5-Hydroxytryptophan:
The Serotonin Solution
This article first appeared in the
March 1997 issue of VRP’s Nutritional News
Read “Controversy
Erupts About Safety of 5-HTP” to learn more about 5-HTP
and depression.
by James South
What
do depression (especially the agitated, anxious, irritable type),(1-6)
anxiety, (7) suicide, (8) alcoholism, (9) violent behavior, (8) PMS, (10)
obesity, (10,11) compulsive gambling, (12) insomnia, (13) carbohydrate
craving, (10) SAD (seasonal affective disorder), (10) and migraine headaches
(14) all have in common? These seemingly disparate conditions may all be
manifestations of a brain serotonin deficiency syndrome according to a
massive body of psychobiology research conducted over the past 30 years.
Serotonin is one of the ten or so major
brain neurotransmitters; there are perhaps 100 minor neurotransmitters.
Neurotransmitters are the biochemicals nerve cells use to “talk” to each
other. There are an estimated 10 - 100 billion neurons in the human brain,
and each neuron may connect to thousands of other neurons. Yet these
interconnecting neurons do not quite touch each other there is a microscopic
gap between them called the “synaptic gap”. As a burst of electric
current travels down the length of a neuron, it releases a packet of
neurotransmitter molecules which are stored at the edge of the synaptic gap.
These neurotransmitters then diffuse across the synaptic gap and “plug in” to
the receptor sites of the next neuron, like keys fitting into locks. When a
sufficient number of molecules have “plugged in” to the corresponding
receptors of the next neuron, this neuron then discharges a burst of
electricity down its cell membrane surface, repeating the process with
neurons to which it connects. Thus, neurons use electricity to propagate a
signal down the length of their own cell structure, but use chemical
neurotransmitter molecules to signal other neurons. When there are inadequate
numbers of neurotransmitters to activate other neurons, various brain
circuits become under- or overactive due to lack of communication between
nerve cells.
Studies with humans and animals have
shown that serotonin nerve circuits promote feelings of well being, calm,
personal security, relaxation, confidence and concentration. (15) Serotonin
neural circuits also help counterbalance the tendency of brain dopamine and
noradrenalin (two other major neurotransmitters) to encourage overarousal,
fear, anger, tension, aggression, violence, obsessive-compulsive actions,
overeating, anxiety and sleep disturbances. (15) Unfortunately, neuroscience
has also discovered that many people suffer from various degrees of brain
serotonin deficiency, leading to a host of mental, emotional and behavioral
problems. To understand why brain serotonin deficiency is becoming ever more
common in modern society, it is necessary to look at how the brain makes
serotonin.
Serotonin Function
Serotonin (also called “5HT”), dopamine, and noradrenalin are the three main “monoamine”
neurotransmitters. They are each made from one specific amino acid. Serotonin
is made from tryptophan, while dopamine and noradrenalin are made from
tyrosine. While other cells outside the brain such as blood platelets and
some intestinal lining cells make and/or use serotonin, all serotonin used by
brain cells must be made within the neurons. Due to the blood-brain barrier,
no serotonin can be “imported” from outside the brain. The blood-brain
barrier serves as a protection device to prevent toxins from entering the
brain, yet this protection comes at a price. Even friendly molecules needed
by the brain, such as amino acids, are limited in their access to the brain.
Nutrients are ferried through the blood-brain barrier by transport molecules,
like passengers on a bus. This creates a special bottleneck for serotonin.
Serotonin itself cannot pass through the blood -brain barrier, while its
precursor tryptophan must share its transport “bus” with five other amino
acids leucine, isoleucine, valine, tyrosine and phenylalanine. In any normal
diet, animal protein-based or vegetarian tryptophan is the least plentiful of
all 20 food amino acids. Thus, tryptophan is typically outnumbered as much as
7-9:1 in its competition to secure its transport through the blood-brain
barrier into the brain. Eating a high protein diet in an attempt to increase
dietary tryptophan (a typical diet provides only 1-1.5 grams/day) only
increases its competition even more. Ironically, the only dietary strategy
that increases brain tryptophan supply is to eat a high carbohydrate, low
protein diet. When large amounts of carbos 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” to
itself, allowing plenty of tryptophan to reach the brain. (10)
This strategy is instinctively known
and practiced by many Americans who eat large amounts of carbos such as
candy, cake, pie, bread, chips, ice cream, etc. when they are feeling
stressed, depressed or anxious. The increased brain serotonin this produces
lowers arousal and anxiety, promoting a (temporary) sense of well-being and
security. However, this strategy comes at a price. The same insulin which
enhances brain serotonin also enhances the conversion of the fats, carbos and
aminos cleared from the blood into stored body fat! Hence the carbo
addiction/obesity-serotonin connection.(10)
Tryptophan v. 5-HTP
In the 1970’s, the American health food industry began to provide an
alternative method of getting more tryptophan to the brain tryptophan
supplements. Many people found that 500 - 3000 mg of supplementary tryptophan
daily provided practical relief from depression, PMS, insomnia and
obsessive-compulsive disorders. Yet in 1989 the FDA removed tryptophan from
the American health food market due to a serious ailment called eosinophilia
myalgia (EMS)caused by a single batch of contaminated tryptophan from a
single Japanese producer. Eight years later, the FDA still shows no signs of
allowing tryptophan back on the market. If the FDA were to reapprove
tryptophan for general use, would it still be the best natural, non-drug way
to deal with the serotonin deficiency syndrome? For several reasons, the
answer is “No.”
It is generally accepted that only
about 1% or less of dietary/supplementary tryptophan ever enters the brain.
The rest is used to make various body proteins; some is converted into
vitamin B-3at a cost of 60 mg tryptophan to make one mg B-3; some is
converted by other body cells into serotonin for their needs; and some may be
broken down through the kynurenine pathway. A liver enzyme, tryptophan
pyrrolase, converts tryptophan into kynurenine, which may then be converted
to hydroxykynurenine (3-OH-K), xanthurenic acid (XA) and hydroxyanthranilic
acid (3-OH-AA) for urinary excretion. Unfortunately, 3-OH-K, XA and 3-OH-AA
are all known to cause liver damage and bladder cancer. (16) It may not be
pure chance or coincidence that nature has arranged tryptophan to be the
least plentiful amino in our diets. Furthermore, there are at least two known
factors which significantly increase liver pyrrolase activity, dramatically
enhancing production of these toxic metabolites.
The first is the stress hormone
cortisol. (13) Cortisol, produced by the adrenal glands, is the “state-of-siege”
stress hormone. It is released in response to unremitting stress which we can
neither fight against nor flee from. Cortisol is known to be elevated
frequently in the very conditions, such as depression, insomnia and obesity,
(13) for which tryptophan /serotonin might be useful. Thus, taking tryptophan
supplements while under elevated cortisol-stress conditions might supply
little extra to the brain for serotonin synthesis, yet dramatically raise
toxic 3-OH-K, XA and 3-OH-AA levels.
The second factor known to increase
liver pyrrolase activity is increased intake of tryptophan! The kynurenine
pathway is the major degradation pathway for tryptophan in the human body,
and higher tryptophan intake automatically induces higher pyrrolase activity.
(13) This explains why studies using tryptophan as an antidepressant
frequently find moderate doses more effective than high doses, and why van
Praag noted in 1981 that “L-tryptophan was found to be effective in [only]
five of the ten double-blind comparative studies.” (5)
Fortunately, a safe, natural and effective
alternative to both tryptophan and the serotonin-potentiating drugs such as
Prozac has been researched for over 25 years, and is now available in the
U.S. without a prescription. This substance is L-5-Hydroxytryptophan (5-HTP).
5-HTP is not produced by bacterial fermentation (as was the tainted
tryptophan) nor chemical synthesis but is extracted from the seeds of the
Griffonia plant.
Tryptophan to Serotonin Conversion
When neurons convert tryptophan into serotonin, they first use a vitamin
B-3-dependent enzyme to convert tryptophan into 5-HTP. A vitamin B6
-dependent enzyme is then used to convert 5-HTP into serotonin. As Zmilacher
et al note: “There are several advantages of considering L-5 -HTP as opposed
to L-Tryptophan as being the major determinant in elevating brain serotonin
levels: L-5-HTP is not degraded by the tryptophan pyrrolase to kynurenine,
the major pathway for peripheral degradation of L-tryptophan (about 98%).
Furthermore, L-5-HTP easily crosses the blood-brain barrier ... .” (1) Additionally,
it should be noted that 5-HTP is not incorporated into proteins, as is
tryptophan; nor is 5 -HTP used to make vitamin B-3, as is tryptophan. Thus,
in comparison to tryptophan, 5-HTP is virtually a “guided missile” directly
targeted to increase brain serotonin. Indeed, some studies have shown better
results using 200 - 300 mg 5-HTP/day as an antidepressant than other studies
using 2000 - 3000 mg or more tryptophan/day. (17)
The enzyme L-aromatic amino acid
decarboxylase (L-AAD) is found outside the brain, and its activity is
especially high in liver, kidney and intestinal lining. L-AAD can convert
5-HTP into serotonin, which cannot cross the blood-brain barrier. Thus, only
5-HTP which actually makes it into the brain intact is usable to increase
brain serotonin supplies. For this reason some studies using 5-HTP have also
employed compounds called “peripheral decarboxylase inhibitors” (PDI’s)-usually
carbidopa or benserazide. PDI’s prevent L-AAD from converting 5-HTP to serotonin
outside the brain. Yet many studies have successfully used 5-HTP without PDI’s,
(1,2,4,6,11) which are prescription drugs and may cause negative side
effects.1 Thus, Takahashi et al reported favorable response in 8 of 24
depressive patients treated with 300 mg 5-HTP daily without a PDI. (6)
A placebo-controlled, double-blind
study reported in 1992 found excellent results treating obesity using 900 mg
5-HTP daily without a PDI, with minimal side effects! (11) Zmilacher et al
treated an equal number of patients for depression using 5-HTP both with and
without a PDI. The study showed no difference in efficacy between the two
treatments. However, the 5-HTP + PDI group had over twice the side effects of
the 5-HTP-only group, including various emotional and bodily side-effects
that showed up in none of the 5-HTP-only subjects. Zmilacher et al concluded:
“... there was no evidence that the administration of benserazide [a PDI]
intensified the efficacy of L-5-HTP [in their clinical trial]. A review of
the literature on this subject revealed that L-5-HTP given alone was more
effective (249 out of 389 patients, 64%) than the combination of L-5-HTP with
a peripheral decarboxylase inhibitor (93 out of 176 patients, 52.9%).” (1)
Poeldinger et al treated depressed patients
with either 5-HTP (without PDI) or fluvoxamine, a Prozac-like drug used in
Europe. The 5-HTP patients showed slightly better treatment response than the
fluvoxamine group, yet significantly fewer and less severe side effects. They
note: “Regarding tolerance and safety, however, oxitriptan [5-HTP] proved
superior to fluvoxamine as was apparent from a marked difference in severity
of untoward side effects between the two compounds. ... The study presented
here ... strongly confirm[s] the efficacy of 5-HTP as an antidepressant.” (4)
Prozac
In a society that has made the book Listening to Prozac a
mega-bestseller, some may still consider serotonin-selective re-uptake
inhibitor (SSRI) drugs such as Prozac the “gold standard” of managing the
serotonin-deficiency syndrome, even though the Poeldinger study showed 5-HTP
to be superior to a major SSRI fluvoxamine. A study reported by Risch and
Nemeroff demonstrates, however, that even those “successfully” treated with
SSRI’s (ignoring their frequent and sometimes serious side effects) are
dependent upon their brains’ producing adequate serotonin from either
tryptophan or 5-HTP. SSRI’s work in effect by conserving existing brain
serotonin supplies by keeping more serotonin in the synaptic gap between
neurons. They achieve this through preventing enzymatic degradation of
synaptic serotonin. SSRI’s do not enhance serotonin production. Risch and
Nemeroff state: “... depressed patients were treated with low -tryptophan
diets that were supplemented with high doses of neutral amino acids [which
compete with tryptophan for transport through the blood-brain barrier] ... .
Remitted depressed subjects receiving serotonergic antidepressants (e.g. ..
fluoxetine [Prozac], fluvoxamine) who were challenged with low-tryptophan diet
supplemented with neutral amino acids promptly relapsed into severe clinical
depression. When the tryptophan supplementation was provided, the patients
promptly recovered ... .” (3)
The many successful published studies
using 5-HTP show that 5-HTP, by naturally elevating brain serotonin, can
alleviate the serotonin-deficiency syndrome without any help from SSRI drugs.
Yet the study related by Risch and Nemeroff eloquently shows that the success
of SSRI drugs is crucially dependent upon the brain producing adequate
serotonin (from either tryptophan or 5-HTP), and that brain serotonin
production is the controlling or rate-limiting variable underlying the
apparent success of SSRI’s. Which is the more logical choice then5-HTP or
SSRI’s?
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