump took to Twitter on Wednesday morning to claim that North Korea’s Kim Jong Un had made a “very wise and well reasoned decision” by backing down from his threats against Guam and not escalating military tensions any further. Vox’s Alex Ward explains why that is worrying, noting that “Trump may interpret Kim’s decision to back down as proof that his own belligerent rhetoric is what produced this current moment of calm.”

Spoiler: It wasn’t.

• A small detail in Ryan Lizza’s New Yorker article on Steve Bannon’s future at the White House has Canadian politicos confused: According to Lizza, Bannon is in regular contact with Gerald Butts, a longtime political advisor for Justin Trudeau, Canada’s liberal heartthrob of a prime minister. The pair are apparently so close that Butts has been pushing Bannon to raise taxes on the rich, as Trudeau did last year.

• There’s been a lot of talk about “antifa” groups — the word is a shortening of “anti-fascist” — in the aftermath of Charlottesville. The sudden rise of the term might suggest to some people that the groups are a new, American-born phenomena, but that’s far from the case, as Dartmouth historian Mark Bray writes for The Post:

“The first antifascists fought Benito Mussolini’s Blackshirts in the Italian countryside, exchanged fire with Adolf Hitler’s Brownshirts in the taverns and alleyways of Munich and defended Madrid from Francisco Franco’s insurgent nationalist army. Beyond Europe, anti-fascism became a model of resistance for the Chinese against Japanese imperialism during World War II and resistance to Latin American dictatorships.

Modern antifa politics can be traced to resistance to waves of xenophobia and the emergence of white power skinhead culture in Britain in the 1970s and ’80s. It also has its roots in self-defense groups organized by revolutionaries and migrants in Germany, as the fall of the Berlin Wall unleashed a violent neo-Nazi backlash.”

Today, you can often see antifa imagery in the terraces of world’s soccer stadiums — clubs in many countries are often linked to right- or left-wing politics and use chants and signs to back their agendas, even in the U.S.

Iranian women sit on street bench in Tehran on Aug. 2. (Nazanin Tabatabaee Yazdi/TIMA via Reuters)

‘Footloose’ in Farsi

If it weren’t so sad, it would be funny.

Six people — four male and two female — were recently arrested in Iran for teaching Zumba, a Colombian fitness routine that’s a hit in the U.S., and other “Western” dance moves. The six filmed themselves and posted the clips on social media apps such as Telegram and Instagram.

“The members of a network teaching and filming Western dances have been identified and arrested,” said Hamid Damghani, a Revolutionary Guard Corps commander in northeast Iran, to Jamejam Online.

Their crime, he said, was seeking to “change lifestyles and promote a lack of hijab.” In Iran, women are required to wear headscarves and modest clothing in public. Women are also banned from dancing in front of men who are not from their immediate families. Authorities have forbidden the teaching of Zumba and other dances, even in women-only gyms.

“The promotion and teaching of dancing in the name of sport in women’s gyms is a serious issue,” Damghani said.

This isn’t the first time authorities have cracked down in this manner.

In 2014, six Iranians were arrested for making a video that showed them dancing to Pharrell Williams’s “Happy.” The young men and women were sentenced to a year in prison and 91 lashes, though both punishments were ultimately suspended. The video caught the attention of authorities after it became something of an online sensation, garnering 1 million views in six months.

The participants later said on state-run television that they were actors and were tricked into making the video for an audition. Their arrests sparked a backlash on social media. Even Williams chimed in, writing on Facebookthat “it is beyond sad that these kids were arrested for trying to spread happiness.”

As is so often the case when it comes to policing how women act, part of the concern stems from how men will respond. According to the Times, religious leaders worried that Zumba could corrupt Iranian men. They’ve even deemed online videos teaching the dance pornographic.

But while such moves may sometimes seem amusing abroad, they’re only the tip of much more sinister crackdowns. This year, for example, at least 22 journalists and activists were imprisoned as part of a crackdown by hard-liners on Western influences and activists ahead of the May presidential election, according to the Center for Human Rights in Iran. — Amanda Erickson

A US-based BBC correspondent recently returned to the country and penned a devastating review of how much stature the U.S. has lost abroad, both among leaders and ordinary citizens. Meanwhile, The Post describes this week’s chaos using foreign correspondent tropes, to hilarious but sobering effect. Elsewhere in the world, Der Spiegel rails against EU plans to house migrants in dangerous Libyan camps, while South Africa’s Mail and Guardian calls the end of Nelson Mandela’s party as we knew it.

America — diminished and dismissed

The US president’s failure to completely condemn far-right groups may leave behind profound effects.

By Katty Kay | BBC • Read more »

What if Western media covered Charlottesville the same way it covers other nations

The world would shake its head at America.

By Karen Attiah | The Washington Post • Read more »

Libyan camps for refugees are not the answer

A recent report compiled by European Union diplomats who visited the country reveals that the idea is completely unworkable.

By Der Spiegel • Read more »

Zuma won, but the ANC will never be a united party again

It doesn’t matter who takes over the ANC in December. The party will never be a united party again.

By Prince Mashele | The Mail and Guardian • Read more »

On Tuesday, President Trump once again morally equated the violence on “both sides” of the events in Charlottesville during a press conference in New York. The Atlantic takes a look at the rise of the violence from the left to see if the president has a point. Meanwhile, Bloomberg reports on an effort to map out what lies beneath New York City, while the New York Times shows what the fight for abortion rights looks like from both sides in Texas.

The rise of the violent left

Antifa’s activists say they’re battling burgeoning authoritarianism on the American right. Are they fueling it instead?

By Peter Beinart | The Atlantic • Read more »

Nobody knows what lies beneath New York City

Subterranean cartographers are bringing to light the dark, tangled truths buried under the streets.

By Greg Milner | Bloomberg • Read more »

A changed landscape for abortion rights in Texas

After access to abortion services were curtailed by Texas law, a photographer set out to document women on both sides of the debate.

By Carolyn Van Houten | The New York Times • Read more »

At least you can’t say the residents of Guam aren’t having a little fun with the long-running threat from North Korea. Thankfully for them and the rest of the world, tensions with North Korea are calming back down — at least for the moment. But Vice President Pence’s quicker-than-expected return to Washington was supposedly triggered by North Korea strategy meetings to be held on Friday, so further fireworks may be coming soon. (Ed Jones/Agence France-Presse via Getty Images)