– with anti-aging therapies
by James South MA
is one of the most widespread
illnesses in the Western world, yet it is also one
of the most misunderstood and undertreated health problems. Approximately
10-14 million people are medically depressed in the U.S. in any given year, yet
only one third of depressives receive treatment (1). "Depression is just as
socially debilitating as coronary artery disease, and more debilitating than
diabetes mellitus or arthritis. Up to 15% of severely ill depressed patients
will ultimately commit suicide" (1).
carries a huge list of costs: up to 30,000 suicides/year in the U.S., fatal
accidents due to impaired concentration and attention; alcohol and drug abuse;
lost jobs and productivity; job related injuries; and dysfunctional families, to
name just a few (1).
normally define major depression as symptoms, lasting two weeks or more (1):
2. Diminished interest or pleasure in normal daily activities
3. Significant weight loss without dieting, or rapid weight gain; loss or excess
4. Insomnia or hypersomnia
5. Psychomotor retardation or agitation
6. Fatigue, loss of energy
7. Feelings of worthlessness or inappropriate guilt
8. Diminished ability to think or concentrate, indecisiveness
9. Recurrent thoughts of death, recurrent suicidal ideation, specific suicide
plan or attempt.
misunderstanding of depression is widespread. A recent survey of the general
population revealed that :
71% thought that mental illnesses were due to emotional weakness;
65% thought it was caused by bad parenting;
45% thought it was the victim's fault and they could will it away,
43% thought mental illness was incurable;
33% thought it was the consequent of sinful behavior; and only
10% thought it had a biological basis or involved the brain.
the past 50 years neuroscience, psychiatry, and pharmacology have demonstrated
unequivocally that compromised brain function plays a key role in depression,
and that proper therapeutic manipulation of brain chemistry can frequently
alleviate or "cure" depression, without resorting to years of
psychoanalysis. Researcher Paul Willner, in his massive
work Depression: Psychobiological
Synthesis, summarizes the
chief neurochemical difficulties in depression: "The major changes in
neurotransmission associated with severe depression are:
(1) a reduced level of dopamine function, related to psychomotor retardation,
and reflecting a reduced level of incentive motivation; (2) a retarded level of
serotonin function, related to psychomotor agitation, and reflecting an
inability to relax;
(3) a reduced level of noradrenalin function, reflecting inability to maintain
(4) cholinergic [acetylcholine] hyperactivity, reflecting a high level of
stress. Antidepressants reverse
these changes, primarily by actions on nor adrenalin and serotonin
dopamine, and noradrenalin are each made from a single amino acid serotonin from
tryptophan, and dopamine / noradrenalin from either phenylalanine or tyrosine.
Hence they are called "monoamine"
(MA) neurotransmitters. Since the 1950's various types of drugs have been used
by doctors and psychiatrists to enhance brain monoamine neurotransmitter
function. The first medical antidepressant (since retired due to toxic side
effects) was iproniazid, a monoamine oxidase inhibitor (MAOI). MAO enzymes are
present inside neurons, as well as other cells including the liver, where they
serve to break down monoamine neurotransmitters.
brain formula Raise your IQ
Some monoamines are broken down by MAOs as soon as they're formed, even before
they can be released into the synaptic gap to "fire" the next neuron.
Monoamines which are discharged into the synaptic gap are sooner or later
re-taken up by the neuron that secreted them. They are then either
repackaged for reuse, or destroyed by MAO enzymes. MAOI drugs thus act to
increase the synaptic availability of monoamines by preventing their breakdown
by MAO enzymes. This may increase the intraneuronal levels of serotonin
and other monoamines by 300% (3). However, MAOls can also increase the
neuronal and blood levels of another substance called "tyramine",
found in many common foods, and induce severe, even fatal, high blood pressure
reactions unless a rigid low-tyramine diet is followed, as well other side
effects, such as postural hypotension, sexual dysfunction, heart problems and
The next generation of drugs believed to enhance brain serotonin and
noradrenalin became available in the 1960s: the tricyclic antidepressants (TCA),
such as imipramine and amitryptilene. Tricyclic antidepressants seem to attach
to and inhibit the neuronal re-uptake sites for serotonin and noradrenalin,
preventing the return of the monoamines to the neuron which secreted them. This
enhances monoamine action in two ways. Since most monoamines returned to their
source neuron are broken down by MAO enzymes, tricyclic antidepressants slow
Tricyclic antidepressants also cause more serotonin and noradrenalin to remain
in the synaptic gap, thereby increasing serotonin/ noradrenalin neuro-transmission.
However, tricyclic antidepressants also affect other receptors on neurons which
respond to acetylcholine, histamine, and dopamine. Tricyclic
antidepressants thus suffer from a wide range of unpleasant side effects,
ranging from drowsiness confusion and blurred vision to hypotension
and movement disorders (5).
Tricyclic antidepressants are now considered "antiquated" by, most
psychiatrists, yet many general practice physicians still favor them.
1980s spawned the current favorites among antidepressant drugs: the serotonin-specific
reuptake inhibitors (SSRIs). The first and most famous of these is
fluoxetine (Prozac®). Other SSRIs such as paroxetine (Paxil®), sertaline
(Zoloft®) and fluroxamine (Luvox®) are also now in vogue in America and
Europe. These drugs are used to treat eating disorders and obsessive-compulsive
disorders as well as depression. They have put serotonin "on the map"
with the general public as "the mood molecule." Serotonin drugs
were the cover story for Time magazine on September 29, 1997. The Time
article noted: "So far, the [drug] tools used to manipulate serotonin in
the brain are more like machetes than scalpels-crudely effective but capable of
doing plenty of collateral damage." Robert Julien, in his text A
Primer of Drug Action, notes that side effects of Prozac may include
nervousness, anxiety, sexual dysfunction, insomnia, nausea, loss of appetite,
motor restlessness and muscle rigidity (5). Psychiatrist Peter Breggin, in
Talking Back to Prozac, also provides evidence that Prozac may actually
damage serotonergic nerves and create an addictive-necessity for long-term
Prozac use, as well as incline some users to sudden suicide with no prior
Thus, given their side
effect profiles, their xenobiotic nature (they're molecules foreign to normal
brain metabolism), and their need for rigid special diets and/or careful,
medical monitoring to insure safe usage, the MAOls, tricyclic
antidepressants, and SSRIs cannot reasonably be considered the ideal
remedies for depression. Fortunately, neuroscience over the past 40 years has
also uncovered some simpler and more natural remedies for depression, as well as
several "life-extension" drugs with far more safe and gentle
AND 5-HTP- NATURES ANSWER TO PROZAC
with humans and animals over the past 35 years have shown that serotonin nerve
circuits promote feelings of well-being, calm, personal security, relaxation,
confidence and concentration (7). Serotonin
neural circuits also help counterbalance the tendency of overactive (e.g. due to
genetics, stress or drugs) dopamine and noradrenalin circuits to encourage
over-arousal, fear, anger, tension, aggression, and violence, obsessive
compulsive actions, anxiety and sleep
disturbance (7). A deficiency of serotonin nerve action has been shown to
manifest as a broad array of emotional and behavioral problems, ranging from
syndrome, anxiety, alcoholism and overeating to compulsive gambling,
fire-starting, thrill-seeking through violence and suicide.
is rarely a problem with the structure or "wiring" of the brain's serotonin
circuits. Rather the problem is caused by a chronic deficit of serotonin
in the nerves which use it as their neurotransmitter.
It is no coincidence that the most popular psychiatric drugs in history
are the SSRIs, and the common thread connecting MAOls, tricyclic
antidepressants, and SSRIs is their serotonin
neural effects. Serotonin
is the "Achilles heel" of the human brain. Yet no neuron
suffered a literal deficiency of these xenobiotic drug molecules.
Serotonin neurons can,
and frequently do, however, suffer a deficit of the raw material from which
neurons normally produce serotonin:
the essential amino acid tryptophan.
In any normal diet, animal
or vegetarian protein base, Tryptophan is the least plentiful of the 22 dietary
amino acids. A typical diet
provides only 0.75 to 1.5 grams tryptophan per/day, yet there is much
competition in the body for this scarce amino.
It 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 the coenzyme form of B3-NAD-at the expensive ratio of 60mg Tryptophan to
one mg niacin(8).
people who are even marginally vitamin B6 deficient, Tryptophan may be
immediately degraded by the liver into the mildly toxic metabolites
hydroxykynurenine, xanthurenic acid, and hydroxyanthranilic acid, then excreted
in urine (9). Thus, the brain typically receives less than l% of ingested
even getting its modest share of dietary Tryptophan is difficult for the brain
due to the blood-brain barrier (BBB). The blood-brain barrier serves as a
protection to prevent many toxins, as well as excesses of nutrients which might
temporarily overwhelm and dysregulate brain function, from entering the brain.
Serotonin itself cannot
penetrate the blood-brain barrier, although Tryptophan can. Yet the blood-brain
barrier creates difficulties even for essential nutrients to enter the brain.
Amino acids must be carried through the blood-brain barrier by a special transport
protein, like passengers on a bus. Unfortunately for serotonin-using
neurons, Tryptophan must share its "transport bus" with 5 other amino
acids: phenylalanine, tyrosine, valine, leucine and isoleucine. Tryptophan
is typically outnumbered about 9:1 in its competition to secure its transport
through the blood-brain barrier into the brain.
a high protein diet to provide more tryptophan only
worsens the problem, by increasing even more the intake of the 5 competing amino
acids. Ironically the only dietary strategy which increases brain tryptophan
is to eat a high carbohydrate/low protein diet.
When large amounts of carbohydrate are eaten, the body secretes large
amounts of the hormone insulin to lower the ensuing high blood sugar. Insulin
also clears from the blood much of the 5 amino acids that compete with tryptophan
for entry through the blood brain barrier.
Insulin has relatively little effect on clearing tryptophan
from the blood, however, thus allowing tryptophan more space on the blood brain
barrier "transport bus," and thus more tryptophan reaches the brain.
R. and J. Wurtman reported in 1988 and 1989 that women suffering from
PMS-related depression were found to spontaneously increase their carbohydrate
food and snack intake, without increasing protein, during their depressive
phase, with a consequent significant decrease in measured depression ratings,
presumably through the insulin-tryptophan-serotonin
mechanism (10,11). Unfortunately, insulin also promotes conversion of the
incoming food to stored body fat. Hence
the high carbohydrate diet method of enhancing brain tryptophan
/serotonin merely trades depression for obesity and chronic carbohydrate
years of research has provided a pair of alternatives to enhance brain serotonin
levels with consequent lessening of serotonin
Many studies have shown both tryptophan and its metabolite,
5-hydroxytryptophan (5-HTP), to be capable of enhancing brain serotonin
and relieving depression when taken as supplements (12-21).
tryptophan as a dietary supplement is the most natural way to solve the brain's
serotonin production problems. A tryptophan
supplement, unlike a high protein diet, will not increase blood levels of tryptophan’s
5 amino competitors. Since the normal dietary intake of tryptophan
is only a gram or so, even a modest amount of supplemental tryptophan
(I to 3 grams) will have a significant effect in boosting blood and brain tryptophan,
and hence brain serotonin levels. Under normal conditions, the brain enzyme
tryptophan hydroxylase (TpH) is only 50% saturated (22). Tryptophan
hydroxylase is the rate-limiting factor in serotonin production, converting
tryptophan hydroxylase to 5-HTP.
This means that an increase in brain tryptophan will automatically tend to
increase brain 5-HTP production.
After tryptophan hydroxylase converts tryptophan to 5-HTP,
a vitamin B6-dependent carboxylase enzyme then rapidly converts 5-HTP
increased brain production of serotonin
supplementation does not automatically increase serotonin nerve activity.
At low levels of psychobiologic arousal, there will be adequate serotonin to
support the correlative low serotonin nerve activity, even when neuron levels of
tryptophan and serotonin are low
(22). This more apathetic, vegetative quiescent variety of depression
("I'm so depressed I can't even get out of bed") is referred to as the
"apathetic-inhibited" type (22). This form of depression represents
more of a deficiency of activity of the dopamine/ noradrenalin "yang"
"get-up-and-go", activating neural circuits, and so tryptophan/
serotonin may offer little relief to, or even worsen, this type of depression.
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. Thus Young and Teff suggest that tryptophan will be most
effective as an anti-depressant in those suffering from
"anxious-agitated" depression, with its high state of stress
arousal, combined with the depression (22). Anxious, agitated depression
occurs when a person's dopaminergic/ noradrenergic activating ("yang")
neural circuits are functioning strongly, without the calming, relaxing,
mellowing serotonin circuits ("yin") functioning strongly as a
The biggest drawback to using
tryptophan to solve serotonin deficiency depression is the activity of the liver
tryptophan degrading enzyme, tryptophan pyrrolase (TP). Tryptophan pyrrolase is
known to be activated by two factors (23). The first is the hormone
cortisol. Cortisol, the "state
of siege" stress hormone, is known to be frequently elevated in the very
conditions, such as depression and insomnia, for which tryptophan might be
helpful, "faking Gerovital-H3, low dose Dilantin, or 7-Keto-DHEA may
provide an anti-cortisol activity to prevent cortisol activation of tryptophan
-destroying tryptophan pyrrolase.
other tryptophan pyrrolase -activating factor is tryptophan itself!
Tryptophan is known to induce and stabilize tryptophan pyrrolase, thus
keeping it active in destroying tryptophan. as it passes through the liver. Thus
Yuweiler and colleagues point out that successful tryptophan antidepressant
studies have generally used low doses (3 grams or less) compared with tryptophan
studies having negative results, which have often used high doses (6-9 grams)
(23). The higher doses could ironically lessen the antidepressant effect of tryptophan
hyperactivating liver tryptophan pyrrolase, which would then catabolize incoming
great efficiency, can Gelling out any hoped-for increase in blood/brain tryptophan.
and Japanese depression research over the past 30 years has focused on 5-HTP as
a natural solution to enhance brain serotonin activity. 5-HTP is the
intermediate between tryptophan and serotonin. Since the rate-limiting, or
problematic step in serotonin production is the
conversion of tryptophan to 5-HTP, using 5-HTP as an antidepressant simply
bypasses the production bottleneck. As Zmilacher and coauthors also note:
"L-5-HTP is not degraded by the tryptophan pyrrolase to kynurenme, the
major pathway for peripheral degradation of L-tryptophan (about 98%).
Furthermore, L-5-HTP easily crosses the blood-brain barrier...."
(24). Byerley and his co-workers also point out another key advantage of 5-HTP
over tryptophan. “administration
of 5-HTP enhances synthesis of serotonin in the brain, but may also effect
noradrenergic [NA] and dopaminergic [DA] neurotransmission. In laboratory
animals as well as human subjects, increased turnover of dopamine and
norepinephrine occurs after 5-HTP administration." (25)
a 1984 paper, van Praag also noted the different effects of tryptophan and 5-HTP
on dopamine/ noradrenalin neurotransmission. Van Praag found significant
increases in the spinal fluid concentration of 5HIAA, the serotonin-metabolite,
after giving both tryptophan and 5-HTP to different test subjects.
Tryptophan, which only raised spinal fluid 5HIAA, 5-HTP also raised spinal
fluid metabolites of Dopamine and Noradrenalin, indicating an activating
effect of 5-HTP of Dopamine/ Noradrenalin neurotransmission as well as
serotonin neurotransmission (26). In
a 1983 report, van Praag also demonstrated that among patients who maintained
their antidepressant effect from 5-HTP over the long term, there was evidence
from spinal fluid metabolites of continuing Dopamine/ Noradrenalin activation
as well as serotonin activation. Among
patients whose initial positive response to 5-HTP dropped off after several
months, van Praag found a drop in their initial high levels of Dopamine/
Noradrenalin spinal fluid metabolites as the 5-HTP antidepressant effects
decreased. When van Praag then
gave these patients supplements of tyrosine, the amino acid from which
Dopamine and Noradrenalin are made, along with their 5-HTP, their depression
once again cleared, while their spinal fluid metabolites of Dopamine/
Noradrenalin also again increased (27). Van
Praag thus demonstrated that 5-HTP is more than just a better Tryptophan, it
is a " Tryptophan plus" due to its Dopamine/ Noradrenalin
their 1988 review of 5-HTP antidepressant studies, Zmilacher and co-writers
report that "Out of the 17
reviewed studies... 60.5% of all the patients (342 out of 565) showed a good
or very good improvement of their depressive state.... A tendency indicating
that L-5-HTP was especially effective in patients with an anxious agitated
depressive syndrome was observed.... An important finding is the very rapid
onset of action (within 3-5 days) in patients responding to treatment."
main drawback to 5-HTP use is its gastrointestinal side effects,
"...gastrointestinal symptoms, such as abdominal cramping, nausea, and
diarrhea, appear to be the most common adverse effect.... Adverse effects
reported infrequently after oral doses include insomnia, headache and [heart]
palpitations." (25) Zmilacher suggests taking 5-HTP with a meal to reduce
Gl side effects. Some researchers
have suggested that enteric coated 5-HTP, which doesn't dissolve until it
reaches the small intestine, will also reduce Gl side effects. (Note: IAS
carries enteric coated 5-HTP). Some
5-HTP researchers give drugs called "peripheral decarboxylase
inhibitors" along with 5-HTP,
both to reduce Gl side effects as well as allegedly to increase treatment
efficacy, yet Zmilacher notes that "A review
of the literature on this subject revealed that L-5-HTP with a peripheral
decarboxylase inhibitor (93 out of 176 patients, 52.9%)." (24) "...
psychopathological side effects [swings from depression to mania or
hypo-mania] have mainly been reported in patients receiving L-5-HTP in
combination with a peripheral decarboxylase inhibitor." (24)
1991 Poeldinger and colleagues reported a landmark double-blind study that
compared 5-HTP with the popular SSRI fluvoxamine (a Prozac
"cousin"). Not only did
5-HTP prove to be slightly superior to fluvoxamine in antidepressant action,
but 5-HTP patients had significantly fewer and less serious side effects
(mostly Gl) than patients receiving fluvoxamine (28).
Thus, not only is 5-HTP an effective and more natural alternative to
the SSRIs, but it is also less side-effect prone.
and 5-HTP may be used separately or together to improve serotonin metabolism,
Tryptophan may best be taken at bedtime, 1-3 grams. 5-HTP may be taken with
meals, 50-100 mg, once or twice daily. Initial symptoms from 5-HTP, if
they occur, will frequently disappear with continued use. If not, then using
only Tryptophan may still provide adequate serotonin antidepressant effect.
and 5-HTP will potentiate the effects of MAOI, tricyclic
SSRI drugs, and they may possibly precipitate the "serotonin
syndrome" if combined with these drugs. The fortunately rare serotonin
syndrome, as reported by H. Stembach in 1991(29), involves extreme
hyperactivity of serotonin neural circuits and may include confusion,
hypomania, agitation, "feeling drunk," as well as extreme
restlessness, muscle twitches, hyperactive reflexes, intense sweating,
shivering, tremor, diarrhea, fever and incoordination.
Occasionally coma or death may result. Thus, although Tryptophan or
5-HTP may be useful to lessen the needed dosage fro those wishing to remain on
standard antidepressant drugs, combining Tryptophan or 5-HTP with
antidepressant drugs, or altering current drug dosages, should be done ONLY
under expert medical supervision to avoid inducing the serotonin syndrome.
Also, one should never suddenly stop antidepressant drugs and replace them
with Tryptophan or 5HTP. Any cessation of current antidepressant drug therapy
should be done gradually, and only under expert medical supervision, to avoid
possible depression relapse.
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