The Carbohydrate Cravers

What causes obesity?

We hypothesized that a defect in the body’s efficient regulatory system could cause obesity–at least in the group of people known as carbohydrate cravers.

At least half of all obese people in the United States crave and consume large amounts of pure carbohydrates, mostly in the form of snack foods.

Studies performed at the M.I.T. Clinical Research Center by Judith Wurtman and Sharon Mark, among others, show that most carbohydrate cravers eat snacks at a regular time of day (between 2 and 4 P.M., for example, or 9 and 11 P.M.), and that they desire nonsweet carbohydrate-rich foods such as pasta and bread as much as sweets.

These snacks make up 25 percent or more of the average patient’s daily calories, an amount that could fully account for his, or more typically her, obesity.

Why do certain people crave carbohydrates at fixed times of the day? We believe that their “need’ stems from a property of their brains–just as it is a property of some people’s brains that requires them to sleep eight or nine hours per night while others do just as well on six or seven.

We know that the release of serotonin is a signal to the brain that a carbohydrate-rich meal has been consumed, as such a meal increases brain levels of serotonin’s precursor, tryptophan.

Perhaps carbohydrate cravers have fewer serotonin-releasing neurons than their non-carbohydrate-craving peers. If so, less serotonin would be released, and the brain would not think the body had eaten enough carbohydrates and thus would instruct it to eat more.

Another possibility is that carbohydrate cravers have fewer molecules for transporting tryptophan at the blood-brain barrier. If that is true, then changes in blood amino-acid levels after a carbohydrate-rich meal would have only a small effect on tryptophan levels in the brain.

Or perhaps a carbohydrate meal is less effective in depressing the amino acids that compete with tryptophan for brain uptake; that could be due to the fact that such people release less insulin or are less responsive to the hormone.

Perhaps carbohydrate cravers almost never have carbohydrates in their meals because their thin carbohydrate-eschewing doctors put them on high-protein, low-carbohydrate diets.

In any event, the ability of serotonin-producing neurons to “monitor’ food-induced changes in blood plasma is of real use to the body. In addition to helping the brain regulate diet, the release of serotonin makes people feel sleepy and less vigorous. It also tends to have a calming effect. Not surprisingly, consumption of carbohydrates induces all these effects.

Indeed, we begin to suspect that some people sense a connection between what they eat and how sleepy or depressed or anxious they feel. They may then “self-medicate’ by choosing foods that produce the desired effect.

For instance, some patients suffering from a kind of depression that recurs each fall or winter experience a severe carbohydrate craving during this time. Perhaps this craving reflects a subconscious desire to “treat’ the depression, since carbohydrates produce some of the same chemical effects on the brain as antidepressant drugs.

Similarly, obese people may eat frequent carbohydrate snacks in a subconscious effort to calm their nerves.

Fooling The Brain

The next logical question to pursue was whether we could develop a treatment for obesity by correcting the defect that causes carbohydrate craving.

For instance, would a drug that could “fool’ the brain into thinking that carbohydrates had been eaten actually diminish a person’s appetite for carbohydrates?

The ideal drug would be one that releases serotonin into brain synapses, or that prolongs the time serotonin molecules remain in the synapses.

And sure enough, experiments have shown that small doses of d-fenfluramine, a typical serotonin releasing drug, lead to a major reduction in obese people’s intake of carbohydrate snacks. Such doses also lead to a smaller but still significant decrease in the number of carbohydrate calories such people choose at mealtime.

However, using drugs is probably not a long-term solution to weight loss for most people. Our experiments suggest that carbohydrate cravers can satisfy their cravings by eating very small portions of foods high in carbohydrates.

For instance, eating gumdrops or a 250-calorie bagel should satisfy the craving about as well as a 1,000-calorie ice cream sundae.

Diet And Depression

The link between serotonin and appetite is only one example of what appears to be a significant correlation between brain chemicals and human behavior.

In fact, some forms of human depression may be related to a deficiency in brain norepinephrine, while others may be due to an inadequate supply of serotonin. That hypothesis is based on the fact that all antidepressant drugs now in use cause some increase in both neurotransmitters.

Since tyrosine can enhance the production of brain norepinephrine, psychiatrists have begun testing the possibility that tyrosine might be effective in treating some depressed patients.

Psychiatrist Alan Gelenberg and neurologist John Growdon, both at Massachusetts General Hospital, have reported that depressed patients feel less suicidal and despondent after receiving large doses of tyrosine. This effect, confirmed by other investigators, is now the subject of a large double-blind study involving 120 patients.

Tyrosine also seems to generate feelings of vigor in people age 40 and older. Furthermore, when tyrosine is given to rats undergoing severe stress, the animals behave normally for a longer time than severely stressed rats who have not been treated.

Tyrosine may accomplish this effect by sustaining the production of norepinephrine in the animals’ brains. It will be interesting to see whether supplemental tyrosine also has an “anti-stress” effect in people.

Treating Senility

While there are many possible therapeutic uses for the nutrients that yield brain chemicals, the one that has attracted the most interest is the use of choline to treat Alzheimer’s Disease, the most common cause of senility. Alzheimer’s disease can first manifest itself as minor incidents of forgetfulness in people as young as 45.

However, the disease eventually destroys memory and intellect. Alzheimer’s disease strikes about 5 percent of Americans by age 65. The disease seems to be associated with damage to the neurons that release acetylcholine into the parts of the brain linked with memory (the hippocampus) and cognition (the cerebral cortices).

This damage, which results in a deficiency of acetylcholine, has been observed during autopsy in virtually all patients who suffered the ailment. About one-third of these patients also suffered impairments in other groups of neurons.

Scientists have yet to understand how the neurons implicated in Alzheimer’s disease are damaged. But many hypotheses are now being investigated, including one developed at M.I.T. that centers on the concept of neuronal “auto-cannibalism.”

Through in vitro experiments with slices of rat brain, Krzysztof Blusztajn, Jean-Claude Maire, and I have found that when there is not enough choline to synthesize acetylcholine, these neurons obtain more of the precursor by chewing up their own cellular membranes, which are rich in lecithin.

If such destruction continues over a long period of time, it could sorely damage the viability of these neurons.

But why would there be an inadequate supply of choline in the first place? Perhaps the system that transports choline across the blood-brain barrier is defective, or the neuron’s ability to trap choline molecules is impaired.

Once the disease process begins, the surviving neurons might begin firing so frequently – to compensate for the neurons destroyed by the disease – that their choline requirements would become abnormally great, leading to secondary auto-cannibalism.

Memory Loss And Milkshakes

Despite uncertainty over the fundamental cause of Alzheimer’s disease, many scientists are exploring ways to treat victims with drugs that raise brain acetylcholine levels, or that mimic the effects of this neurotransmitter on nerve cells.

One way to increase the production of brain acetylcholine–at least in the laboratory rat–is to administer choline or the molecule phosphatidylcholine, known as lecithin.

While patients can raise their blood (and brain) choline levels by eating three-egg omelets three times daily (eggs are rich in lecithin), most people would soon tire of such a diet. Besides, nine eggs per day would also provide more than a sensible intake of fat.

So scientists have taken to administering phosphatidylcholine, usually purified from soya beans and mixed in a frappe, or, more recently, available in prepackaged mixes of chicken soup.

Although large doses of choline (and tyrosine) are often administered in such experiments, there seem to be few side effects in patients. This may be because choline and tyrosine enhance production of neurotransmitter only in neurons that are actively firing.

Initially, investigators interested in the effect of choline on Alzheimer’s disease based their studies on the way dopa, an amino acid not normally found in the diet, was used to treat Parkinson’s disease. Thus, they gave patients doses of choline only for days or weeks.

A few of these studies yielded transient improvements in some patients; most yielded no useful results at all. More recently, scientists have begun giving patients phosphatidylcholine for six months or more with better results.

In one double-blind study, directed by Raymond Levy, a professor of psychiatry at the Maudsley Hospital in London, 51 patients with Alzheimer’s disease received 25 grams of 95 percent pure phosphatidylcholine or its placebo (a cherry-flavored frappe containing margarine) daily for six months.

The patients were tested monthly for changes in their memory and cognitive functions, and all were followed for another six months after treatment.

Paradoxically, the patients who complied well with the requirements of the study–drinking all of the lecithin frappe and exhibiting large increases in plasma choline levels–failed to show consistent improvement in intellectual function or their ability to care for themselves. But patients who complied less well–only doubling their plasma choline levels–improved throughout the treatment period.

Perhaps too much choline is not good; perhaps the patients who responded had a disease involving only neurons that convert choline into acetylcholine, while the non-responders also suffered deficits in other types of neurons. Perhaps the people who were less sick to start with remembered each day how badly the lecithin frappe had tasted on the previous day, and decided, on occasion, not to drink it.

Only further studies will tell whether the apparent therapeutic effect in some patients is real and confirmable and important. If so, it will constitute the first treatment to significantly benefit patients with Alzheimer’s disease.

We should remember that for the first seven years that physicians attempted to use dopa to treat Parkinson’s disease–now a universally accepted treatment–almost every description of its effects was negative.

It took an investigative genius–Dr. George Cotzias of Brookhaven National Laboratory–to devise a way to exploit dopa’s useful effects. However, we should also remember that many proposed treatments appear to work when first tested on small groups of patients, but then lose their apparent efficacy with larger patient samples.

Other scientists have found that administering choline helps curb the facial tics that afflict patients suffering from another neurological disease, tardive dyskinesia. This disease often occurs in patients treated with antidepressant or anti-schizophrenic drugs for a long time.

Some scientists have also found lecithin beneficial in controlling mania, the side of manic depression that produces hyperactivity and feelings of extreme elation. But all these results still require large-scale confirmation.

Now that pure, palatable lecithin is available in chicken-soup mixes to physicians with government approval, such large-scale studies can finally be performed. But even if results are positive, thorny regulatory issues must be resolved before such nutrients can be widely used to treat disease.

For instance, should these nutrients be classified as drugs, as food, or in a distinct category all their own?

The nutrients are now considered experimental drugs, and their use is closely supervised by the Food and Drug Administration (FDA). But categorizing them as commercial drugs would be difficult because nutrients simply cannot be tested for safety the same way drugs are.

For example, to win FDA approval for marketing a drug, a pharmaceutical company must show that a dosage 100 times greater than the one proposed is not toxic to laboratory animals. While researchers can give such high doses of drugs, which come in milligram amounts, they can’t possibly administer such high doses of nutrients, which come in gram amounts and are already present in the daily diet.

For example, an animal (or human) would have to eat 800 to 1,000 eggs per day to consume 100 times more lecithin than normally found in the diet. The body simply cannot accommodate that high a dosage–either in food or purified form.

Nor can these nutrients be properly classified as food, since they are not designed to affect only nutrition and taste. The FDA is considering creating a distinct category for these nutrient-drugs.

However, there will probably be little impetus for action until scientists are certain that nutrients such as tyrosine, tryptophan, and lecithin can indeed modify behavior and ameliorate disease.

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