5-HTP (5 hydroxy-tryptophan) is a naturally occurring substance in the human body that is also the rate-limiting step in the biochemical synthesis of serotonin. In this synthesis, L-tryptophan is converted to 5-HTP by the enzyme tryptophan hydrolase, and then serotonin is produced from 5-HTP. If the tryptophan hydrolase enzyme is inhibited, serotonin is not produced. Several factors might inhibit this enzyme, such as stress, vitamin B6 deficiency, insufficient magnesium, and insulin resistance. No significant level of 5-HTP is in the diet, but dietary supplements of 5-HTP made from the African plant Griffonin simplicifolia are available. Supplementation of 5-HTP bypasses any deficiency or dysfunction in this enzyme's metabolism of serotonin and therefore results in higher serotonin levels.
Although the hypothesis that serotonin levels can be improved with the supplementation of 5-11TP is probable, the clinical evidence for its efficacy is poor, and more well-designed studies are needed to ascertain which conditions respond best to supplementation. Additionally, wider availability of 5-HTP supplements requires quality assurances that eos-inophilia-myalgia syndrome (EMS)-type reactions will not occur (see the "Safety/Dosage" subsection of this section).
A meta-analysis of the literature published from 1966 to 2000 on the use of 5-HTP and L-tryptophan for unipolar depression found that of 108 studies, only 2 (one on 5-HTP} met the study criteria. The review analysis suggested that both 5-HTP and L-tiyptophan are better than placebo in the treatment of depression. The authors concluded that although positive studies are numerous, they are of poor quality and better-designed research is needed to make clinical recommendations (Shaw et al., 2002a, 2002b).
An open comparison between 5-HTP and tranylcypromine was conducted in patients with major depression who were unsuccessfully treated by at least two other cyclic antidepressant drugs. The 5-HTP -treated group showed no improvement, whereas the trany Icy pro mine-treated group showed efficacy in 50% of the patients tested. Those that responded to the tranylcypromine had depression that was more endogenous and of shorter duration than those that did not respond to its treatment (Nolen et al., 1988).
A double-blind, placebo-controlled comparison was conducted on 5-HTP and clomipramine in anxiety patients. A 90-item symptoms checklist and the state scale of the Spieiberger State-Trait Anxiety Inventory were used as assessment parameters. The study found that 5-HTP did not alter the associated depressive symptomatology and compared with a placebo, showed only a moderate reduction in all the rating scales, whereas clomipramine showed significant improvements in all the rating scales (Kahn et al., 1987).
Major depressive patients who were unsuccessfully treated by other reuptake inhibitors were enrolled in an open, controlled, crossover comparison between 5-HTP and tranylcypromine. After 4 weeks of treatment (in a crossover design), no responses were found in the 17 patients in the 5-IITP group, but 15 of the 26 patients in the tranylcypromine group responded- The authors concluded that 5-HTP was not a viable option for patients with major depression that had not responded to other reuptake inhibitors (Nolen et al., 1985).
The influence of 5-HTP on obesity was studied in 20 obese patients in a double-blind, randomized, placebo-controlled study. Either a placebo or 900 mg/day of 5-HTP was given to the subjects for two consecutive 6-week periods, with no dietary restrictions prescribed for the first period and a 5,040-kJ/day diet prescribed for the second period. The treatment group showed a significant weight loss for both periods of 5-HTP treatment, along with reductions in carbohydrate intake and increases in early satiety (Cangiano et al., 1992).
In a double-blind, crossover study involving 19 obese women, 5-HTP (8 mg/kg daily) was administered to subjects with body mass indexes between 30 and 40 for 5 weeks. No changes in mood were observed with 5-HTP administration, but it did result in decreased food intake and weight loss (Ceci et al., 1989).
Puttini and Caruso (1992) tested 5-HTP in fibromyalgia patients using an open 90-day study design. The clinical variables tested for fibromyalgia (tender points, anxiety, pain, quality of sleep, and fatigue) showed an overall improvement compared with baseline, with approximately 50% of patients showing a "good" or "fair" clinical improvement. About 30% of the subjects treated reported side effects, but only one patient withdrew from the study for that reason.
In an earlier study on 5-HTP for fibromyalgia, 50 patients were enrolled in a double-blind, placebo-controlled study design. The authors found that all clinical parameters significantly improved, noting only mild or transient side effects (Caruso et ah, 1990).
Insomnia and Sleep Disorders
5-1ITP was tested in a double-blind, placebo-controlled, crossover study of 48 students with recurring headaches and sleep disorders. The authors concluded that 5-HTP can reduce headaches and sleep disorders, especially frequent awakenings and parasomnias (De Ciorgis et al., 1987).
Because previous studies on 5-HTP had been inconclusive, a double-blind crossover study involving 31 patients looked at the role of 5-HTP in mitigating chronic primary headache. In the treatment group, 5-HTP was administered in doses of 400 mg/day orally for 2 months. Treatment with 5-HTP resulted in a nonsignificant reduction in severity and frequency of headache, and mild and transient side effects occurring in 19% of the treatment group (De Benedittis and Massei, 1985).
In a study to characterize the clinical subgroup that responds best to 5-11TP treatment, 100 patients with chronic primary headache were given 300 mg/day. The clinical subgroup that responded best was identified as having major mood disturbances, minor frequency of anxiety, and previous positive response to pizotifcn treatment, longer disease occurrence, and higher frequency of associated symptoms (Bono et al., 1984).
Because diabetes mellitus is associated with low levels of serotonin in the brain, carbohydrate cravings, and overeating, the use of 5-1ITP was clinically tested for its ability to normalize serotonin and eating behaviors in diabetic patients. In a double-blind, placebo-controlled, randomized study, 5-HTP was given to 25 overweight patients with diabetes mellitus in 750-mg/day doses or placebo for 2 weeks. Treatment with 5-HTP resulted in significant reductions of brain tiyptophan, body weight, and daily energy intake compared with placebo (Cangiano et al., 1998).
Generally, the initial dosage recommended for 5-HTP is 50 mg 3 times daily, and the dosage is increased to up to 900 mg/day until the desired effect is noted. Not enough clinical data are available to safely recommend 5-HTP treatment in pregnant or lactating women. Interactions may exist between 5-HTP and other antidepressant products, especially selective serotonin reuptake inhibitors.
The foremost concern regarding the use of 5-IITP is the possibility of people contracting EMS, similar to a 1983 episode in which a contaminated batch of L-tryptophan was linked lo production methods involving bacterial fermentation followed by inadequate filtration. Because 5-HTP is produced by extraction from plant sources, however, such contamination is unlikely to occur. Nonetheless, two reported cases of HMS-like symptoms have been described in patients taking 5-HTP. One case in 1980 involved the use of very high doses (1,400 mg/day); the product itself was never tested for contamination. A second case involved a family (a mother and two children) who had been confirmed to have taken contaminated 5-IITP (Bono et al., 1994; Michelson et al., 1994).
Another concern regarding the use of 5-1ITP is the possibility of developing heart valve disease. In 1997, the Food and Drug Administration (FDA) banned the sale of redux and fen-phen because of an "unacceptable risk" of developing heart valve disease. According to Michael Murray, there have been "no reports of heart valve disease or other problems related lo serotonin syndrome in people who take 5-HTP by itself" (Puttini and Caruso, 1992).