5-HT (5-Hydroxytryptophan)

by Timothy C. Birdsall, N.D.


5-Hydroxytryptophan (5- HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, insomnia, binge eating associated with obesity, chronic headaches, and insomnia.

(Altern Med Rev 1998;3(4):271-280)


5-Hydroxytryptophan (5-HTP) (see Figure 1) is an aromatic amino acid naturally produced by the body from the essential amino acid L-tryptophan (LT). Produced commercially by extraction from the seeds of the African plant, Griffonia simplicifolia, 5-HTP has been used clinically for over 30 years. The clinical efficacy of 5-HTP is due to its ability to increase production of serotonin in the brain.

Metabolism of Tryptophan and Serotonin Serotonin

(5-hydroxytryptamine), dopamine, and norepinephrine are the three main “monoamine” neurotransmitters, each produced endogenously from one specific amino acid. Tryptophan is converted into serotonin, while dopamine and norepinephrine are made from tyrosine. In the central nervous system (CNS), serotonin has been implicated in regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensation.

While other cells outside the brain, such as blood platelets and some enterocytes, make and/or use serotonin, all serotonin used by brain cells must be made within the neurons, since serotonin cannot cross the blood-brain barrier. Therefore, the synthesis of serotonin is heavily dependent upon the availability of LT within the CNS. The production and subsequent transport of LT from the bloodstream into the CNS can be compromised by several factors:

1) Stress, elevated cortisol levels, vitamin B6 deficiency, and even high dosages (above 2,000 mg) of LT, which all stimulate the conversion of LT to kynurenine, lowering serum LT levels.

2) Elevated serum levels of kynurenine inhibit transport of LT into the CNS, and reduce CNS serotonin levels.

3) Transport of LT across the blood-brain barrier requires binding to a transport molecule, which LT shares with five other amino acids (tyrosine, phenylalanine, valine, leucine and isoleucine). Since LT is present in foods in relatively small amounts in comparison to these other amino acids, as little as one percent of dietary LT may be transported into the CNS.

4) LT is used by the body for other metabolic purposes in addition to serotonin production, including protein synthesis and the creation of niacin.

Biochemistry and Metabolism of 5-http

5- HTP is the intermediate metabolite of LT in the production of serotonin . Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. Tryptophan hydroxylase can be inhibited by numerous factors, including stress, insulin resistance, vitamin B6 deficiency, and insufficient magnesium. In addition, these same factors can increase the conversion of LT to kynurenine via tryptophan 2,3-dioxygenase, making LT unavailable for serotonin production.

5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. Absorption of 5-HTP is not affected by the presence of other amino acids; therefore, it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production.

Serotonin levels in the brain are highly dependent on levels of 5-HTP and LT in the central nervous system (CNS). 5-HTP easily crosses the blood-brain barrier, not requiring the presence of a transport molecule. LT, on the other hand, requires use of a transport molecule to gain access to the CNS. Since LT shares this transport molecule with several other amino acids, the presence of these competing amino acids can inhibit LT transport into the brain.

Mechanisms of Action

5-HTP acts primarily by increasing levels of serotonin within the central nervous system. Other neurotransmitters and CNS chemicals, such as melatonin, dopamine, nor-epinephrine, and beta-endorphin have also been shown to increase following oral administration of 5-HTP. This ability to increase not only serotonin levels in the brain, but also dopamine and norepinephrine, allows 5-HTP to produce some significant and unique effects on brain chemistry and on serotonin-related conditions which other substances, including LT, cannot duplicate.

Clinical Studies Using 5-http

Depression: Much of the published research on 5-HTP has to do with its use in the treatment of depression. Since the early 1970s, at least 15 studies have evaluated the clinical effects of 5-HTP on depression. These are summarized in. Taken together, these studies examined a total of 511 patients with different types of depression. Of these 511 subjects, 285 (56%) showed significant improvement while taking 5-HTP.

In addition, biochemical studies show 5-HTP is closely involved in depressive disorders. In a study employing positron-emission tomography (PET) scanning, eight healthy volunteers and six people diagnosed with major depression received infusions of radiolabelled 5-HTP. The researchers found significantly less 5-HTP crossed the blood-brain barrier into the brains of the depressed subjects than into the brains of the normal controls. The authors suggested the transport of 5-HTP across the blood-brain barrier may be compromised in major depression, which might make the brain dependent on LT to 5-HTP conversion in the brain.

Some concern has arisen regarding whether 5-HTP should be used only in conjunction with a peripheral decarboxylase inhibitor (PDI) such as carbidopa. The argument is essentially that without a PDI, 5-HTP will be converted into serotonin in the peripheral circulation, negating any potential CNS bene-fit from 5-http. However, this argument ignores scores of clinical studies in which 5-HTP was given alone and in which significant clinical benefit was seen, with no significant adverse effects.

The first large clinical trial using 5-HTP in depression was conducted by Sano in 1972. Using an open trial design, a total of 107 patients with endogenous unipolar or bipolar depression were given daily oral dosages of 5-HTP from 50 to 300 mg. Significant improvement was observed in 74 of the patients (69%), and no significant side effects were reported. The response rate in most of these patients was quite rapid (less than two weeks).

The issue of speed of response was subsequently addressed in a study of 59 patients with eight different types of depression. 5-HTP was administered orally in dosages from 150 to 300 mg daily for a period of three weeks. Thirteen patients (22%) were markedly improved, and another 27 patients (45.8%) showed moderate improvement. Of these 40 patients who improved, 20 (50%) began to show improvement within three days, and 32 patients (80%) improved within two weeks of beginning treatment with 5-HTP.15 In contrast to many conventional antidepressants which may take 4 weeks or longer to achieve therapeutic response in most patients, those taking 5-HTP appear to have a significantly more rapid response.

Japanese researchers administered 5-HTP to 24 patients hospitalized for depression. After two weeks of treatment, a “marked amelioration of depressive symptoms” was observed in seven patients diagnosed with unipolar depression. The administration of 5-HTP was also associated with a 30 percent increase in the levels of 5-hydroxyindolacetic acid, the primary metabolite of serotonin, in the patients’ cerebrospinal fluid. This suggested the exogenous 5-HTP was being converted to serotonin within the CNS.

5-HTP vs. Conventional Anti-depressants: The current conventional therapies of choice for depression are the selective serotonin reuptake inhibitors (SSRIs). A 1991 Swiss study evaluated 5-HTP in comparison to an SSRI drug in a double-blind, multicenter study design. A total of 36 subjects, all of whom were diagnosed with some form of depression, received either 100 mg of 5-HTP three times per day, or 150 mg of fluvoxamine (an SSRI) three times daily. The subjects were evaluated at 0, 2, 4, and 6 weeks, using four evaluation tools: the Hamilton Rating Scale for Depression (HRSD), a standard depression rating scale; a patient-performed self-assessment; the investigator’s assessment of severity; and a global clinical impression.

Both treatment groups showed significant and nearly equal reductions in depression beginning at week two and continuing through week six. After four weeks, 15 of the 36 patients treated with 5-HTP, and 18 of the 33 patients treated with fluvoxamine had improved by at least 50 percent, according to the HRSD scores. By week six, the two groups had about equal numbers showing 50 percent improvement. When the numbers were totaled at the end of the study, the researchers found the mean percentage improvement from baseline to the final assessment was slightly greater for patients treated with 5-HTP. The number of treatment failures was higher in the fluvoxamine group (5/29, 17%) than in the 5-HTP group (2/34, 6%), although neither of these differences were statistically significant. All four evaluation tools yielded similar results.

The study also looked at the incidence of adverse effects from both treatments, which were found to be rare and generally mild, usually occurring during the first few days of treatment and then disappearing. Overall, 5-HTP appeared to be slightly better tolerated than fluvoxamine, although the results did not reach the level of statistical significance. Tolerance was assessed as being “good to very good” in 34/36patients receiving 5-HTP (94.5%), compared to 28/33 in the fluvoxamine group (84.8%).

5-HTP has also been compared in a few studies with conventional tricyclic antidepressants (chloripramine and imipramine) – the most effective drugs for treating depression until the development of the SSRIs. The studies found 5-HTP to be at least as effective as these drugs in treating severe depression, while displaying fewer side effects. In severe cases, 5-HTP dosages as high as 1200 mg daily were used.

Fibromyalgia: Primary fibromyalgia syndrome is characterized by general musculo-skeletal aching, multiple tender points, fatigue, morning stiffness, and sleep disturbances. Fibromyalgia patients have been found to have low serotonin and tryptophan 32,33levels, and some studies have shown symptomatic improvement with the use of tricyclic and SSRI antidepressants.34,35 These findings suggest 5-HTP might be useful in the treatment of fibromyalgia, and three clinical trials have demonstrated significant improvement in symptoms, including pain, morning stiffness, anxiety, and fatigue.

Caruso et al conducted a double-blind, placebo-controlled study in 50 fibromyalgia patients, administering 100 mg of 5-HTP three times daily for a period of 30 days. Significant improvements were seen in number of tender points (p<0.001), subjective pain severity (p<0.001), morning stiffness (p=0.017), sleep patterns (p<0.001), anxiety ratings (p<0.001), and fatigue ratings (p=0.003). The incidence of side effects in the 5-HTP group was low (6/25 patients), and no significant laboratory abnormalities were reported during the study.

In a longer-term study, a total of 50 patients diagnosed with primary fibromyalgia syndrome were given 100 mg 5-HTP three times per day for 90 days in an open study. Patients were assessed at the beginning of the study and after 15, 30, 60, and 90 days of treatment. The clinical variables evaluated included: total number of tender points, pain intensity, sleep quality, morning stiffness, anxiety, and fatigue. All of these measures showed significant improvement throughout the length of the study (p<0.001). A total of 15 patients (30%) reported side effects from the 5-HTP, but in only one case were they severe enough for the patient to be withdrawn from the study.

In a randomized, placebo-controlled study of 200 fibromyalgia patients who were also migraine sufferers, 5-HTP (400 mg/day) was compared to a tricyclic drug (amitriptyline) and a monoamine oxidase inhibitor (MAOI) drug (pargilyne or phenelzine). The combination of 5-HTP (200 mg/day) with an MAOI was also evaluated. Patients were treated for a total of 12 months and kept a daily pain diary by means of a visual analogic scale. At the end of the twelve-month trial period, all treatment regimens showed significant improvement over placebo (p<0.0001), although the combination of 5-HTP with the MAOI was the most effective. 5-HTP alone was as effective as the tricyclic or MAOI drugs. No patients withdrew from the study due to side effects; eight percent of the patients taking 5-HTP alone reported some degree of stomach upset.

Obesity: During dieting, serum tryptophan levels and CNS serotonin levels drop dramatically.39-41 These low serotonin levels in obese patients have been associated with carbohydrate cravings and resultant binge eating. It has been theorized that 5-HTP can help prevent this dieting-associated decline in serotonin, thus enhancing weight loss. Three clinical trials in obese patients have demonstrated decreased food intake and subsequent weight loss with 5-HTP supplementation.

Using a placebo-controlled, double-blind protocol, researchers at the University of Rome evaluated the effects of 5-HTP (300 mg three times daily) on the eating habits and weight loss of 20 obese female patients. All patients had a body mass index between 30 and 40, and were determined to consume an excess of food daily, based on calculated energy needs. The twelve-week study period was divided into two six-week sections. During the first six weeks, the patients took either 5-HTP or placebo, but no dietary restrictions were placed on them. In the second six-week period, the patients were placed on a 1200 calorie per day diet, while continuing to take either the 5-HTP or placebo. Subjects compiled detailed 3-day food diaries once every two weeks.

Those in the placebo group did not experience significant weight loss in either of the two periods (94.3 – 5.6 kg vs. 93.2 – 5.3 kg ), while the subjects in the 5-HTP group showed significant weight loss in both the first period (99.7 – 5.9 kg vs. 98.0 – 5.0 kg, p<0.03) and the second period (98.0 – 5.0 vs. 94.7 – 5.1 kg, p<0.02). The placebo group also did not show significant change in their calorie intake, even in the second period when instructed to reduce food intake, while the 5-HTP group had a significant spontaneous dietary intake reduction during the first period, from 3220 calories/day to 1879 calories/day (p<0.001), with carbohydrate intake falling by 50 percent. During the second period, the calorie intake of the 5-HTP group decreased further, to 1268 calories/day (p<0.01), with further reductions in carbohydrates. The researchers interpreted these findings as supporting the theory that 5-HTP decreased carbohydrate cravings and binge eating, even in the absence of a structured diet.

At this high dosage of 5-HTP (900 mg/day), about 80 percent of the subjects initially reported experiencing some nausea. However, this side effect was not severe enough to cause any of the subjects to drop out of the study, and was less frequent during the second six-week period, suggesting that this symptom may be a transitory effect of 5-HTP administration.

Chronic Headaches: Chronic headaches, especially migraines, are considered by some researchers to be the result of low serotonin levels, probably as the result of increased breakdown of serotonin by the enzyme monoamine oxidase. Low serotonin levels are thought to lower pain thresholds in chronic headache sufferers, allowing other headache triggers to more easily “set off” a headache.

5-HTP has been used successfully in the prevention of chronic headaches of various types, including migraine, tension headaches, and juvenile headaches. In a large study of 124 subjects, the ability of 5-HTP to prevent migraines was compared to methysergide, one of the most commonly used migraine drugs. At a dosage of 600 mg daily for six months, 5-HTP totally prevented or substantially decreased the number of migraine attacks in 75 percent of the subjects. However, this difference was not determined to be statistically significant. In a study of 48 elementary and junior high school students, 5-HTP (4.5 mg/kg/day) produced a 70 percent decrease in headache frequency, compared to an 11 percent decrease in the placebo group.

Insomnia: 5-HTP has been shown to be beneficial in treating insomnia, especially in improving sleep quality by increasing REM sleep.53-55 Eight normal subjects were monitored to determine the effect of 5-HTP on rapid eye movement (REM) sleep. A total of 600 mg 5-HTP was administered to the subjects in the following manner: 200 mg at 9:15 pm, followed by 400 mg at 11:15 pm. A significant increase in the amount of REM sleep was observed while the subjects were taking 5-HTP (118 – 14 mins vs. 98 – 11 mins, p<0.005). A smaller study using a 200 mg dose also showed increases in REM sleep, but to a lesser degree. The smaller dose is probably preferable, since, according to anecdotal reports, higher doses may have a tendency to cause very vivid dreams or nightmares.


Initial dosage for 5-HTP is usually 50 mg three times per day with meals. If the clinical response is inadequate after two weeks, dosage may be increased to 100 mg three times per day. For insomnia, the dosage is usually 100-300 mg before bedtime. Because some patients may experience mild nausea when initiating treatment with 5-HTP, it is advisable to begin with 50 mg doses and titrate upward.

Drug-Nutrient Interactions

Although no specific reports have been published, it is possible that 5-HTP, when taken in combination with either a selective serotonin reuptake inhibitor (SSRI) antidepressant such as fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), or fluvoxamine (Luvox), or an MAOI antidepressant such as phenelzine (Nardil) or tranylcypromine (Parnate) may cause a condition known as serotonin syndrome. This syndrome has been reported in patients taking LT at doses above 1200 mg/day along with MAOIs, but was not identified in a 12-month study with 5-HTP (200 mg/day) taken in conjunction with an MAOI drug.

Serotonin syndrome is characterized by agitation, confusion, delirium, tachycardia, diaphoresis, and blood pressure fluctuations. Should serotonin syndrome be suspected, 5-HTP and any other precipitating drug (SSRI or MAOI) should be discontinued immediately. Because of the possibility of serotonin syndrome, 5-HTP should probably not be used in patients currently being treated with either an SSRI or MAOI antidepressant. If it is used in conjunction with either of these prescription drugs, e.g. short-term dual therapy while changing over from an SSRI to 5-HTP, the practitioner and patient should be aware of the potential symptoms of this condition.


One additional concern regarding 5-HTP is the possibility of an eosinophilia-myalgia syndrome (EMS) similar to the illness linked to contaminated LT. The contamination identified in certain batches of LT has been related to production methods using bacterial fermentation and subsequent inadequate filtration. This is unlikely to occur with 5-HTP, since it is produced by extraction from plant sources. Two cases of EMS-like symptoms have been described in patients taking 5-HTP. One case reported in 1980 involved the use of very high doses (1400 mg daily). Because contamination of LT was not identified as a factor in EMS until 1990, the product consumed by this patient was not tested for contamination. The second case involved a mother and two children who were confirmed to have taken contaminated 5-HTP.

Because of the possibility of serotonin syndrome (see above), 5-HTP should be used with caution in patients currently being treated or who have recently been treated with either an SSRI or an MAOI antidepressant.

There are no adequate, well-controlled studies on the use of 5-HTP in pregnancy, therefore, it should not be used while pregnant.

Side Effects

Some patients may initially experience mild nausea when taking 5-HTP. This effect is usually transitory, and is best dealt with by initiating therapy at low doses (50 mg three times daily) and increasing the dosage gradually if necessary.