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.
What do depression
(especially the agitated, anxious, irritable type), anxiety, suicide,
alcoholism, violent behavior, PMS, obesity, compulsive gambling,
insomnia, carbohydrate craving, SAD (seasonal affective disorder), and
migraine headaches 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.
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 (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)
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
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."
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.
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)
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)
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)
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)
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?
source of nutrients and supplements.
did we qualify them ?
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