Answer to Prozac®
by James South, M.A.
The "serotonin deficiency syndrome"
is one of the most common and widespread disorders of human
psychobiology in the modern world. Prozac® allegedly increases
the amount of serotonin in the synaptic gap that slightly
separates nerve cells from each other. (For more on the
"allegedly" see the excellent book, Talking Back to Prozac,
by psychiatrist Peter Breggin).
Greater amounts of serotonin in the synaptic gap increases
communication between serotonin-using neurons, allowing the
brain's multiple and critically important serotonin neural
circuits to function more reliably, powerfully and effectively.
Tryptophan and Serotonin Action
Studies with humans and animals conducted over the past 30 years
show that serotonin nerve circuits promote feelings of well
being, calm, personal security, relaxation, confidence and
Serotonin neural circuits also help counterbalance the tendency
of brain dopamine and noradrenaline circuits to encourage
over-arousal, fear, anger, tension, aggression, violence,
obsessive-compulsive actions, over-eating (especially
carbohydrates), anxiety and sleep disturbances.
A broad array of emotional and behavioral problems, including
depression, PMS, anxiety, alcoholism, insomnia, violence,
aggression, suicide and compulsive gambling, has been designated
the serotonin deficiency syndrome. The serotonin deficiency
syndrome is caused by a chronic deficit of serotonin in the
nerves that use it as their neurotransmitter. This deficit in
turn derives from various problems relating to the nutritional
biochemistry of tryptophan.
Tryptophan: The Essential Amino Acid
Tryptophan is one of the eight essential amino acids found in
the human diet. Essential amino acids must be obtained preformed
from food or supplements. Non-essential aminos (there are 14)
can be made from the essential aminos, or other non-essential
In any normal diet, tryptophan is the least plentiful of all 22
amino acids. A typical diet provides only 1 to 1.5 grams of
tryptophan per day. To compound the problem, there is much
competition in the body for this scarce amino acid. Tryptophan
is used to make various proteins, and in people with low to
moderate intakes of vitamin B3 niacin/niacinamide), tryptophan
may be used by the liver to make B3 at the expensive ratio of 60
mg tryptophan to 1 to 2 mg B3.
In people who are even marginally vitamin B6 deficient,
tryptophan may be rapidly degraded into mildly toxic metabolites
such as hydroxykynurenine, xanthurenic acid and
The brain typically receives less than one percent of ingested
tryptophan. However, getting even this meager share of
tryptophan (the only normal dietary raw material for serotonin
manufacture) is a difficult task for the brain, due to the blood
brain barrier (BBB).
The BBB serves as a protection to prevent toxins (and even
excessive levels of nutrients which might temporarily overwhelm
and dysregulate brain function) from entering the brain. Thus,
the BBB makes it hard even for brain essential nutrients to
enter the brain. Serotonin by itself cannot penetrate the BBB,
but its precursor, tryptophan, can. Nutrients must be ferried
through the BBB by transport molecules, like passengers on a
bus. Unfortunately for the serotonin-using nerves, tryptophan
must share its "transport bus" with five other amino acids:
tyrosine, phenylalanine, valine, leucine and isoleucine. Thus,
tryptophan is typically out-numbered about 8 to 1 n the
competition to secure its transport through the BBB into the
Tryptophan's Effects on Carbohydrates and Obesity
Eating a high protein diet to provide more tryptophan only
worsens the problem by increasing the intake of the five
competing aminos even more. Ironically, the only dietary
strategy that increases brain tryptophan supply is to eat a high
When large amounts of carbohydrates are eaten, the body secretes
large amounts of the hormone insulin to lower the ensuing high
blood sugar. The insulin also clears from the blood most of the
five amino acids that compete with tryptophan for a ride to the
brain. Tryptophan then has the "bus" all to itself, allowing
more tryptophan to reach the brain.
This strategy is instinctively known and practiced by many
people who consume large amounts of carbohydrates such as bread,
cakes, pies, ice cream, chips, pizza and candy—especially when
they are feeling depressed, stressed or anxious.
The increased brain serotonin produced by this practice lowers
arousal and anxiety, promoting a (temporary) sense of well-being
and security. However, this strategy comes at a price. The same
insulin that enhances brain serotonin also enhances the
conversion of the fats, carbohydrates and amino acids cleared
from the blood into stored body fat!
Hence the carbohydrate addiction/ obesity/serotonin connection.
Taking tryptophan as a supplement is the most natural way to
defeat the brain's serotonin production problems. Unlike
ingesting a high protein diet, isolated supplemental tryptophan
intake will not increase blood levels of its five amino
competitors. Since the normal dietary intake is only 1 to 1.5
grams per day, even a modest amount of tryptophan
supplementation (500 mg to 3,000 mg) will have a significant
effect in boosting blood and brain tryptophan levels.
Under normal conditions, the brain enzyme tryptophan hydroxylase
(TH) is only 50 percent saturated. This means the serotonin
production machinery is 50 percent idle. Thus, an increase in
raw material (tryptophan) will tend to automatically increase
brain serotonin introduction.
TH converts tryptophan to 5-hydroxytryptophan (5-HTP). A vitamin
B6-dependant carboxylase enzyme then converts 5-HTP to
serotonin, and more serotonin more effectively activates the
calming, mood-elevating, impulse and appetite-controlling
serotonin neural circuits.
Tryptophan—When Less is More!
In the case of tryptophan supplements, more is not always
better. In the many human clinical studies using tryptophan to
treat depression, published since the 1970s, studies using
moderate tryptophan doses (1 to 3 gm daily) have frequently
shown better results than high doses (6 to 9 grams daily). This
is due to a liver enzyme called tryptophan pyrrolase (TP). TP is
a key enzyme in the normal pathways for liver-tryptophan
TP is known to be activated by at least two factors. The first
is the stress hormone cortisol. Cortisol, produced by the
adrenal glands, is the "state of siege" stress hormone.
It is released in response to unremitting chronic stress, which
we can neither fight against nor flee from. Cortisol is known to
be frequently elevated in the very conditions, such as
depression, insomnia and obesity, for which tryptophan/serotonin
might be helpful.
Thus, taking tryptophan while under elevated cortisol-stress
conditions might supply little extra to the brain, because of
cortisol's activation of TP.
The other factor known to elevate liver TP activity is,
ironically, increased intake of tryptophan. Since the TP-using
kynurenine pathway is the major tryptophan degradation pathway,
significantly elevated tryptophan intake automatically induces
higher TP activity. Again, if liver TP activity seriously
increases, more supplemental tryptophan will not necessarily
translate into increased brain serotonin.
Thus, the lowest tryptophan dose that successfully alleviates
serotonin-deficiency symptoms is the most efficacious (i.e.,
more is not always better).
Fortunately, clinical and anecdotal evidence shows that even 500
mg to 1,500 mg of supplemental tryptophan, taken at bedtime on a
regular basis, is frequently sufficient to ease
This low dose will usually not seriously elevate tryptophan-destroying
TP activity. Niacinamide (vitamin B3) is known to inhibit liver
TP; it is also the vitamin that activates the enzyme that
converts tryptophan to 5-HTP. Thus, taking 100 mg B3 several
times daily with meals will also serve to enhance the
effectiveness of low-moderate tryptophan doses.
Taking 25 mg to 50 mg of vitamin B6 once or twice daily with
meals will also augment tryptophan-serotonin conversion, since
B6 activates the decarboxylase enzyme that converts 5-HTP to
Tryptophan: The Natural Antidepressant
The published research of S.N. Young and H.M. van Praag (two of
the world's chief experts on tryptophan-serotonin metabolism and
psychobiology), suggest that tryptophan will likely be of most
benefit to people suffering from depression of the type that
Young refers to as "anxious-agitated." Young notes that
increased brain production of serotonin through tryptophan
supplementation does not automatically increase serotonin nerve
Young's research indicates that at low levels of psychobiologic
arousal, there will be adequate neuronal serotonin to support
the correlative low-level serotonin nerve activity, even when
nerve serotonin levels are low. At higher levels of arousal,
however, the more rapid turnover of serotonin in the synaptic
gap will require higher levels of serotonin production to
adequately maintain the greater activity of serotonin circuits.
Young refers to those suffering depression of a more vegetative,
passive, quiescent variety as the "apathetic inhibited" type.
Given that serotonin neural circuits frequently serve to
counterbalance the arousing activating dopamine/noradrenaline
circuits (the neural circuits activated by cocaine and
amphetamine, and to a lesser extent, coffee), Young's
observations make perfect sense.
Anxious, agitated depression occurs when a person's dopamine/noradrenaline
activating arousal circuits (Yang) are functioning strongly,
without the calming, relaxing, mellowing serotonin circuits
(Yin) functioning strongly as a complementary counterbalance.
Tryptophan provides the anxious agitated depressive with that
needed "Yin" counterbalance, thereby restoring a sense of well
being and behavioral self-control.
Van Praag's research has shown that for many people suffering
depression, combining the amino-acid tyrosine with tryptophan
works much better than taking tryptophan alone. These would be
Young's "apathetic inhibited" types, where both the serotonin
tranquility/well-being circuits and the "get up and go"
(vigorous action) dopamine/noradrenaline circuits are
Tyrosine is the precursor for both dopamine and noradrenaline.
The enzyme that converts tyrosine to its next step on the
dopamine/noradrenaline pathway is tyrosine hydroxylase. Tyrosine
hydroxylase is normally at least 25 percent unsaturated (i.e.,
25 percent "idle"), so that providing supplemental tyrosine (100
to 500 mg with meals) increases brain dopamine/noradrenaline
production and nerve activity.
The increased dopamine/noradrenaline neural activity then
requires greater complementary serotonin neural activity, which
is provided by the tryptophan supplementation.
Tryptophan's General Uses
Research has shown that tryptophan/ serotonin is effective for
more than depression. Various forms of defective impulse control
and obsessive compulsive disorders are also strongly affected by
serotonin nerve activity. Suicidal behavior, compulsive
gambling, irrationally dangerous thrill seeking behavior and
pyromania (compulsive fire-starting), have been shown to be
correlated with low serotonin neural activity, combined with
excessive dopaminergic/noradrenergic activity.
Chronic alcoholism may also have a serotonin component. Research
with animals and humans has shown that alcohol initially
increases serotonin nerve activity; yet chronic alcohol use
impairs tryptophan entry into the brain. Thus, chronic
alcoholism may involve a vicious spiral of a brief
alcohol-induced increase of serotonin neural activity, with
consequent sense of well-being, combined with an ever-worsening
baseline state of serotonin nerve activity due to alcohol's
impairment of brain tryptophan transport.
Tryptophan and Sleep
In recent years, melatonin has gained the reputation as the
natural answer to insomnia. Yet the fact that melatonin is made
in the pineal gland from serotonin is frequently overlooked.
Thus, supplemental tryptophan may induce one's pineal gland to
naturally increase its melatonin production. Also, important
sleep-regulating nerve circuits in the brainstem (the raphe
nuclei) use serotonin as their neurotransmitter, so it is
unreasonable to expect melatonin alone to provide optimal
Low dose melatonin (0.5 mg to 1 mg) plus tryptophan (500 mg to
1,500 mg) may prove more effective for many people with serious
Tryptophan's Role in Dementia
Recent research has shown that the depression that frequently
accompanies and even predates the movement disorders of
Parkinson's disease is primarily due to the hypofunction of
serotonin nerves. Consequently, tryptophan may be a useful
adjunct to L-Dopa/deprenyl treatment of Parkinson's.
In the latter stages of Alzheimer's disease, heightened
irritability and unprovoked aggression frequently accompany the
mental decline. Recent research has shown partial destruction of
key serotonergic neural circuits to be involved. Supplemental
tryptophan may optimize the activity of remaining serotonergic
Tryptophan and 5-HTP
Supplemental 5-Hydroxytryptophan (5-HTP), the interwww.y between
tryptophan and serotonin, is also available as a natural remedy
for the serotonin deficiency syndrome, yet tryptophan offers a
major advantage over 5-HTP for many people.
There are nerves that line the intestinal tract that use
serotonin as their neurotransmitter. These nerves contain the
carboxylase enzyme that converts 5-HTP to serotonin, but not the
hydroxylase enzyme that converts tryptophan to 5-HTP. Thus, when
5-HTP is swallowed, large amounts of 5-HTP may be picked up by
these intestinal serotonergic neurons and quickly converted to
serotonin, leading to hyperactivity of these nerves.
This in turn may lead to nausea, vomiting, cramping,
constipation and/or diarrhea. Indeed, the research published on
5-HTP since the 1970s has consistently shown various forms of
intestinal discomfort to be the main side effect of 5-HTP use.
Because these intestinal neurons cannot convert tryptophan to
5-HTP, tryptophan does not cause intestinal distress.
Tryptophan: Its Synergistic Combinations
A practical program to relieve the many forms of serotonin
deficiency syndrome will ideally combine moderate amounts of
tryptophan (500 mg to 1,500 mg), 5-HTP at 33 mg to 100 mg (if
well tolerated) and melatonin (0.5 mg to 1 mg) taken at bedtime.
Melatonin actually promotes increased brain serotonin through
its ability to reduce cortisol levels. Reduced cortisol levels
will lessen the activity of liver pyrrolase, the enzyme that
GH3/KH3, Dilantin (phenytoin) and magnesium may also lower
cortisol activity. Standardized extracts of St. John's Wort (0.3
percent hypercin) may also synergize with tryptophan to optimize
serotonin levels. Research summarized in Hypericum and
Depression by H. Bloomfield and colleagues suggests three
complementary mechanisms of action whereby St. John's Wort may
St. John's Wort seems to be a weak serotonin reuptake inhibitor
(and thus a more natural and safer equivalent of Prozac), a weak
MAO inhibitor (MAO enzymes break down neuronal serotonin), and a
cortisol inhibitor. The standard St. John's Wort dosage is 300
mg three times daily—however, less may be needed when combined
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Young SN, Teff KL "Tryptophan availability, 5HTP synthesis and
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Maurizi CP, "The therapeutic potential for tryptophan and
melatonin" Med Hypoth 1990; 31:233-42.
Van Praag HM et al "Therapeutic indications for serotonin
potentiating compounds, a hypothesis" Biol Psychiat 1987;
Van Praag HM "In search of the action of anti-depressants: 5HTP,
tyrosine mixtures in depression" Neuropharmacol 1983; 22:433-40.
Robertson J, Monte T. Natural Prozac, San Francisco, Harper
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