FOCUS ON TRYPTOPHAN
by John W. Crayton, MD, Professor of Psychiatry at Loyola University Medical School, Maywood, Illinois, and Chief, Section of Biological Psychiatry, Hines Veterans Administration Hospital, Hines, Illinois.
Over the past ten years, our research laboratories have focused considerable attention on the role that tryptophan plays in normal brain function. As the essential amino acid precursor for the production of the neurotransmitter serotonin in the body, dietary tryptophan has been found to play a critical role in optimal mental activity. Studies from our laboratory and others suggests that this amino acid may play important roles in the regulation of food intake, the maintenance of good sleep, and mood regulation, to name just three of its more important functions. In this "Doctor's Corner" column, I shall describe the current status of our understanding of tryptophan's role in the brain and some of the new ways now available for studying its activity.
When we eat foods containing tryptophan, such as poultry meats, milk, and other high-protein foods, tryptophan is released from these proteins and enters the circulation. Under most "normal" situations (we will leave aside for now the problem of deciding what is "normal") we eat enough foods containing tryptophan so that no deficiency of this amino acid occurs. A large amount of this tryptophan is taken up by so-called "mast cells" in the wall of the intestinal tract where it is metabolized into serotonin and stored there. A lesser, but equally important amount is taken up by the brain through an active, energy-requiring "transporter pump."
The transporter pump for tryptophan has some interesting properties that influence how much tryptophan can get into the brain. First, the transporter pump is shared by other so-called "large neutral amino acids," abbreviated LNAA. What this means is that if other LNAA's are present-as they would be if we were eating a balanced diet-then tryptophan would "compete" with the other LNAA's for access to the transporter pump. What this means is that if we eat a diet that contains relatively large amounts of protein (made up of all of the amino acids) the amount of tryptophan entering the brain will be substantially less than the amount entering the brain while on a low protein diet.
On the other hand, if we eat a high carbohydrate-low protein meal, the amount of tryptophan entering the brain will be significantly increased compared with the normal situation.
Why is this important? Because these changes in tryptophan movement into the brain have a direct impact on the amount of serotonin produced by the brain, and serotonin is one of the most potent brain chemicals or "neurotransmitters". Only approximately one brain cell or "neuron" in one thousand uses serotonin as its neurotransmitter, yet alterations in the activity in these few neurons can have dramatic effects on a variety of brain functions. By altering tryptophan levels through what we eat, we have a means of altering the activity in these powerful serotonin neurons in the brain.
In collaboration with Lukasz Konopka and Bonnie Spring in our laboratories, we have been studying the effects on brain function produced by lowering the amount of tryptophan entering the brain by using a high-carbohydrate, tryptophan-free test meal. Four to five hours after such a test meal, brain serotonin levels are approximately 85% lower than normal. If we study brain activity at this time, using a computer-driven electroencephalogram, which allows us to "map" the distribution of brain activity, we find that in certain individuals there is a significant reduction in the amount of activity in the frontal regions of the brain-areas involved in mood and sensation processing.
These findings are consistent with other work that suggests that there is a "positive mood center"-a "Happy Center"-in the left frontal region of the brain, and a "negative mood center" or "Sad Center" in the right frontal region of the brain. These findings may help explain why people who have a stroke affecting the left frontal region of the brain are much more likely to develop a significant depression compared with those who experience a right-side stroke. These results-together with the findings from the tryptophan lowering test-point to a particular region of the brain where serotonin is having its mood-enhancing effect. Using approaches such as this may make it easier to develop and monitor the effects of new anti-depressant medication.
Does tryptophan itself have antidepressant effects? There have been a number of studies using tryptophan as a treatment for depression over the past 25 years. The results are mixed. Some studies showed a small but significant effect of tryptophan on depression while others did not. Perhaps tryptophan will need to be tried in conjunction with other nutrients such as vitamins or co-factors in the synthesis of serotonin in order for an effect to be seen. Or the tryptophan may have to be taken together with a low-protein meal in order for it to have a maximal effect.
Another application of this tryptophan-lowering test is the identification of people who may be "at risk" for depression, meaning that they would be more likely to develop depression. When tested with the tryptophan-lowering meal, individuals who are likely to become depressed actually show a lowering of their mood during the test session; people who are not likely to become depressed do not become depressed during the tryptophan-lowering procedure. People who show signs of depression during the test will quickly regain their normal mood state following a resumption of their regular diet.
In the tryptophan-lowering studies described above, we have been able to show that the brain's responsivity to sensations such as sounds is significantly altered during the low-tryptophan phase of the test. In this study, we examine the brain's responses to a series of graded sounds-from soft to quite loud. The brain responses of individuals can be measured with sophisticated electroencephalographic equipment that is linked to computers. Previous investigators found that people differ substantially in their responsivity to sounds-some people's brains have the capacity to dampen loud sounds so that they don't produce as much of an electrical signal in the brain, while other's brains seem to show an increased electrical response in parallel with the intensity of the sound. The first group have been called "reducers", while the second group are termed "augmenters". Recent studies have suggested that whether someone is an "augmenter" or a "reducer" depends on how active the tryptophan/serotonin nerve cells in the brain are. Our recent studies show that anti-depressant medications-ones that would be expected to increase serotonin activity-do, in fact, cause "augmenters" to respond more like "reducers". These findings may suggest that increasing tryptophan or serotonin levels may enhance one's capacity to deal with loud, unpleasant noises.
What have we learned from these studies that NOHA members can "take home"?
This work reinforces the importance of this powerful neurotransmitter system in the regulation of mood and sensation-modulation. Both of these effects may be related to the role of tryptophan and serotonin in the induction of sleep. Some people find that they can go to sleep more easily with 500 mg of tryptophan-either alone or in combination with a carbohydrate meal or even a small amount of a serotonin-enhancing agent like amitriptyline (e.g.. 25 mg). Others find that they can reduce jet lag by increasing their tryptophan levels-with supplements or carbohydrate meals-when they want to go to sleep; and decreasing their tryptophan levels-by eating a high-protein meal-when they want to be up and active.
Ever since a batch of supplemental tryptophan from one supplier was linked to a serious "Eosinophilic myalgia syndrome" a few years ago, it has been more difficult to obtain tryptophan. However, all indications are that current supplies, although spotty, are safe and may well be effective in certain individuals. Keep in mind, however, that for most people, more than adequate amounts of tryptophan are available in a regular, balanced diet.
Article from NOHA NEWS, Vol. XXVI, No. 1, Winter 2001, pages 3-4.