with anti-aging therapies
by James South MA

Depression 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).

Untreated depression 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).

Psychiatrists normally define major depression as symptoms, lasting two weeks or more (1):  

1. Depressed mood
2. Diminished interest or pleasure in normal daily activities
3. Significant weight loss without dieting, or rapid weight gain; loss or excess of appetite
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. 

Public 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.

During 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 effort; and 
(4) cholinergic [acetylcholine] hyperactivity, reflecting a high level of stress.  Antidepressants reverse these changes, primarily by actions on nor adrenalin and serotonin neurons." (2)

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. 

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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 insomnia (4). 

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 monoamine breakdown. 

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.

The 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 warning (6).

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 antidepressant effect.


Studies 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   depression, premenstrual syndrome, anxiety, alcoholism and overeating to compulsive gambling, fire-starting, thrill-seeking through violence and suicide.

There 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).

In 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 Tryptophan.

Yet 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.

Eating 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 addiction/ over-consumption.

35 years of research has provided a pair of alternatives to enhance brain serotonin levels with consequent lessening of serotonin related depression.  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).


Linking 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 to serotonin.

However, increased brain production of serotonin through tryptophan 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.

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.  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 complementary counterbalance.

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.

The 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 by hyperactivating liver tryptophan pyrrolase, which would then catabolize incoming tryptophan with great efficiency, can Gelling out any hoped-for increase in blood/brain tryptophan.


European 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)

In 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.  

Unlike 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 neuroactivation.

In 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." (24).

The 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)

In 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.

Tryptophan 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.

Tryptophan and 5-HTP will potentiate the effects of MAOI, tricyclic antidepressants, and 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.   continued on Page 2