L-Tryptophan  Natures 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 concentration.

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 amino acids.

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 hydroxyanthranilic acid.

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 brain.

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 carbohydrate diet.

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 breakdown.

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 serotonin-deficiency problems.

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 serotonin.

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 activity. activity.

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 underactive.

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 insomnia relief.

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 insomnia.

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 neural circuits.

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 degrades tryptophan.

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 increase serotonin.

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 with tryptophan.

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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; 22:205-12.

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 1997.

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