Phenylalanine and 5-HTP Will Go to Your Head
Nourish Your Brain with
Amino Acids
Phenylalanine and 5-HTP are the precursors
of vital monoamine neurotransmitters
By Will Block
omething 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 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
get that small!
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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.
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!
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."
- Restak R. Mysteries of the
Mind. National Geographic
Society, Washington DC, 2000.
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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).
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The
reaction sequences shown here involve
two valuable nutritional supplements:
phenylalanine and 5-HTP.
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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.
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.
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.
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.
References
- 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.
- 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.
Will Block is
the publisher and editorial director of Life
Enhancement magazine.
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