Phenylalanine and 5-HTP Will Go to Your Head

Phenylalanine and 5-HTP are the precursors of vital monoamine neurotransmitters

Something wondrous is happening inside your head. The reason you’re able to see and understand and remember these words is because neurotransmitters in your brain are facilitating the billions of individual neural impulses necessary to make it possible. On a slow day, your brain makes the busiest beehive look as though it were frozen in ice. Nothing in the world compares with your brain for seething, but exquisitely organized, activity at the molecular level—or at any level. If it weren’t stashed inside your head, it would belong on a pedestal in the Smithsonian Museum!

Inside your brain’s neurons (nerve cells), neural impulses are carried in the form of tiny electrochemical currents. But how do these currents cross the synapses—the junctions (about one-billionth of an inch wide) between neurons? They’re carried by neurotransmitter molecules, of which there are dozens of different kinds—over 100 if you include neuromodulators; these are chemicals that subtly influence the actions of the neurotransmitters themselves and are necessary for the process to work properly.

Until recently, it was thought that a given neuron utilized only one kind of neurotransmitter, but we now know that many neurons utilize two or more different kinds, which greatly complicates our attempts to understand the workings of the brain. Making sense of the Tower of Babel would probably have been easier.

The Big Four Neurotransmitters

To keep things more or less manageable, neuroscientists have concentrated their studies mainly on four important neurotransmitters: dopamine, noradrenaline, serotonin,and acetylcholine. The first three of these, belonging to a class of chemicals called monoamines, are the ones of interest in this article. Two of the monoamines—dopamine and noradrenaline—are catecholamines (as is the stress hormone adrenaline, which we’re not concerned with here).*

*The familiar terms adrenaline and noradrenaline, although still used by laypeople, are obsolete, having long ago been replaced in scientific usage by the terms epinephrine and norepinephrine.

The monoamines play central roles in our mood states as well as in our experience of fear and pleasure. They are also believed to play a key role in many cognitive functions, such as attention, learning, and memory. There is abundant evidence that complex interactions among these various neurotransmitter systems are more the rule than the exception, making their study very difficult. Disruptions in the levels and balance among the neurotransmitters contribute to the cognitive impairments associated with many psychiatric disorders, such as depression, schizophrenia, and attention-deficit hyperactivity disorder (ADHD), and with neurological disorders, such as Parkinson’s disease. Even in the absence of such maladies, however, age takes its toll on our levels of these neurotransmitters (see the sidebar “The Incredible Shrinking Brain”).

The Incredible Shrinking Brain
Your brain won’t 
that small!
Want to lose some weight? Grow older! Starting in our 20s, our brains begin to shrink—very slowly at first, but the pace accelerates as the decades go by, producing a roughly 10% weight loss in brain matter by age 90—and at present there’s little we can do about it. Little, but perhaps not nothing. Brain studies with rodents and humans have shown that some substances, including lithium, can stimulate neurogenesis, the growth of new neurons, as well as the growth of support cells called neuroglia, leading (in the latter case) to substantial increases in gray matter. Who knows where this promising research may lead? (See “Can Lithium Benefit Brain Health?” in the June 2004 issue.)

It was long thought that brain shrinkage was caused by a progressive loss of neurons throughout the entire brain, but that idea is in serious doubt. In the hippocampus, for example, actual cell counts show that the number of neurons doesn’t change much with age—which is a good thing, because the hippocampus is intimately involved in learning and memory. Other cortical areas are also unaffected.1

Then why do our brains shrink? Most neurologists believe that it’s due to a loss of neuroglia, as well as reductions in the dense jungles of interconnections among the neurons. Also, subcortical cells are lost, particularly in those widely distributed areas from which ascending neuronal projections fan out to influence the entire brain. These areas have jokingly been called “juice machines” because they distribute the vital neurotransmitters dopamine, noradrenaline, serotonin, and acetylcholine, which energize the brain (these molecules are also synthesized locally in the synaptic terminals of the neurons that need them).

Thus, these four neurotransmitters are gradually reduced through normal aging, in part because the brain cells that produce them are lost. For a double whammy, aging also increases our production of monoamine oxidase-B (MAO-B), one of two forms of the enzyme that breaks down the three monoamine neurotransmitters.* And for a triple whammy, MAO-B generates toxic, brain-damaging free radicals, which further accelerate the aging process. Gaaah—it’s enough to make you lose your mind!

*Acetylcholine is attacked not by monoamine oxidase (because it’s not a monoamine), but by the enzyme acetylcholinesterase, whose production also increases with age.

The good news, though, is that people with no neurological disease tend to maintain their intellectual performance until at least age 80, even if there’s some slowdown in the central processor and some degree of memory impairment. Furthermore, we can fight the brain-aging process by maintaining good cerebrovascular health so as to minimize the age-related decrease in cerebral blood flow, which is typically about 20%. And we can take antioxidants to reduce the destructive effects of free radicals. For the supplements needed to boost our neurotransmitter levels, see the sidebar, "Supplements for Neurotransmitters."

  1. Restak R. Mysteries of the Mind. National Geographic Society, Washington DC, 2000.
Supplements for Neurotransmitters

The precursors of the monoamine neurotransmitters are amino acids found in our foods. For the catecholamines dopamine and noradrenaline, the precursors are phenylalanine and tyrosine—in that order in the biosynthetic pathway. Tyrosine could be taken as a supplement—so why is phenylalanine preferred instead? Because tyrosine does not provide the same uplifting benefits as phenylalanine, which is required for the production of a metabolite, phenylethylamine, whose mood-elevating properties augment those of noradrenaline.

For serotonin, the precursor amino acid from foods is tryptophan, but it’s not available as a supplement, owing to a misguided ruling by the FDA in 1989. A batch of tryptophan from a Japanese supplier caused severe side effects, which were due not to the tryptophan itself but to a contaminant from a faulty manufacturing process. The FDA responded by banning the importation and over-the-counter sale of tryptophan—a perfectly safe amino acid that we eat every day in our food. That ban is still in effect—except, strangely enough, for infant formulas, where the use of tryptophan is mandated, because its absence could be life-threatening! Go figure.

Thankfully, the ban did not extend to the next molecule in the biosynthetic pathway, 5-HTP, which is the immediate precursor of serotonin. 5-HTP is not found in our food, but it’s a safe and effective supplement.

Acetylcholine is not a monoamine, but it’s vitally important for many aspects of neural function in the brain and throughout the body. To help boost our levels of this neurotransmitter and maintain the health of our cholinergic system, we can take the precursor compound choline and the dual-function acetylcholinesterase inhibitor galantamine (see the article on page 4 of this issue).

The reaction sequences shown here involve 
two valuable nutritional supplements: 
phenylalanine and 5-HTP.
Amino Acids Produce the Monoamines

The monoamines are made in our brains from amino acid precursors found in the foods we eat (and a few of the supplements we take). The amino acid phenylalanine, e.g., is converted in our brains to tyrosine (an amino acid that is also found in our foods), then to dopa, and then to dopamine, which is itself converted to noradrenaline, and then adrenaline. Similarly, the amino acid tryptophan is converted to 5-hydroxytryptophan (5-HTP), which goes to serotonin, then N-acetylserotonin, then the hormone melatonin.

None of these conversions is complete, i.e., not all phenylalanine goes to tyrosine, not all tyrosine goes to dopa, etc., so the overall yield tends to diminish as the reaction sequence proceeds. All the reactions are in equilibrium and can go in either direction, to varying degrees, depending on the prevailing physical and chemical conditions in the cell. Furthermore, these reactions are not the only ones possible: other reactions involving the same compounds can siphon them off in other directions for different purposes (and the preceding comments apply to all these reactions as well).

Nutrient Depletion—A Window on the Brain

As mentioned above, there is evidence that dopamine, noradrenaline, and serotonin may modulate learning and memory, as well as mood, anxiety, and other aspects of mental status. Deficits or excesses of these molecules can alter our brain activity in many ways, most of which are poorly understood, if at all. There have been relatively few studies seeking to explore the direct cognitive effects of manipulating the levels of the monoamines, mainly because of the lack of suitable methods that do not produce side effects such as nausea and sedation.

There is one simple and safe way, however, to manipulate the levels of these monoamines (downward only): restrict the availability of their amino acid precursors by briefly withholding them from the subjects’ nutrition. The technique, called nutrient depletion, entails giving the subjects (after a day of low-protein diet and then overnight fasting) an amino acid “cocktail” that is nutritionally well balanced except for its lack of the precursor molecules in question: phenylalanine and tyrosine for dopamine and noradrenaline (which we can refer to simply as catecholamines), and tryptophan for serotonin.

The monoamines play central roles 
in our mood states. They are also 
believed to play a key role in many 
cognitive functions, such as 
attention, learning, and memory.

In the ensuing cellular process of protein synthesis from the amino acids, any residual stores of phenylalanine, tyrosine, and tryptophan will be scavenged in order to make up for the deficiencies in the cocktail, while residual stores of the other amino acids will be untouched. This will create an acute (but harmless) deficiency in the three amino acids of interest—and that, in turn, will prevent the synthesis of catecholamines and serotonin, for about 5–6 hours. During that period, cognitive tests can be performed to observe the effects of these neurotransmitter deficits.

Australian Researchers Open the Window

Researchers in Australia recently conducted two nutrient-depletion studies of this kind.1,2 In the first study, phenylalanine/tyrosine depletion (to reduce catecholamine levels) and tryptophan depletion (to reduce serotonin levels) were undertaken separately, to see what the effects of the individual reductions would be. In the second study, all three amino acids were depleted, to see how a simultaneous reduction in all three of the monoamines would affect cognition. We’ll call these the Separate Study and the Combined Study, respectively.

The Separate Study Shows Minor Memory Impairments

In the Separate Study, the researchers recruited 20 healthy young women (average age 22), of whom 13 completed the entire sequence of cognitive tests.1 These were carried out at intervals over a period of several months and were timed so that the women’s menstrual cycles would not skew the results. Women were recruited because prior evidence had shown that tryptophan depletion reduces brain serotonin levels disproportionately more in females than in males (this is but one of many known examples of differences in brain chemistry between men and women). On the other hand, the authors stated that there is little evidence of a gender difference in the cognitive response to reduced serotonin levels.

At different times throughout the study, all the women received one of three different amino acid cocktails: (1) a balanced mixture containing 16 amino acids, including phenylalanine, tyrosine, and tryptophan; (2) the same mixture but without phenylalanine and tyrosine; and (3) the same mixture but without tryptophan. The women were given blood tests and tests of mood state and cognitive function before receiving the cocktail, and again 5 hours later, after spending the intervening time in a quiet room, with benign (nonexciting) reading materials and videos but no physical activity or undue distractions.

For the cognitive testing, the researchers used elements of the Cognitive Drug Research assessment system, a computerized battery of tests described as having a demonstrated sensitivity to acute changes in cognitive function and good validity as measures of memory and attention (which are categorized in many highly specific ways). From this CDR system, the researchers chose the following six tests, which were conducted using a computer monitor and a pushbutton for registering responses:

Word-list learning (immediate and delayed word recall) • Secondary memory (delayed word recognition) • Spatial working memory • Verbal working memory • Attention (consisting of simple reaction time, choice reaction time, and vigilance tests) • Perceptual processing

The results of the two nutrient-depletion regimens were different—and limited. Phenylalanine/tyrosine depletion (lower catecholamine levels) impaired the subjects’ spatial working memory, whereas tryptophan depletion (lower serotonin levels) impaired delayed memory recall on a structured word-learning task. In neither case was there any impairment in measures of attention, learning, verbal working memory, or subjective mood state.

The Combined Study Shows No Memory Impairment

In the Combined Study, the subjects (again 20 healthy young women, average age 22) were given an amino acid cocktail depleted of all three amino acids, resulting in reduced levels of the catecholamines and serotonin simultaneously.2 The researchers again used elements of the CDR assessment system, choosing the following 12 tests:

Word presentation • Immediate word recall • Delayed word recall • Delayed word recognition • Picture presentation • Delayed picture recognition • Digit vigilance (sustained attention) • Numeric working memory (digit scanning) • Spatial working memory • Simple reaction time • Choice reaction time • Critical flicker fusion (psychomotor function)

As a first guess, one might expect that the result of this combined trial would be the sum of the two separate trials, i.e., a simultaneous impairment of both spatial working memory and delayed memory recall—but this was not the case. Instead, the researchers observed an impairment only in sustained attention (in a digit-vigilance task involving the matching of numbers on the computer screen). There were no impairments in learning, memory, or any other cognitive function.

Give Your Brain an Edge

The puzzling results of these three trials are in partial agreement and partial disagreement with those of similar trials conducted by other researchers. So what does it all mean? Frankly, no one knows for sure. The conflicting evidence is so complicated and confusing that it will take much more research to sort it all out.

Meanwhile, however, we can be sure that, all else being equal, it’s better to have healthy neurotransmitter levels than not—and amino acid supplements are a way to counteract the age-related decline in our levels of these vital substances. It makes sense to give your brain the benefit of every possible nutritional edge so that it continues to deserve its place on that pedestal.


  1. Harrison BJ, Olver JS, Norman TR, Burrows, GD, Wesnes KA, Nathan PJ. Selective effects of acute serotonin and catecholamine depletion on memory in healthy women. J Psychopharmacol 2004;18(1):32-40.
  2. Matrenza C, Hughes J-M, Kemp AH, Wesnes KA, Harrison BJ, Nathan PJ. Simultaneous depletion of serotonin and catecholamines impairs sustained attention in healthy female subjects without affecting learning and memory. J Psychopharmacol 2004;18(1):21-31.