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L-5-Hydroxy-tryptophan:

5-HTP And Serotonin Deficiency Syndrome

Once readily available as a nutritional supplement, tryptophan is now one of the most difficult substances to obtain in the United States. In November of 1990, tryptophan was removed from shelves after being implicated in the outbreak of EMS (Eosinophilia-Myalgia Syndrome), a dangerous and potentially deadly blood disease usually associated with parasitic infections or severe allergy. Though tryptophan was eventually "exonerated" (see below) the ban on its sale has not been lifted, nor is it likely that it ever will be.

The era following the ban on tryptophan saw the introduction of a new class of prescription drugs, the SSRIs (Selective Serotonin Reuptake Inhibitors). Whereas tryptophan worked by elevating brain serotonin levels via normal metabolic pathways, SSRI drugs such as Paxil, Zoloft and Prozac were designed to regulate brain serotonin levels by preventing the presynaptic resorption of synaptic serotonin. Common to both tryptophan and the SSRIs is their efficacy in the management of serotonin-deficiency syndrome.

Now a safe, natural and effective alternative to both tryptophan and the reuptake inhibitors is available in the U.S. The substance, L-5-hydroxytryptophan (5-HTP) has been researched for over 25 years. Unlike tryptophan, 5-HTP is not produced by bacterial fermentation nor chemical synthesis, but is extracted from the seed of the Griffonia plant, commonly used in the preparation of lectins—pharmaceutical-grade compounds used in blood typing for transfusions and bone marrow transplants.

The impact that tryptophan and the SSRIs have had on American culture (Prozac spawned the bestselling book "Listening to Prozac") illustrates just how widespread serotonin deficiency is in our society. In fact, many people suffer from various degrees of brain serotonin deficiency, leading to a host of mental, emotional and behavioral problems. To understand the basis of serotonin deficiency, we need to first look at serotonin and its precursors.

Tryptophan

Tryptophan is a naturally occurring amino acid required for the production of melatonin and serotonin, two neurohormones necessary for sleep and mood regulation. Melatonin, N-acetyl-5-methoxytryptamine, is produced by the pituitary gland in response to scotic (darkness) perception, and is required for the modulation and initiation of regular sleep cycles. Serotonin (5-HT), the precursor to melatonin, functions as an inhibitory neurotransmitter to reduce excitatory activity, dampening the effects of dopamine and noradrenaline that stimulate overarousal, fear, anger, tension, aggression, violence, obsessive-compulsive actions, overeating, anxiety and sleep disturbances. Human studies show that serotonin plays an integral role in supporting feelings of well being, calmness, security, relaxation, confidence and concentration. Conversely, a deficiency of serotonin may be central in the development of depression, sleep disorders, obesity and addiction.

Serotonin (5-HT)

In the mid-nineteenth century scientists were aware of a substance in serum known to cause powerful contractions of smooth muscle organs. Over a hundred years later American scientists at the Cleveland Clinic, investigating the cause of high blood pressure succeeded in isolating the substance, naming it "serotonin." At roughly the same time investigators in Italy were characterizing a substance found in high concentrations in chromaffin cells of the intestinal mucosa that also constricted smooth muscular elements, particularly in the gut. This material was called "enteramine." Eventually both compounds were purified, crystallized, and found to be 5-hydroxytryptamine (5-HT).

Serotonin is produced primarily by platelets, mast cells, and enterochromaffin cells. Serotonin is also produced in neurons, though in far lower concentration than elsewhere in the body. In fact, only about 1-2% of all serotonin in the body is located in the brain. Since 5-HT cannot cross the blood-brain barrier, brain cells must synthesize their own supply. Production of serotonin in the brain first requires the uptake of the amino acid tryptophan, the primary substrate for synthesis. Plasma tryptophan is derived mainly from dietary sources, and decreases of dietary tryptophan can profoundly lower levels of brain serotonin. Additionally, entry of tryptophan into the brain faces stiff competition from other amino acids, including the aromatic amino acids (tyrosine and phenylalanine), the branched-chain amino acids (leucine, isoleucine, and valine), and others (i.e., methionine and histidine). Because of this competition, brain levels of tryptophan are determined not only by plasma concentration of tryptophan, but by plasma concentrations of competing neutral amino acids as well.

Diet and Serotonin

Dietary intake of protein and carbohydrates can have a profound influence on brain tryptophan and serotonin levels. A typical diet provides about 1 to 1.5 grams of tryptophan per day, but even this small amount has a difficult time crossing the blood-brain barrier. Attempts to elevate tryptophan uptake by selecting a diet rich in tryptophan-containing protein have the opposite effect of increasing amino acid competition blocking uptake. Conversely, a successful dietary strategy for increasing tryptophan uptake requires a diet high in carbohydrates and low in protein. The resulting elevation of blood-sugar levels stimulates the release of insulin which clears away competing amino acids and increases the transport of tryptophan across the blood-brain barrier. This simple dietary strategy is practiced daily by millions of Americans as they consume "comfort" foods such as candy, pastries, ice cream, etc. when stressed, depressed or anxious. While this approach can successfully increase serotonin levels and create a temporary sense of calmness and well-being, the long-term effect is the increased storage of body fat and tendency towards obesity.

5-HTP and Obesity

Decreased brain serotonin levels are associated with obesity due to overeating. A relative deficiency of serotonin is believed to be associated with the brain’s perception of starvation and hunger. Evidence for serotonin’s regulation of appetite for carbohydrate-rich food was initially supported by animal studies using drugs that altered serotonergic neurotransmission.

In 1988 Wurtman et a1. reported on the mediating effects of brain serotonin on the eating behavior of obese, carbohydrate-craving individuals. In those reports, more than 150 obese subjects (20% to 50% over normal body weight) who implicated snacking as responsible for their obesity, were studied. A large proportion of the obese subjects experienced episodes of carbohydrate craving at characteristic times of the day (i.e., 4 p.m. or 9 p.m.). During such episodes, more than 800 calories of starchy and sweet carbohydrate snack foods (bagels, crackers. cookies) were consumed. Despite alternative access to high-protein snack foods.

(cold meats, tuna or chicken salads, and cheese), the subjects persisted in eating only the carbohydrate snack foods. The excessive calorie intake was confined to snack periods; in contrast, food intake at mealtimes remained normal with respect to calorie, protein, and carbohydrate contents.

During clinical trials with obese subjects, intake of 5-HTP led to a voluntary decrease in caloric intake of both carbohydrates and fats, but not of protein. A significant loss of weight occurred, due to a voluntary decrease in caloric intake and not because of a restrictive diet.

5-HTP and Sleep

Perhaps the most immediate effect of 5-HTP is its ability to induce sleep when taken on an empty stomach about one hour before going to bed. Elderly persons frequently have difficulty falling asleep at night as well. Both tryptophan and serotonin (5-HT) are precursors to the sleep inducing molecule, melatonin, as mentioned above.

5HTP and Depression

When 5-HT was first found in the mammalian central nervous system, various theories arose connecting numerous forms of mental illness with biochemical abnormalities in its synthesis. This line of thought was further supported by the observation that the tranquilizing substance, reserpine, was observed to deplete brain 5-HT. During this phase of depletion profound behavioral depression was observed.

The pharmaceutical control of brain serotonin levels is the mechanism of many commonly prescribed drugs used in the treatment of depression. The efficacy of Prozac and other SSRI’s is dependent upon the brain’s availability of serotonin precursors like tryptophan or its derivative, 5-HTP. When patients taking SSRI’s are fed a special diet devoid of tryptophan, a relapse into depression is experienced, despite the continued presence of the SSRI. Supplementation with tryptophan quickly restores the antidepressant effects of the SSRI. One six-week study of 69 subjects that compared that use of 5-HTP to a standard SSRI found that both compounds possessed equal antidepressant capabilities. More importantly, those taking 5-HTP had one-half as many moderate-to-severe side effects as those taking the SSRI. A review of results of 17 clinical trials utilizing 5-HTP, primarily for depression, concluded that "oral administration of 5-HTP is associated with few adverse effects."

5-HTP and PDI’s

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, which are prescription drugs and may cause negative side effects.

One study reported favorable response in 8 of 24 depressive patients treated with 300 mg 5-HTP daily without a PDI. In yet another trial, an equal number of patients were treated for depression using 5-HTP both with and without a PDI. The study found 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. This lead the researchers to conclude: "... 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%)."

In another study, researchers 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 noted: "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."

Safety

Serotonin deficiency can be manifested in a variety of forms, including depression, anxiety, migraines, obsessive-compulsive behaviors, sleep-

lessness and other behavioral disorders. Many of these problems are currently being treated with SSRI’s that work by blocking the reuptake of serotonin into the neurons and keeping them in the synapses. 5-HTP offers many of the benefits of a SSRI with few if any side effects.

5-hydroxy-L-tryptophan (5-HTP) is considered by many researchers to be the safest tryptophan alternative available, and many successful published studies using 5-HTP show that 5-HTP, by naturally elevating brain serotonin, can alleviate serotonin-deficiency syndrome without any help from SSRI drugs. 5-HTP is more expensive than tryptophan prior to the 1990 ban, it is also ten times as effective (a 50 mg capsule of 5-HPT is generally regarded as equivalent to 500 mg of tryptophan). As a nutritional supplement, 5-HTP is commonly taken in dosages of 50 to 100 milligrams (mg) per day, as a safe dose. In fact, one placebo-controlled, double-blind study conducted in 1992 found excellent results treating obesity using 900 mg 5-HTP daily with minimal side effects. Studies using doses up to 3,000 mg per day of 5-HTP have been used in cases of myoclonus (severe muscular contractions). Vitamin B-6 (pyridoxine) is required for the enzymatic conversion of 5-HTP into serotonin, and should regularly be taken on the same day as 5-HTP, preferably 6 hours prior to 5-HTP consumption. B-6 is also an important cofactor for the enzyme that degrades toxic tryptophan metabolites and may delay the rise in plasma levels of serotonin (from 5-HTP).

Contraindications

5-HTP should not be used by persons taking anti-depressant drugs, MAO inhibitors; selective serotonin reuptake inhibitors (e.g. Prozac), tricyclic medications, weight loss medications, anti-parkinson medications (e.g. L-dopa), barbiturates and other tranquilizing drugs, antihistamines and cold medications, alcoholic beverages, cancer chemotherapy, or antibiotic medications. Furthermore, 5-HTP can potentiate the effects of certain tranquilizing drugs and alcohol.