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Read "Controversy Erupts About Safety of 5-HTP" to learn more about 5-HTP and depression.
5-Hydroxytryptophan: The Serotonin Solution
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 (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 brainsuch as blood platelets and some intestinal lining cellsmake 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 acidsleucine, isoleucine, valine, tyrosine and phenylalanine. In any normal dietanimal 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, 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 braintryptophan 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 ailmenteosinophilia 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)
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)
studies using 5-HTP show that 5-HTP, by naturally elevating brain
can alleviate the serotonin-deficiency syndrome without any help from
drugs. Yet the study related by Risch and Nemeroff eloquently shows
the success of SSRI drugs is crucially dependent upon the brain
adequate serotonin (from either tryptophan or 5-HTP), and that brain
production is the controlling or rate-limiting variable underlying the
apparent success of SSRI's. Which is the more logical choice then5-HTP
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