Catecholamines Kick Out the Demons of Depression
Phenylalanine May Also Help with Weight Loss
neurotransmitters dopamine and noradrenaline
This article originally appeared in the July 1999 issue of Life Enhancement. Its reappearance is timely because there is a renewed interest in the amino acid phenylalanine, a precursor to the neurotransmitter molecules dopamine and noradrenaline. Although it is well known that boosting the synaptic levels of these neurotransmitters can help alleviate depression, it is not so well known that phenylalanine can help reduce food intake through its ability to stimulate release of the satiety hormone CCK.
I would scarcely kick to come to the top.
— John Keats
Metabolic pathway of phenylalanine, tyrosine, and the catecholamines.
Despair and hopelessness, so characteristic of serious depression, had engulfed the poet John Keats when he wrote to a friend in 1818. He could not have known that a chemical compound called phenylalanine (which had not yet been discovered) might provide a helpful “kick” for his own soul as well as for many other depressed souls in their struggle to remain afloat.
The demons of depression exact a terrible toll on human happiness and productivity—even on life itself. But scientists’ quest to understand the origins of this affliction, and to ameliorate it, continues to bear fruit. A recent study at the Yale University School of Medicine has shown a strong link between depression and low levels of compounds called catecholamines (cat-eh-coal-ah-meens´) in our bodies.1
That in itself is not news, but there is an intriguing twist. It was found that people who suffer from bouts of clinical depression are biochemically different from those who are normal and healthy. This is true even when the depression-prone individuals are in remission and appear to be normal and healthy. They are, in a sense, biochemical time bombs ready to go off into another depressive episode.
But what lights the fuse? Perhaps a better question is: is there a way to dampen the fuse so it fizzles before anything goes boom? Neither question has a simple answer, but much research points to the catecholamines.
What Are Catecholamines?
Catecholamines are biologically active compounds that play key roles in metabolism and cardiovascular function. These simple, structurally similar organic compounds also play vital roles in regulating the function of our nervous systems, both central and peripheral. Without them, our bodies would be like the Internet if all the transmission lines failed—dead. One catecholamine in particular, noradrenaline, is involved in mood regulation.
Catecholamines are obtained exclusively by synthesis from nutrient molecules—mainly the amino acids phenylalanine and tyrosine—in our foods. In normal metabolism, phenylalanine converts to tyrosine, which converts via dopa to the catecholamine dopamine; dopamine is the immediate precursor of noradrenaline, which converts to adrenaline.
One way to ensure adequate levels of these essential compounds is by consuming their nutrient precursors via supplementation. Phenylalanine can be taken as a supplement; tyrosine can too, but it does not provide the same uplifting benefits as phenylalanine, because the latter is required for the production of a metabolite, phenylethylamine, whose mood-elevating properties augment those of noradrenaline.
The “Big Three” Catecholamines
The best-known catecholamines are dopamine, noradrenaline, and adrenaline. (Scientists prefer the terms norepinephrine and epinephrine for noradrenaline and adrenaline, but the latter terms are still being used.) Dopamine and noradrenaline are neurotransmitters—compounds that mediate the flow of impulses between neurons. Adrenaline is a stress hormone responsible for the well-known “fight or flight” response, which prepares the body to cope with crises.
Dopamine deficiency is implicated in some forms of depression and in Parkinson’s disease; conversely, excessive dopamine levels are implicated in some forms of psychosis, such as schizophrenia. Noradrenaline is prevalent in the peripheral nervous system but is also found, in much lower concentrations, in the brain (adrenaline is found in the brain too, at lower concentrations still). In some types of depression, there is a noradrenaline deficit in certain regions of the brain, and some antidepressants drugs are designed to boost these levels by interfering with the mechanism that keeps them down.
Catecholamine Deficiency Leads to Depression in Depression-Prone Patients
In the Yale study mentioned above (a randomized, placebo-controlled, double-blind, crossover trial), Dr. R. M. Berman and his colleagues administered a compound, alpha-methylparatyrosine, that inhibits the synthesis of catecholamines from their chemical precursors. The subjects had a history of clinical depression and had been in remission and medication-free for at least three months.
Quick: what do rabbits, pigs, monkeys, and humans have in common? A lot, actually, but one thing is that they (and other species as well) have all been shown to eat less when injected with a polypeptide hormone called cholecystokinin (CCK). It’s not that CCK makes them sick, but rather that it induces a feeling of satiety, or fullness. And even if you’re a pig (a real pig), you tend to stop eating when your stomach feels full.
How CCK accomplishes this trick is not clear, but some evidence points to a direct action on the pyloric sphincter (the valve between the stomach and the duodenum), causing a delay in the gradual, hours-long process of releasing the stomach’s contents to the intestines. That would send a message to the brain saying, “Hey, I’m getting full! Make this guy stop eating!”
Be that as it may, few people would want to try to lose weight by getting daily injections of CCK, even if they could afford it. A better way would be to stimulate the body’s own production of CCK, which, as it happens, is produced naturally by the small intestine in response to the presence of fats. This causes the gallbladder to contract, releasing bile into the intestine to help digest the fats. The presence of CCK in the bloodstream (which it enters via the intestinal wall) also causes the secretion of digestive enzymes from the pancreas, as well as insulin and glucagon.
Those are useful functions, obviously, but it’s CCK’s satiety effect that is of interest here. Which brings us back to the question of how to stimulate this effect. It has long been known that phenylalanine is a potent releaser of CCK, but experiments in the 1980s to cause a suppression of food intake with phenylalanine doses of as much as 10 g failed to show any such effect.
CCK Levels Increase 5-Fold in 20 Minutes
In 1994, two British researchers tried again, this time being careful to ascertain both the degree to which phenylalanine caused blood levels of CCK to increase and the precise time at which the levels peaked.1 In preliminary experiments, they found that oral administration of 10 g of phenylalanine in human test subjects caused a 5-fold increase in CCK levels, peaking 20 minutes after the supplement was taken. That, they concluded, was the correct time at which to give the subjects a meal to see what effect the enhanced CCK levels might have.
The subjects were six healthy, not overweight adults (four men and two women, average age 30). After an 8-hour fast starting at midday, they were given the phenylalanine at 8 P.M., followed 20 minutes later by a buffet-style supper at which they could choose freely and eat and drink whatever they liked. The caloric content of all the foods was known, and the subjects’ intakes were measured, as were their CCK levels before the meal. (As in the preliminary experiments, there was a 5-fold increase in CCK during the 20-minute period.)
The study was placebo-controlled, with each subject acting as his or her own control via phenylalanine and placebo trials that were conducted in identical fashion at least seven days apart. The trial was single-blind—the researchers knew who was getting what in each session, but the subjects did not.
Caloric Intake Drops About 30%
The results showed a significant satiety effect with phenylalanine: the subjects consumed an average of 1587 kilocalories (1 kilocalorie = 1000 calories = 1 Calorie) after taking placebo, but only 1089 kilocalories after taking phenylalanine—a 31% reduction in caloric intake. (If you count the 42 kilocalories contributed by the 10 g of phenylalanine, their intake was really 1131 kilocalories, a 29% reduction.) There were no reports of any side effects.
An important feature of this experiment was that the phenylalanine was taken with 200 ml (7 fl oz) of water, which acted as a physical “load” on the stomach, causing some distension. The stimulation produced by such loading interacts with CCK’s biochemical action to reduce food intake. In other words, CCK works much better with a load than without one.
Thus, if these results are borne out, it may be possible to lose weight through the satiety effect by taking phenylalanine with a glass of water 20 minutes before a meal. The smaller the amount taken, the smaller the effect is likely to be, but there is some evidence that even very small amounts of supplemental phenylalanine (less than a gram) may influence appetite.2
The results were dramatic: depleting the catecholamines produced marked symptoms of depression in the experimental group, as measured by the Hamilton Depression Rating Scale. By contrast, the control group was almost totally unaffected. The authors concluded that
Catecholamine Deficiency is Implicated in Age-Related Mental Problems
Several earlier short-term studies had shown that inhibition of catecholamine synthesis did not have any effect on the mood of normal, healthy people who had never suffered from clinical depression. They were clearly more resilient than those whose prior depression had made them vulnerable to a temporary depletion of these vital molecules.
This does not mean, however, that maintaining optimal levels of catecholamines is not important for normal, healthy people. Catecholamines are very important for good mental health, especially as we grow older and our output of these neurotransmitters gradually declines. Most of the mental failings that often accompany aging, such as loss of memory, loss of mental alertness and energy, tendency toward depression, vulnerability to stress, and Alzheimer’s and Parkinson’s diseases, are associated with reduced levels of noradrenaline or dopamine.
Phenylalanine Can Help Fight Depression and Sustain Mood
There is a growing body of both anecdotal evidence and clinical observations showing that phenylalanine supplements can alleviate the symptoms of some forms of depression. It can also boost various aspects of mental function in healthy people who wish to maximize their ability to stay that way.2 In one such clinical study published in 1984, the authors concluded that “The results support the view that the brain is able to use dietary amino acids to enhance production of brain neuroamines capable of sustaining mood.”3
The Orthomolecular Approach
The two main goals of nutritional intervention—to alleviate the symptoms of disease and to optimize a state of health—exemplify an approach to health care called orthomolecular medicine, or orthomolecular psychiatry when it’s aimed at mental disorders. (The prefix ortho is from the Greek orthos, meaning correct.)
The underlying idea is that many diseases or disorders result from imbalances in the concentrations of certain compounds normally found in the body, and that such conditions can best be treated by administering one or more of those compounds or their natural precursors (plus any relevant cofactors) so as to restore the correct balance and, therefore, good health. The optimal concentrations of the compounds in question may differ greatly from the concentrations actually provided by the person’s genetic makeup or normal diet—hence the need for nutrient supplementation.
Pauling’s LegacyThe leading figure in the orthomolecular school of medicine was the late Linus Pauling, one of the greatest scientists who ever lived. Part of Pauling’s legacy is the increasing acceptance of his conviction that the orthomolecular approach to therapy, prophylaxis, and health optimization, particularly in cases of mental disorder, is generally the best. In his own words, “Significant improvement in the mental health of many persons might be achieved by the provision of the optimum molecular concentrations of substances normally present in the human body.”4
And remember: if you start feeling down or depressed, it may not be all in your head. You may be able to kick-start your mental energy again just by putting the correct molecules in your stomach.
- Berman RM, Narasimhan M, Miller HL, Anand A, Cappiello A, Oren DA, Heninger GR, Charney DS. Transient depressive relapse induced by catecholamine depletion: potential phenotype vulnerability marker? Arch Gen Psychiatry 1999 May;56(5):395-403.
- Hendler SS. The Doctors’ Vitamin and Mineral Encyclopedia. Simon & Schuster, New York, 1990, pp 225-8.
- Kravitz HM, Sabelli HC, Fawcett J. Dietary supplements of phenylalanine and other amino acid precursors of brain neuroamines in the treatment of depressive disorders. J Am Osteopath Assoc 1984;84/1 Suppl:119-23.
- Pauling L. Orthomolecular psychiatry: varying the concentrations of substances normally present in the human body may control mental disease. J Nutr Environ Med 1995;5/2:187-98.